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Objective: A well-established bidirectional relationship exists between sleep and epilepsy. Patients with epilepsy tend to have less efficient sleep and shorter rapid eye movement (REM) sleep. Seizures are far more likely to arise from sleep transitions and non-REM sleep compared to REM sleep. Delay in REM onset or reduction in REM duration may have reciprocal interactions with seizure occurrence. Greater insight into the relationship between REM sleep and seizure occurrence is essential to our understanding of circadian patterns and predictability of seizure activity. We assessed a cohort of adults undergoing evaluation of drug-resistant epilepsy to examine whether REM sleep prior to or following seizures is delayed in latency or reduced in quantity., Methods: We used a spectrogram-guided approach to review the video-electroencephalograms of patients' epilepsy monitoring unit admissions for sleep scoring to determine sleep variables., Results: In our cohort of patients, we found group- and individual-level delay of REM latency and reduced REM duration when patients experienced a seizure before the primary sleep period (PSP) of interest or during the PSP of interest. A significant increase in REM latency and decrease in REM quantity were observed on nights where a seizure occurred within 4 h of sleep onset. No change in REM variables was found when investigating seizures that occurred the day after the PSP of interest. Our study is the first to provide insight about a perisleep period, which we defined as 4-h periods before and after the PSP., Significance: Our results demonstrate a significant relationship between seizures occurring prior to the PSP, during the PSP, and in the 4-h perisleep period and a delay in REM latency. These findings have implications for developing a biomarker of seizure detection as well as longer term seizure risk monitoring., (© 2024 International League Against Epilepsy.)

Objective: Interactions between enzyme-inducing anti-seizure medications (EI-ASMs) and antiretroviral drugs (ARVs) can lead to decreased ARV levels and may increase the likelihood of viral resistance. We conducted a study to determine if co-usage of ARVs and EI-ASMs is associated with ARV-resistant human immunodeficiency virus (HIV) among people living with HIV in Zambia., Methods: Eligible participants were ≥18 years of age and concurrently taking ASMs and ARVs for at least 1 month of the prior 6-month period. Data were obtained regarding medication and HIV history. CD4 counts, plasma viral loads (pVLs), and HIV genotype and resistance profile in participants with a pVL >1000 copies/mL were obtained. Pearson's test of independence was used to determine whether treatment with EI-ASM was associated with pVL >1000/mL copies., Results: Of 50 participants, 41 (82%) were taking carbamazepine (37 on monotherapy), and all had stable regimens in the prior 6 months. Among the 13 ARV regimens used, 68% had a tenofovir/lamivudine backbone. The majority (94%) were on a stable ARV regimen for >6 months. Median CD4 nadir was 205 cells/mm 3 (interquartile range [IQR] 88-389), and 60% of participants had commenced ARV treatment before advanced disease occurred. Mean CD4 count at enrollment was 464 cells/mm 3 (SD 226.3). Seven participants (14%) had a CD4 count <200 cells/mm 3 . Four (8%) had a pVL >1000 copies/mL; all were on carbamazepine. Three participants with elevated pVL had a CD4 count <200 cells/mm 3 . None had documented adherence concerns by providers; however, two had events concerning for clinical failure. HIV genotype testing showed mutations in three participants. Carbamazepine was not found to correlate with elevated pVL (P = .58)., Significance: EI-ASMs are commonly used in sub-Saharan Africa. Despite concurrent use of EI-ASMs and ARVs, the majority of participants showed CD4 counts >200 cells/mm 3 and were virally suppressed. Carbamazepine was not associated with an increased risk of virological failure or ARV-resistant HIV., (© 2020 International League Against Epilepsy.)

Objective: We conducted clinical testing of an automated Bayesian machine learning algorithm (Epilepsy Seizure Assessment Tool [EpiSAT]) for outpatient seizure risk assessment using seizure counting data, and validated performance against specialized epilepsy clinician experts., Methods: We conducted a prospective longitudinal study of EpiSAT performance against 24 specialized clinician experts at three tertiary referral epilepsy centers in the United States. Accuracy, interrater reliability, and intra-rater reliability of EpiSAT for correctly identifying changes in seizure risk (improvements, worsening, or no change) were evaluated using 120 seizures from four synthetic seizure diaries (seizure risk known) and 120 seizures from four real seizure diaries (seizure risk unknown). The proportion of observed agreement between EpiSAT and clinicians was evaluated to assess compatibility of EpiSAT with clinical decision patterns by epilepsy experts., Results: EpiSAT exhibited substantial observed agreement (75.4%) with clinicians for assessing seizure risk. The mean accuracy of epilepsy providers for correctly assessing seizure risk was 74.7%. EpiSAT accurately identified seizure risk in 87.5% of seizure diary entries, corresponding to a significant improvement of 17.4% (P = .002). Clinicians exhibited low-to-moderate interrater reliability for seizure risk assessment (Krippendorff's α = 0.46) with good intrarater reliability across a 4- to 12-week evaluation period (Scott's π = 0.89)., Significance: These results validate the ability of EpiSAT to yield objective clinical recommendations on seizure risk which follow decision patterns similar to those from specialized epilepsy providers, but with improved accuracy and reproducibility. This algorithm may serve as a useful clinical decision support system for quantitative analysis of clinical seizure frequency in clinical epilepsy practice., (Wiley Periodicals, Inc. © 2019 International League Against Epilepsy.)

Structural magnetic resonance imaging (MRI) is of fundamental importance to the diagnosis and treatment of epilepsy, particularly when surgery is being considered. Despite previous recommendations and guidelines, practices for the use of MRI are variable worldwide and may not harness the full potential of recent technological advances for the benefit of people with epilepsy. The International League Against Epilepsy Diagnostic Methods Commission has thus charged the 2013-2017 Neuroimaging Task Force to develop a set of recommendations addressing the following questions: (1) Who should have an MRI? (2) What are the minimum requirements for an MRI epilepsy protocol? (3) How should magnetic resonance (MR) images be evaluated? (4) How to optimize lesion detection? These recommendations target clinicians in established epilepsy centers and neurologists in general/district hospitals. They endorse routine structural imaging in new onset generalized and focal epilepsy alike and describe the range of situations when detailed assessment is indicated. The Neuroimaging Task Force identified a set of sequences, with three-dimensional acquisitions at its core, the harmonized neuroimaging of epilepsy structural sequences-HARNESS-MRI protocol. As these sequences are available on most MR scanners, the HARNESS-MRI protocol is generalizable, regardless of the clinical setting and country. The Neuroimaging Task Force also endorses the use of computer-aided image postprocessing methods to provide an objective account of an individual's brain anatomy and pathology. By discussing the breadth and depth of scope of MRI, this report emphasizes the unique role of this noninvasive investigation in the care of people with epilepsy., (Wiley Periodicals, Inc. © 2019 International League Against Epilepsy.)

Objectives: Neuroinflammation, implicated in epilepsy, can be imaged in humans with positron emission tomography (PET) ligands for translocator protein 18 kDa (TSPO). Previous studies in patients with temporal lobe epilepsy and mesial temporal sclerosis found increased [11C]PBR28 uptake ipsilateral to seizure foci. Neocortical foci present more difficult localization problems and more variable underlying pathology., Methods: We studied 11 patients with neocortical seizure foci using [11C]PBR28 or [11C] N,N-diethyl-2-(4-methoxyphenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-acetamide (DPA) 713, and 31 healthy volunteers. Seizure foci were identified with structural magnetic resonance imaging (MRI) and ictal video-electroencephalography (EEG) monitoring. Six patients had surgical resections; five had focal cortical dysplasia type 2A or B and one microdysgenesis. Brain regions were delineated using FreeSurfer and T1-weighted MRI. We measured brain radioligand uptake (standardized uptake values [SUVs]) in ipsilateral and contralateral regions, to compare calculated asymmetry indices [AIs; 200% *(ipsilateral - contralateral)/(ipsilateral + contralateral)] between epilepsy patients and controls, as well as absolute [11C]PBR28 binding as the ratio of distribution volume to free fraction (V T /f P ) in 9 patients (5 high affinity and 4 medium affinity binders) and 11 age-matched volunteers (5 high-affinity and 6 medium affinity) who had metabolite-corrected arterial input functions measured., Results: Nine of 11 patients had AIs exceeding control mean 95% confidence intervals in at least one region consistent with the seizure focus. Three of the nine had normal MRI. There was a nonsignificant trend for patients to have higher binding than volunteers both ipsilateral and contralateral to the focus in the group that had absolute binding measured., Significance: Our study demonstrates the presence of focal and distributed inflammation in neocortical epilepsy. There may be a role for TSPO PET for evaluation of patients with suspected neocortical seizure foci, particularly when other imaging modalities are unrevealing. However, a complex method, inherent variability, and increased binding in regions outside seizure foci will limit applicability., (Published 2019. This article is a U.S. Government work and is in the public domain in the USA.)

Objective: To assess the ability of functional MRI (fMRI) to predict postoperative language decline compared to direct cortical stimulation (DCS) in epilepsy surgery patients., Methods: In this prospective case series, 17 patients with drug-resistant epilepsy had intracranial monitoring and resection from 2012 to 2016 with 1-year follow-up. All patients completed preoperative language fMRI, mapping with DCS of subdural electrodes, pre- and postoperative neuropsychological testing for language function, and resection. Changes in language function before and after surgery were assessed. fMRI activation and DCS electrodes in the resection were evaluated as potential predictors of language decline., Results: Four of 17 patients (12 female; median [range] age, 43 [23-59] years) experienced postoperative language decline 1 year after surgery. Two of 4 patients had overlap of fMRI activation, language-positive electrodes in basal temporal regions (within 1 cm), and resection. Two had overlap between resection volume and fMRI activation, but not DCS. fMRI demonstrated 100% sensitivity and 46% specificity for outcome compared to DCS (50% and 85%, respectively). When fMRI and DCS language findings were concordant, the combined tests showed 100% sensitivity and 75% specificity for language outcome. Seizure-onset age, resection side, type, volume, or 1 year seizure outcome did not predict language decline., Significance: Language localization overlap of fMRI and direct cortical stimulation in the resection influences postoperative language performance. Our preliminary study suggests that fMRI may be more sensitive and less specific than direct cortical stimulation. Together they may predict outcome better than either test alone., (Published 2019. This article is a U.S. Government work and is in the public domain in the USA.)

Objective: We aimed to predict language deficits after epilepsy surgery. In addition to evaluating surgical factors examined previously, we determined the impact of the extent of functional magnetic resonance imaging (fMRI) activation that was resected on naming ability., Method: Thirty-five adults (mean age 37.5 ± 10.9 years, 13 male) with temporal lobe epilepsy completed a preoperative fMRI auditory description decision task, which reliably activates frontal and temporal language networks. Patients underwent temporal lobe resections (20 left resection). The Boston Naming Test (BNT) was used to determine language functioning before and after surgery. Language dominance was determined for Broca and Wernicke area (WA) by calculating a laterality index following statistical parametric mapping processing. We used an innovative method to generate anatomic resection masks automatically from pre- and postoperative MRI tissue map comparison. This mask provided the following: (a) resection volume; (b) overlap between resection and preoperative activation; and (c) overlap between resection and WA. We examined postoperative language change predictors using stepwise linear regression. Predictors included parameters described above as well as age at seizure onset (ASO), preoperative BNT score, and resection side and its relationship to language dominance., Results: Seven of 35 adults had significant naming decline (6 dominant-side resections). The final regression model predicted 38% of the naming score change variance (adjusted r 2  = 0.28, P = 0.012). The percentage of top 10% fMRI activation resected (P = 0.017) was the most significant contributor. Other factors in the model included WA LI, ASO, volume of WA resected, and WA LI absolute value (extent of laterality)., Significance: Resection of fMRI activation during a word-definition decision task is an important factor for postoperative change in naming ability, along with other previously reported predictors. Currently, many centers establish language dominance using fMRI. Our results suggest that the amount of the top 10% of language fMRI activation in the intended resection area provides additional predictive power and should be considered when planning surgical resection., (Published 2019. This article is a U.S. Government work and is in the public domain in the USA.)

Objective: The role of neuroinflammation in mesial temporal lobe epilepsy (MTLE), and how it relates to drug resistance, remains unclear. Expression levels of the inflammatory enzymes cyclooxygenase (COX)-1 and COX-2 have been found to be increased in animal models of epilepsy. Knowing the cellular expression of COX-1 and COX-2 is the key to understanding their functional role; however, only 3 studies have investigated COX-2 expression in epilepsy in humans, and there are no reports on COX-1. In addition, previous studies have shown that certain inflammatory proteins up-regulate ATP binding cassette (ABC) transporter expression (thought to be responsible for drug resistance), but this relationship remains unclear in human tissue. This study sought to measure the expression of COX-1, COX-2, and translocator protein 18 kDa (TSPO, an inflammation biomarker acting as a positive control), as well as ABC transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), in brain tissue samples from people with drug-resistant MTLE., Methods: Formalin-fixed paraffin-embedded surgical brain tissue was obtained from 33 patients with drug-resistant MTLE. Multiplex immunofluorescence was used to quantify the expression and distribution of COX-1, COX-2, TSPO, P-gp, and BCRP., Results: COX-1 was expressed in microglia, and COX-2 and TSPO were expressed in microglia and neurons. BCRP density correlated significantly with TSPO density, suggesting a potential relationship between inflammatory markers and efflux transporters., Significance: To the best of our knowledge, this study is the first to measure the cellular expression of COX-1, COX-2, and TSPO in microglia, astrocytes, and neurons in surgical brain tissue samples from patients with drug-resistant MTLE. Further research is needed to determine the effects of the COX inflammatory pathway in epilepsy, and how it relates to the expression of the ABC transporters P-gp and BCRP., (Wiley Periodicals, Inc. © 2018 International League Against Epilepsy.)

Generic antiepileptic drugs (AED) are significantly cheaper than brand name drugs, and may reduce overall health care expenditures. Regulatory bodies in Europe and North America require bioequivalence between generic and innovator drugs with regard to area under the plasma concentration-time curve (AUC) and peak plasma concentration (C max ); strict cutoff values have been defined. The main issue is if bioequivalence ensures therapeutic equivalence. Are switches from brand to generic, or between generic AEDs entirely safe or potentially harmful in patients with epilepsy? We summarized and evaluated the available evidence from bioequivalence, health care utilization, and clinical studies on safety of generic AEDs. In most cases, variations in AUC and C max were negligible when comparing innovator and generic AEDs. Due to interindividual pharmacokinetic and pharmacodynamic variability, measured differences between innovator and generic drugs may be the same as differences between different lots of the same brand. Studies from several countries based on insurance data have reported an increase in health care usage after switch from brand to generic AEDs; switchback rates are significantly higher for AEDs compared to other compounds. Patients may be confused, and nonadherence may increase, when AEDs are switched between manufacturers, perhaps due to changes in medication shape and color. But clinical studies do not report changes in seizure frequency and tolerability attributable to generics. Sufficient evidence indicates that most generics are bioequivalent to innovator AEDs; they do not pose a relevant risk for patients with epilepsy. However, some patients are reluctant towards variations in color and shape of their AEDs which may result in nonadherence. We recommend administering generics when a new AED is initiated. Switches from brand to generic AEDs for cost reduction and between generics, which is rarely required, generally seem to be safe, but should be accompanied by thorough counseling of patients on low risks., (Wiley Periodicals, Inc. © 2018 International League Against Epilepsy.)

Using approximations based on presumed U.S. time zones, we characterized day and nighttime seizure patterns in a patient-reported database, Seizure Tracker. A total of 632 995 seizures (9698 patients) were classified into 4 categories: isolated seizure event (ISE), cluster without status epilepticus (CWOS), cluster including status epilepticus (CIS), and status epilepticus (SE). We used a multinomial mixed-effects logistic regression model to calculate odds ratios (ORs) to determine night/day ratios for the difference between seizure patterns: ISE versus SE, ISE versus CWOS, ISE versus CIS, and CWOS versus CIS. Ranges of OR values were reported across cluster definitions. In adults, ISE was more likely at night compared to CWOS (OR = 1.49, 95% adjusted confidence interval [CI] = 1.36-1.63) and to CIS (OR = 1.61, 95% adjusted CI = 1.34-1.88). The ORs for ISE versus SE and CWOS versus SE were not significantly different regardless of cluster definition. In children, ISE was less likely at night compared to SE (OR = 0.85, 95% adjusted CI = 0.79-0.91). ISE was more likely at night compared to CWOS (OR = 1.35, 95% adjusted CI = 1.26-1.44) and CIS (OR = 1.65, 95% adjusted CI = 1.44-1.86). CWOS was more likely during the night compared to CIS (OR = 1.22, 95% adjusted CI = 1.05-1.39). With the exception of SE in children, our data suggest that more severe patterns favor daytime. This suggests distinct day/night preferences for different seizure patterns in children and adults., (Wiley Periodicals, Inc. © 2018 International League Against Epilepsy.)

Epilepsy can be a devastating disorder. In addition to debilitating seizures, epilepsy can cause cognitive and emotional problems with reduced quality of life. Therefore, the major aim is to prevent the disorder in the first place: identify, detect, and reverse the processes responsible for its onset, and monitor and treat its progression. Epilepsy often occurs following a latent period of months to years (epileptogenesis) as a consequence of a brain insult, such as head trauma, stroke, or status epilepticus. Although this latent period clearly represents a therapeutic window, we are not able to stratify patients at risk for long-term epilepsy, which is prerequisite for preventative clinical trials. Moreover, because of the length of the latent period, an early biomarker for treatment response would be of high value. Finally, mechanistic biomarkers of epileptogenesis may provide more profound insight in the process of disease development., (Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.)

Objective: Our objective was to develop a generalized linear mixed model for predicting seizure count that is useful in the design and analysis of clinical trials. This model also may benefit the design and interpretation of seizure-recording paradigms. Most existing seizure count models do not include children, and there is currently no consensus regarding the most suitable model that can be applied to children and adults. Therefore, an additional objective was to develop a model that accounts for both adult and pediatric epilepsy., Methods: Using data from SeizureTracker.com, a patient-reported seizure diary tool with >1.2 million recorded seizures across 8 years, we evaluated the appropriateness of Poisson, negative binomial, zero-inflated negative binomial, and modified negative binomial models for seizure count data based on minimization of the Bayesian information criterion. Generalized linear mixed-effects models were used to account for demographic and etiologic covariates and for autocorrelation structure. Holdout cross-validation was used to evaluate predictive accuracy in simulating seizure frequencies., Results: For both adults and children, we found that a negative binomial model with autocorrelation over 1 day was optimal. Using holdout cross-validation, the proposed model was found to provide accurate simulation of seizure counts for patients with up to four seizures per day., Significance: The optimal model can be used to generate more realistic simulated patient data with very few input parameters. The availability of a parsimonious, realistic virtual patient model can be of great utility in simulations of phase II/III clinical trials, epilepsy monitoring units, outpatient biosensors, and mobile Health (mHealth) applications., (Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.)

Objective: Sudden unexplained death in epilepsy (SUDEP) during inpatient electroencephalography (EEG) monitoring has been a rare but potentially preventable event, with associated cardiopulmonary markers. To date, no systematic evaluation of alarm settings for a continuous pulse oximeter (SpO 2 ) has been performed. In addition, evaluation of the interrelationship between the ictal and interictal states for cardiopulmonary measures has not been reported., Methods: Patients with epilepsy were monitored using video-EEG, SpO 2 , and electrocardiography (ECG). Alarm thresholds were tested systematically, balancing the number of false alarms with true seizure detections. Additional cardiopulmonary patterns were explored using automated ECG analysis software., Results: One hundred ninety-three seizures (32 generalized) were evaluated from 45 patients (7,104 h recorded). Alarm thresholds of 80-86% SpO 2 detected 63-73% of all generalized convulsions and 20-28% of all focal seizures (81-94% of generalized and 25-36% of focal seizures when considering only evaluable data). These same thresholds resulted in 25-146 min between false alarms. The sequential probability of ictal SpO 2 revealed a potential common seizure termination pathway of desaturation. A statistical model of corrected QT intervals (QTc), heart rate (HR), and SpO 2 revealed close cardiopulmonary coupling ictally. Joint probability maps of QTc and SpO 2 demonstrated that many patients had baseline dysfunction in either cardiac, pulmonary, or both domains, and that ictally there was dissociation-some patients exhibited further dysfunction in one or both domains., Significance: Optimal selection of continuous pulse oximetry thresholds involves a tradeoff between seizure detection accuracy and false alarm frequency. Alarming at 86% for patients that tend to have fewer false alarms and at 80% for those who have more, would likely result in a reasonable tradeoff. The cardiopulmonary findings may lead to SUDEP biomarkers and early seizure termination therapies., (Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.)

Objective: Functional magnetic resonance imaging (fMRI) activation of the mesial temporal lobe (MTL) may be important for epilepsy surgical planning. We examined MTL activation and lateralization during language fMRI in children and adults with focal epilepsy., Methods: One hundred forty-two controls and patients with left hemisphere focal epilepsy (pediatric: epilepsy, n = 17, mean age = 9.9 ± 2.0; controls, n = 48; mean age = 9.1 ± 2.6; adult: epilepsy, n = 20, mean age = 26.7 ± 5.8; controls, n = 57, mean age = 26.2 ± 7.5) underwent 3T fMRI using a language task (auditory description decision task). Image processing and analyses were conducted using Statistical Parametric Mapping (SPM8); regions of interest (ROIs) included MTL, Broca's area, and Wernicke's area. We assessed group and individual MTL activation, and examined degree of lateralization., Results: Patients and controls (pediatric and adult) demonstrated group and individual MTL activation during language fMRI. MTL activation was left lateralized for adults, but less so in children (p's < 0.005). Patients did not differ from controls in either age group. Stronger left-lateralized MTL activation was related to older age (p = 0.02). Language lateralization (Broca's and Wernicke's) predicted 19% of the variance in MTL lateralization for adults (p = 0.001), but for not children., Significance: Language fMRI may be used to elicit group and individual MTL activation. The developmental difference in MTL lateralization and its association with language lateralization suggests a developmental shift in lateralization of MTL function, with increased left lateralization across the age span. This shift may help explain why children have better memory outcomes following resection compared to adults., (Wiley Periodicals, Inc. © 2015 International League Against Epilepsy.)

Objective: To develop a better understanding of mechanisms of seizures and long-term epileptogenesis using neurocysticercosis., Methods: A workshop was held bringing together experts in epilepsy and epileptogenesis and neurocysticercosis., Results: Human neurocysticercosis and parallel animal models offer a unique opportunity to understand basic mechanisms of seizures. Inflammatory responses to degenerating forms and later-stage calcified parasite granulomas are associated with seizures and epilepsy. Other mechanisms may also be involved in epileptogenesis., Significance: Naturally occurring brain infections with neurocysticercosis offer a unique opportunity to develop treatments for one of the world's most common causes of epilepsy and for the development of more general antiepileptogenic treatments. Key advantages stem from the time course in which an acute seizure heralds a start of the epileptogenic process, and radiographic changes of calcification and perilesional edema provide biomarkers of a chronic epileptic state., (Wiley Periodicals, Inc. © 2014 International League Against Epilepsy.)

Objective: To compare manual and automated preoperative and postoperative hippocampal volume measurements in patients with intractable epilepsy., Methods: We studied 34 patients referred to the Clinical Epilepsy Section, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH) for evaluation of intractable epilepsy and 21 normal volunteers who received 1.5 or 3 T GE Signa magnetic resonance imaging (MRI) scans. Hippocampal volumes were traced manually on each slice and assembled into three-dimensional volumes by investigators who were blinded to other data. Automated volumetric measurements were obtained using FreeSurfer. Statistical analysis was performed with GraphPad Prism., Results: Automated hippocampal volumes were larger than manual volumes in both patients and normal volunteers (p < 0.05). Right to left hemisphere hippocampal ratio and percent of hippocampus resected did not differ significantly by segmentation method. It was not possible to obtain accurate total resection volumes with the automated method., Significance: Values such as side-to-side ratio and percent resected may be more directly translatable between manual and automated methods than absolute measures of volume. Accurate determination of resection volumes is important for studies of the effects of surgery on both seizure control and postoperative neuropsychological deficits. Our preliminary data suggest that FreeSurfer may provide an accurate and simple method for quantitating hippocampal resections. However, it may be less valuable for large or extratemporal resections, or when distortions of normal anatomy are present. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here., (Published 2014. This article is a U.S. Government work and is in the public domain in the USA.)

Purpose: To determine the effect of seizure focus location within the left hemisphere on the expression of regional language dominance., Methods: In this cross-sectional study we investigated 90 patients (mean age 23.3 ± 12.9 years) with left hemisphere focal epilepsy (mean age onset 11.7 ± 8.3 years). Eighteen patients had a frontal lobe focus and 72 had a temporal lobe focus (43 mesial; 29 neocortical). Subjects performed an auditory word definition language paradigm using 3 Tesla blood oxygen level dependent (BOLD) EPI functional magnetic resonance imaging (fMRI). Data were analyzed in SPM2. Regional laterality indices (LIs) for inferior frontal gyrus (IFG), and Wernicke's area (WA), were calculated using a bootstrap method. Categorical language dominance and mean LI were analyzed., Key Findings: Mean WA LI was lower for subjects with a mesial temporal focus compared with a frontal focus (p = 0.04). There was a greater proportion of atypical language in WA for subjects with a mesial temporal focus compared with a frontal focus (χ(2) = 4.37, p = 0.04). WA LI did not differ for subjects with a neocortical focus compared with a mesial focus or a frontal focus. Mean IFG LI and proportion of atypical language in IFG were similar across seizure focus groups. Age and age of onset were not correlated with mean laterality in WA or IFG. Epilepsy duration tended to be negatively correlated with WA LI (r = -0.18, p = 0.10), but not IFG LI., Significance: Temporal lobe foci have wide-ranging effects on the distributed language system. In contrast, the effects of a frontal lobe focus appear restricted to anterior rather than posterior language processing areas., (Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.)

Purpose: Blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI), an important research and clinical tool, depends on relatively greater transient increases in (regional cerebral blood flow) rCBF than cerebral metabolic rate for oxygen during neural activity. We investigated whether reduced resting rCBF in patients with temporal lobe epilepsy affects BOLD signal during fMRI language mapping., Methods: We used [(15)O] water positron emission tomography (PET) to measure rCBF, and 3 Tesla echo planar imaging (EPI) BOLD fMRI with an auditory description decision task in 33 patients with temporal lobe epilepsy (16 men; mean age 33.6 ± standard deviation [SD] 10.6 years; epilepsy onset 14.8 ± 10.6 years; mean duration 18.8 ± 13.2 years; 23 left focus, 10 right focus). Anatomic regions drawn on structural MRI, based on the Wake Forest Pick Atlas, included Wernicke's area (WA), inferior frontal gyrus (IFG), middle frontal gyrus (MFG), and hippocampus (HC). Laterality indices (LIs), and asymmetry indices (AIs), were calculated on coregistered fMRI and PET., Key Findings: Twelve patients had mesial temporal sclerosis (seven on the left), two patients had a tumor or malformation of cortical development (both left), one patient a right temporal cyst, and 18 patients had normal MRI (14 left). Decreasing relative left WA CBF correlated with decreased left IFG voxel activation and decreasing left IFG LI. However, CBF WA AI was not related to left WA voxel activation itself or WA LI. There was a weak positive correlation between absolute CBF and fMRI activation in left IFG, right IFG, and left WA. Patients with normal and abnormal MRI did not differ in fMRI activation or rCBF AIs., Significance: Reduced WA rCBF is associated with reduced fMRI activation in IFG but not WA itself, suggesting distributed network effects, but not impairment of underlying BOLD response. Hypoperfusion in TLE does not affect fMRI clinical value., (Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.)

Purpose: Memory deficits and depression are common in patients with temporal lobe epilepsy (TLE). Previous positron emission tomography (PET) studies have shown reduced mesial temporal 5HT1A-receptor binding in these patients. We examined the relationships among verbal memory performance, depression, and 5HT1A-receptor binding measured with 18F-trans-4-fluoro-N-2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl-N-(2-pyridyl) cyclohexane carboxamide (18FCWAY) PET in a cross-sectional study., Methods: We studied 40 patients (24 male; mean age 34.5 ± 10.7 years) with TLE. Seizure diagnosis and focus localization were based on ictal video-electroencephalography (EEG) recording. Patients had neuropsychological testing with Wechsler Adult Intelligence Score III (WAIS III) and Wechsler Memory Score III (WMS III) on stable antiepileptic drug (AED) regimens at least 24 h since the last seizure. Beck Depression Inventory (BDI) scores were obtained. We performed interictal PET with 18FCWAY, a fluorinated derivative of WAY 100635, a highly specific 5HT1A ligand, and structural magnetic resonance imaging (MRI) scans to estimate partial volume and plasma free fraction corrected 18FCWAY volume of distribution (V/f1)., Key Findings: Hippocampal V/f1 was significantly lower in area ipsilateral than contralateral to the epileptic focus (73.7 ± 27.3 vs. 95.4 ± 28.4; p < 0.001). We found a significant relation between both left hippocampal 18FCWAY V/f1 (r = 0.41; p < 0.02) and left hippocampal volume (r = 0.36; p < 0.03) and delayed auditory memory score. On multiple regression, there was a significant effect of the interaction of left hippocampal 18FCWAY V/f1 and left hippocampal volume on delayed auditory memory, but not of either alone. High collinearity was present. In an analysis of variance including the side of the seizure focus, the effect of left hippocampal 18FCWAY V/f1 but not focus laterality retained significance. Mean BDI was 8.3 ± 7.0. There was a significant inverse relation between BDI and 18FCWAY V/f1 ipsilateral to the patient's epileptic focus (r = 0.38 p < 0.02). There was no difference between patients with a right or left temporal focus. There was no relation between BDI and immediate or delayed auditory memory., Significance: Our study suggests that reduced left hippocampal 5HT1A-receptor binding may play a role in memory impairment in patients with TLE., (Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.)

Recognition of limited economic resources, as well as potential adverse effects of "over testing," has increased interest in "evidence-based" assessment of new medical technology. This creates a particular problem for evaluation and treatment of epilepsy, which are increasingly dependent on advanced imaging and electrophysiology, since there is a marked paucity of epilepsy diagnostic and prognostic studies that meet rigorous standards for evidence classification. The lack of high quality data reflects fundamental weaknesses in many imaging studies but also limitations in the assumptions underlying evidence classification schemes as they relate to epilepsy, and to the practicalities of conducting adequately powered studies of rapidly evolving technologies. We review the limitations of current guidelines and propose elements for imaging studies that can contribute meaningfully to the epilepsy literature., (Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.)

Purpose: Neuroimaging studies suggest a history of febrile seizures, and depression, are associated with hippocampal volume reductions in patients with temporal lobe epilepsy (TLE)., Methods: We used radial atrophy mapping (RAM), a three-dimensional (3D) surface modeling tool, to measure hippocampal atrophy in 40 patients with unilateral TLE, with or without a history of febrile seizures and symptoms of depression. Multiple linear regression was used to single out the effects of covariates on local atrophy., Key Findings: Subjects with a history of febrile seizures (n =15) had atrophy in regions corresponding to the CA1 and CA3 subfields of the hippocampus contralateral to seizure focus (CHC) compared to those without a history of febrile seizures (n = 25). Subjects with Beck Depression Inventory II (BDI-II) score ≥ 14 (n = 11) had atrophy in the superoanterior portion of the CHC compared to subjects with BDI-II <14 (n = 29)., Significance: Contralateral hippocampal atrophy in TLE may be related to febrile seizures or depression., (Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.)

Objective: To evaluate the relationship between hippocampal volume loss, depression, and epilepsy., Background: There is a significantly increased incidence of depression and suicide in patients with epilepsy. Both epilepsy and depression are associated with reduced hippocampal volumes, but it is uncertain whether patients with both conditions have greater atrophy than those with epilepsy alone. Previous studies used depression measures strongly weighted to current state, and did not necessarily assess the influence of chronic major depressive disorder ("trait"), which could have a greater impact on hippocampal volume., Methods: Fifty-five epilepsy patients with complex partial seizures (CPS) confirmed by electroencephalography (EEG) had three-dimensional (3D)-spoiled gradient recall (SPGR) acquisition magnetic resonance imaging (MRI) scans for hippocampal volumetric analysis. Depression screening was performed with the Beck Depression Inventory (BDI, 51 patients) and with the structured clinical inventory for DSM-IV (SCID, 34 patients). For the BDI, a score above 10 was considered mild to moderate, above 20 moderate to severe, and above 30 severe depression. MRI and clinical analysis were performed blinded to other data. Statistical analysis was performed with Systat using Student's t test and analysis of variance (ANOVA)., Results: There was a significant interaction between depression detected on SCID, side of focus, and left hippocampal volume. Patients with a diagnosis of depression and a right temporal seizure focus had significantly lower left hippocampal volume. A similar trend for an effect of depression on right hippocampal volume in patients with a right temporal focus did not reach statistical significance., Conclusions: Our results suggest that patients with right temporal lobe epilepsy and depression have hippocampal atrophy that cannot be explained by epilepsy alone.

Background: Positron emission tomography (PET) with (18)F-fluorodeoxyglucose (FDG) shows widespread hypometabolism even in temporal lobe epilepsy (TLE) patients with mesial temporal foci. (18)F-trans-4-fluoro-N-2-[4-(2-methoxyphenyl) piperazin-1-yl]ethyl-N-(2-pyridyl)cyclohexane carboxamide ((18)F-FCWAY) PET may show more specific 5-HT(1A)-receptor binding reduction in seizure initiation than in propagation regions. (18)FCWAY PET might be valuable for detecting epileptic foci, and distinguishing mesial from lateral temporal foci in MRI-negative patients with TLE., Methods: We performed (18)F-FCWAY-PET and (18)F-FDG-PET in 12 MRI-negative TLE patients who had had either surgery or subdural electrode recording, and 15 healthy volunteers. After partial volume correction for brain atrophy, free fraction-corrected volume of distribution (V/f1) measurement and asymmetry indices (AIs) were computed. We compared (18)F-FCWAY-PET and (18)F-FDG-PET results with scalp video electroencephalography (EEG), invasive EEG, and surgical outcome., Results: Mean (18)F-FCWAY V/f1, compared with normal controls, was decreased significantly in fusiform gyrus, hippocampus, and parahippocampus ipsilateral to epileptic foci, and AIs were significantly greater in hippocampus, parahippocampus, fusiform gyrus, amygdala, and inferior temporal regions. Eleven patients had clearly lateralized epileptogenic zones. Nine had congruent, and two nonlateralized, (18)F-FCWAY PET. One patient with bitemporal seizure onset had nonlateralized (18)F-FCWAY-PET. (18)F-FDG-PET showed congruent hypometabolism in 7 of 11 EEG-lateralized patients, bilateral hypometabolic regions in one, contralateral hypometabolism in one, as well as lateralized hypometabolism in the patient with bitemporal subdural seizure onset. Patients with mesial temporal foci tended to have lower superior and midtemporal (18)F-FCWAY V/f1 binding AI than those with lateral or diffuse foci., Conclusion: (18)F-FCWAY-PET can detect reduced binding in patients with normal MRI, and may be more accurate than (18)F-FDG-PET.

Human herpes virus 6 (HHV6) infection is nearly ubiquitous in childhood and may include central nervous system invasion. There are two variants, HHV6A and HHV6B. Usually asymptomatic, it is associated with the common, self-limited childhood illness roseola infantum and rarely with more severe syndromes. In patients with immune compromise, subsequent reactivation of viral activity may lead to severe limbic encephalitis. HHV6 has been identified as a possible etiologic agent in multiple sclerosis, myocarditis, and encephalitis. A preponderance of evidence supports an association between HHV6 and febrile seizures. An ongoing multicenter study is investigating possible links between HHV6 infection, febrile status epilepticus, and development of mesial temporal sclerosis (MTS). Investigation of temporal lobectomy specimens showed evidence of active HHV6B but not HHV6A replication in hippocampal astrocytes in about two-thirds of patients with MTS but not other causes of epilepsy. It has been suggested that HHV6B may cause "excitotoxicity" by interfering with astrocyte excitatory amino acid transport. Although conventional inflammatory changes are not found in most MTS specimens, inflammatory modulators may play a role in neuronal injury leading to MTS as well. If the link between early viral infection, complex or prolonged febrile seizures, and later development of intractable temporal lobe epilepsy is confirmed, new therapeutic approaches to a common intractable epilepsy syndrome may be possible.

Purpose: To study the relation of hippocampal 5HT1A receptor binding to symptoms of depression in patients with temporal lobe epilepsy. Depression is common in people with epilepsy, and reduced 5HT1A binding has been reported in patients with primary depressive disorders., Methods: We studied 45 patients with temporal lobe epilepsy confirmed by ictal video-EEG recording. Mood was assessed with the Beck Depression Inventory (BDI). Positron emission tomographic measurement of 5HT1A receptors was performed with 18F-FCWAY, a highly specific silent antagonist. 3D-T1-weighted MRI was used to correct for structural atrophy. Receptor distribution volume (V) was corrected for plasma tracer free fraction (f1)., Results: There was a significant inverse relation between ipsilateral hippocampal v/f1 and the BDI. For contralateral hippocampus, there was a nonsignificant trend. Patients with BDI > 20 had significantly lower ipsilateral hippocampal V/f1 than patients in the low and medium groups. There was no significant effect of the presence of mesial temporal sclerosis, focus laterality, or gender on the BDI., Conclusions: Our study shows a relationship between hippocampal 5HT1A binding and depressive symptoms measured by the BDI in patients with epilepsy. The findings parallel results in patients with MDD.

In North America, overall epilepsy incidence is approximately 50/100,000 per year, highest for children below five years of age, and the elderly. The best data suggest prevalence of 5-10/1000. Potential effects of gender, ethnicity, access to care and socioeconomic variables need further study. Studies of epilepsy etiology and classification mainly were performed without modern imaging tools. The best study found an overall standardized mortality ratio (SMR) for epilepsy relative to the general population of 2.3. There is evidence to suggest a greater increase in patients with symptomatic epilepsy, particularly children. People with epilepsy are more likely to report reduced Health-related Quality of Life than controls. They have reduced income, and are less likely to have full-time employment. They suffer from persistent stigma throughout the region, in developed as well as developing countries. Poor treatment access and health care disparities for people with epilepsy may be related to insufficient economic resources, rural isolation, gender, ethnicity, and lack of public and physician knowledge of modern approaches to epilepsy care. Despite high costs and severe disability, epilepsy may attract somewhat less research funding from public and private sources than other less common chronic neurological disorders. A Plan for Epilepsy in North America should address: basic and clinical research; primary prevention research; translation to care; stigma, quality of life, and self-management; industry relations; government and regional relations; and regional integration and resource sharing.

Purpose: To study the effect of antiepileptic drugs (AEDs) on 5-HT(1A)-receptor binding in patients with temporal lobe epilepsy. 5-HT(1A)-receptor binding, measured by positron emission tomography, is reduced in patients with temporal lobe epilepsy. Antiepileptic drugs may act on the serotonergic system, as shown in animal models, and thus affect receptor-binding measurements., Methods: We analyzed the effect of AEDs on 5-HT(1A)-receptor binding in 31 patients and 10 normal controls. Patients with structural lesions, progressive neurologic disorders, or taking other medications were excluded. None had a seizure for >or=2 days before positron emission tomography (PET). [(18)F]FCWAY PET was performed on a GE Advance scanner with continuous EEG monitoring. Functional images of the distribution volume (V) were generated. Anatomic regions of interest were applied to co-registered PET images, after correction for partial-volume effect., Results: Patients had significantly higher [(18)F]FCWAY free fraction (f(1)) than did controls. No AED effects were observed on interictal [(18)F]FCWAY binding after correction for plasma free fraction. [(18)F]FCWAY V/f1 reduction in epileptic foci was not affected by AEDs., Conclusions: 5-HT(1A)-receptor binding is reduced in temporal lobe epileptic foci after partial-volume correction. AED plasma free fractions should be measured when PET receptor studies are performed in patients with epilepsy.

Purpose: Hypothalamic hamartomas (HHs) have been associated with uncontrolled seizures, and aggressive therapy including surgery is often recommended. However, some patients, particularly those with other findings associated with Pallister-Hall syndrome (PHS), have a more benign course., Methods: Thirty-seven of 40 PHS patients and 16 of 16 patients with isolated HH had a lesion confirmed on magnetic resonance imaging (MRI). Records for all patients were reviewed for the following information: presence of seizures, age at seizure onset, seizure type, seizure frequency, number of antiepileptic medications (AEDs) at the time of evaluation, past AEDs, MRI characteristics of the HH, presence of endocrine dysfunction, and presence of developmental and behavioral problems., Results: All isolated HH patients had a history of seizures, compared with 13 of 40 PHS patients (all PHS patients with seizures had hamartomas). In isolated HH, seizures started earlier in life, occurred more frequently, and were harder to control than those in patients with PHS. Isolated HH patients were more likely to have behavioral and developmental problems than were PHS patients. The T2 signal of the hamartoma was isointense to gray matter in the majority of PHS patients, but showed a significant increase in all but one patient with isolated HH., Conclusions: Patients with isolated HH have a distinct clinical phenotype, showing more severe seizures and neurologic dysfunction, HH showing increased T2 signal, and are more likely to have precocious puberty. In contrast, PHS patients usually have well-controlled seizures and other endocrine disturbances than precocious puberty. Patients with HH with or without seizures should be evaluated carefully for other clinical manifestations of PHS, particularly before surgery is considered.

Purpose: To assess the evidence demonstrating efficacy, tolerability, and safety of seven new antiepileptic drugs (AEDs) [gabapentin (GBP), lamotrigine (LTG), topiramate (TPM), tiagabine (TGB), oxcarbazepine (OXC), levetiracetam (LEV), and zonisamide (ZNS)] in the treatment of children and adults with refractory partial and generalized epilepsies., Methods: A 23-member committee, including general neurologists, pediatric neurologists, epileptologists, and doctors in pharmacy, evaluated the available evidence based on a structured literature review including MEDLINE, Current Contents, and Cochrane Library for relevant articles from 1987 to March 2003., Results: All of the new AEDs were found to be appropriate for adjunctive treatment of refractory partial seizures in adults. GBP can be effective for the treatment of mixed seizure disorders, and GBP, LTG, OXC, and TPM for the treatment of refractory partial seizures in children. Limited evidence suggests that LTG and TPM also are effective for adjunctive treatment of idiopathic generalized epilepsy in adults and children, as well as treatment of the Lennox-Gastaut syndrome., Conclusions: The choice of AED depends on seizure and/or syndrome type, patient age, concomitant medications, and AED tolerability, safety, and efficacy. The results of this evidence-based assessment provide guidelines for the prescription of AEDs for patients with refractory epilepsy and identify those seizure types and syndromes for which more evidence is necessary.

Purpose: To assess the evidence demonstrating efficacy, tolerability, and safety of seven new antiepileptic drugs [AEDs; gabapentin (GBP), lamotrigine (LTG), topiramate (TPM), tiagabine (TGB), oxcarbazepine (OXC), levetiracetam (LEV), and zonisamide (ZNS), reviewed in the order in which these agents received approval by the U.S. Food and Drug Administration] in the treatment of children and adults with newly diagnosed partial and generalized epilepsies., Methods: A 23-member committee, including general neurologists, pediatric neurologists, epileptologists, and doctors in pharmacy, evaluated the available evidence based on a structured literature review including MEDLINE, Current Contents, and Cochrane Library for relevant articles from 1987 until September 2002, with selected manual searches up to 2003., Results: Evidence exists, either from comparative or dose-controlled trials, that GBP, LTG, TPM, and OXC have efficacy as monotherapy in newly diagnosed adolescents and adults with either partial or mixed seizure disorders. Evidence also shows that LTG is effective for newly diagnosed absence seizures in children. Evidence for effectiveness of the new AEDs in newly diagnosed patients with other generalized epilepsy syndromes is lacking., Conclusions: The results of this evidence-based assessment provide guidelines for the prescription of AEDs for patients with newly diagnosed epilepsy and identify those seizure types and syndromes for which more evidence is necessary.

Purpose: Studies using magnetic resonance imaging have shown that reduced hippocampal volume is associated with a history of febrile seizures, the duration of epilepsy, and the number of generalized tonic-clonic seizures. It is uncertain whether these factors have the same influence on functional as on structural measures of the integrity of the epileptogenic zone., Methods: We used positron emission tomography (PET) with fluorine 18 2-deoxyglucose to study 91 patients with temporal lobe seizure foci localized by ictal video-EEG. PET was performed in the awake interictal resting state with ears plugged and eyes patched. We recorded surface EEG during injection (5 mCi) and the 30-min uptake period. We used a standard template to analyze PET scans., Results: A significant negative relation was found between the duration of epilepsy and hippocampal glucose metabolism ipsilateral to the epileptic focus. Patients with a history of either any febrile seizures, or complex, or prolonged febrile seizures, did not have greater hypometabolism ipsilateral to the epileptic focus than did patients without a febrile seizure history. We found no effect of generalized tonic-clonic seizure history., Conclusions: Longer epilepsy duration is associated with greater hypometabolism, suggesting that epilepsy is a progressive disease.

Purpose: Reports conflict on the relation of glucose metabolism to hippocampal volume in temporal lobe foci. Previous studies usually have used side-side ratios rather than regional metabolic rates., Methods: We measured hippocampal volume and glucose metabolism in 37 patients with temporal epileptogenic zones identified by ictal video-EEG telemetry. Metabolic rates were normalized to global brain mean., Results: Both 18-fluoro-2-deoxyglucose-PET and volumetric MRI lateralized the epileptic focus determined by ictal video-EEG. There were significant correlations between left-right metabolic asymmetry and hippocampal formation volume left-right ratios. Comparisons between normalized metabolism and hippocampal formation volume, ignoring the side of the epileptic focus, showed significant relations between left hippocampal volume and left inferior lateral temporal metabolism, right hippocampus and right inferior mesial temporal, and left hippocampus and left inferior mesial temporal metabolism. In contrast, when normalized metabolism was compared with hippocampal volume in the epileptic focus, no relation was found., Conclusions: Our study suggests that the relation between hippocampal volume and glucose metabolism breaks down in epileptic foci and that hypometabolism is not dependent on neuronal loss. It is consistent with data suggesting that hypometabolism is an independent predictor of surgical outcome.

Purpose: To examine the relationship between frequency of complex partial (CPS) and secondarily generalized tonic-clonic seizures (sGTCS) on hippocampal volume (HV) and temporal lobe metabolism., Methods: We performed volumetric magnetic resonance imaging (MRI) and positron emission tomography with 18fluorodeoxyglucose (18FDG-PET) in 32 patients with epilepsy. Temporal lobe foci were localized by ictal video-EEG., Results: We did not find any association between CPS frequency or lifetime number of sGTCS and HV or metabolism ipsilateral to electroencephalographic focus., Conclusion: The progress of metabolic or pathologic abnormalities of temporal lobe epilepsy may not be altered by adequate seizure control. The presence of an epileptic focus might be associated with progressive neuronal injury even in clinically well-controlled patients.

Purpose: To study the value of [18F]2-deoxyglucose (FDG)-positron emission tomography when surface ictal EEG is nonlocalizing., Methods: FDG-PET scans were performed in 46 patients with complex partial seizures (CPS) not localized by ictal surface-sphenoidal video-EEG (VEEG) telemetry. Interictal PET was performed with continuous EEG monitoring, and images were analyzed with a standard template. Forty patients subsequently had subdural and 6 had depth electrodes (invasive EEG, IEEG); 22 had bilateral implants. A focus was detected in 40, and 35 had temporal lobectomy based on IEEG localization., Results: There was a close association between IEEG and PET localization (p < 0.01): 26 patients had relative unilateral temporal FDG-PET hypometabolism, all had congruent IEEG, and 18 of 23 were seizure-free after temporal lobectomy. Five patients had unilateral frontotemporal hypometabolism (3 of 5 were seizure-free), 1 had frontal hypometabolism, and 14 had no lateralized PET abnormality (4 of 7 were seizure-free). Patients who became seizure-free had significantly higher lateral temporal asymmetry index (AI). PET showed > or = 15% relative temporal hypometabolism (AI) in 12 of 22 patients with nonlateralized surface ictal VEEG and was capable of distinguishing between frontal and temporal foci in 16 of 24 patients with lateralized, but not localized, surface ictal video-EEG., Conclusions: FDG-PET provides valuable data in patients with unlocalized surface ictal EEG and can reduce the number of patients who require IEEG studies. Quantitation is necessary for optimal PET interpretation.

To study quantitative alterations in regional cerebral blood flow (rCBF) accompanying seizures, and to assess the utility of ictal activation PET scanning as a noninvasive clinical tool for localization of epileptogenic foci, we used pentylenetetrazole (PTZ) to induce seizures during 15O-water positron emission tomography (PET) CBF measurement in 15 patients with uncontrolled complex partial seizures (CPS) who had been referred for surgical evaluation. Continuous EEG monitoring was performed during the PET scans. After baseline scans were obtained, each patient was injected with 150-300 mg PTZ. Two patients had generalized tonic-clonic seizures (GTCs). CBF increases were asymmetrical. Two patients (in 1 the seizure occurred spontaneously, without PTZ injection) who had CPS had bitemporal 70-80% increases in CBF. Thalamic CBF increased during both CPS and GTCS. Five patients had an increase in focal EEG interictal abnormality, accompanied by focal flow decreases in 3. PTZ injection not accompanied by clinical seizures did not increase CBF. Partial seizures may be associated with bilateral increases in CBF, and subcortical gray regions are involved in ictal activation.

We compared the effect of valproate (VPA) on cerebral metabolic rate for glucose (CMRGlc) and cerebral blood flow (CBF), measured with 18F-2-deoxyglucose (18FDG) and 15O water positron emission tomography (PET), in 10 normal volunteers. Mean VPA dose was 17.7 mg/kg, and mean VPA level was 82.1 mg/L (+/-16.5) for 4 weeks. VPA reduced global CMRGlc by 9.4% (9.60 +/- 0.76 vs. 8.59 +/- 1.02 mg Glc/min/100 g, p < 0.05) and regionally in all anatomic areas (p < 0.05 for 11 of 26 areas). VPA diminished global CBF by 14.9% (56.55 +/- 6.70 vs. 47.48 +/- 4.42 ml/min/100 g, p < 0.002) and regionally in all anatomic areas (p < 0.05 for 12 of 26 areas). No significant correlation was noted between VPA level and either global CMRGlc or CBF. The effect of VPA on global CMRGlc is similar to that of carbamazepine (CBZ) and phenytoin but less than that of phenobarbital, valium, or combination therapy with VPA and CBZ. VPA reduced regional CBF (rCBF) but not CMRGlc in the thalamus, an effect that may be associated with VPA's mechanism of action against generalized seizures.

We used electrical stimulation mapping to compare performance on auditory and visual naming tasks in inferotemporal, lateral temporal, frontal, and parietal cortex in 8 temporal lobe epilepsy (TLE) patients with subdural electrodes placed for preoperative language localization. Performance on auditory responsive naming (ARN) and visual confrontation naming (VCN) was best during stimulation of parietal cortex and was equally impaired during stimulation of inferotemporal and frontal cortex. In contrast, ARN performance was significantly poorer than VCN performance during stimulation of anterior and posterior lateral temporal cortex. In most patients, stimulation of inferotemporal cortex at relatively low stimulus intensities (< or = 5 mA) during either ARN or VCN elicited reproducible errors in which patients could describe, gesture, spell, or draw, but not name, in response to auditory or visual cues. Inferotemporal and frontal cortex appear to be multimodality language regions distinct from lateral temporal cortex.

We studied the effect of felbamate (FBM) monotherapy on seizure rate in patients with partial and secondarily generalized seizures undergoing presurgical monitoring at a single site. The study design was a double-blind placebo-controlled parallel monotherapy trial. Forty patients whose seizures had not been controlled by standard antiepileptic drugs (AEDs) were randomized. Seizure type was confirmed by video-EEG monitoring. All baseline AEDs were discontinued, and patients were drug-free for 5.3 +/- 2.4 days before randomization to FBM or placebo. After a 4-day titration, seizures were counted for 14 days. Patients receiving FBM had significantly lower seizure rates, whether all randomized patients, patients who survived titration, or study completers were compared. Eight of 19 placebo patients randomized to placebo, as compared with 13 of 21 receiving FBM, completed the 18-day study. Two FBM patients dropped out due to seizures, and 6 dropped out due to side effects, including anxiety, difficulty sleeping, abdominal discomfort, acute psychosis, and orobuccal dyskinesias. Ten placebo patients met the criteria for premature discontinuation owing to seizures, and 1 hd an episode of panic. There was no evidence of hepatic or hematologic toxicity. FBM reduces seizure frequency in patients with localization-related epilepsy.

A 28-year-old woman with epilepsy developed the new onset of paroxysmal tongue tingling during subdural electrode monitoring. Her symptoms coincided with electrographic seizure activity arising from an area of the perisylvian region that had not previously been involved in her habitual seizures. At electrode removal, a focal 2 x 2 cm hematoma was detected and evacuated from beneath these electrode contacts. Unexpected episodic events may represent nonhabitual seizure activity related to the surgical procedure.

Adult patients with left, right, or bilateral temporal lobe epilepsy or absence epilepsy, and normal controls completed the Buss-Durkee Hostility Inventory (BDHI), a standardized questionnaire of aggressive tendencies. Patients with left temporal lobe seizure foci scores higher on the Suspicion scale than did other patients or controls (p < 0.05). Factor analysis scale scores identified three factors: hostile feelings, covert aggression, and overt aggression. The groups differed on their pattern of factor scores (p < 0.01): patients with left temporal lobe epilepsy scored higher than other groups on hostile feelings, normal controls scored higher on Covert aggression, and bitemporal patients scores higher on Overt aggression. Patients with absence seizures did not differ from controls. Lateralization of the seizure focus in patients with temporal lobe epilepsy may alter expression of aggressive behavior.

We studied 24 patients with partial seizures receiving carbamazepine (CBZ) monotherapy and 40 normal controls, 17 of whom were tested with and without CBZ therapy. Autonomic nervous system assessment included baseline heart rate (HR) and blood pressure (BP); BP and HR changes during orthostasis and cold pressor test (CPT); and HR changes during sinus arrhythmia, Valsalva maneuver, and cold face test with apnea (CFTA). Our study demonstrated normal interictal autonomic function in patients with epilepsy, but, variations in BP and HR during orthostasis and CPT were significantly (p < 0.05) higher in epilepsy patients than in controls with or without CBZ. Epilepsy patients had higher initial increases in BP and greater subsequent decreases in BP than did nonmedicated controls during CPT. Controls with CBZ had higher HR during orthostasis and CFTA than did those without CBZ. CBZ levels correlated with baseline and orthostatic BP and HR during deep breathing (sinus arrhythmia). Our results showed that patients with epilepsy have greater BP and HR variability and reactivity than controls, attributable in part to CBZ levels.

We measured lumbar cerebrospinal fluid (CSF) levels of somatostatin, cholecystokinin, neurotensin, atrial natriuretic factor, vasoactive inhibitory peptide, neuropeptide Y, adrenocorticotrophic hormone, corticotropin releasing hormone, beta-endorphin, metenkephalin, cortisol, alanine, glycine, aspartate, glutamate, taurine, and gamma-aminobutyric acid in 25 inpatients with epilepsy at known interictal and postictal times and in 11 neurologically normal volunteers. There were no significant differences between interictal or postictal complex partial seizures (CPS), postictal generalized tonic-clonic seizures (GTC), and control CSF neuropeptide, cortisol, and amino acid (AA) levels. However, there were nonsignificant trends for CSF levels of several neuropeptides to be increased after CPS and GTC as compared with interictal baseline levels. There were significant correlations between levels of certain CSF neuropeptides or (AAs) and serum antiepileptic drug (AED) levels. Several correlations were noted between CSF levels of AAs, including a correlation between the excitatory neurotransmitters aspartate and glutamate identified only after CPS.

We measured CSF and serum concentrations of monoamines and monoamine metabolites in normal control subjects and in patients with partial epilepsy between and less than 2 h after complex partial seizures (CPS) or secondarily generalized tonic-clonic seizures (SGTCs). After SGTCs, concentrations of norepinephrine in CSF were significantly higher (p less than 0.05) than interictal concentrations, concentrations after PSs, and concentrations in control subjects. Serum epinephrine levels also were significantly higher after SGTCs than interictal and control subjects' levels. CSF HVA levels were significantly higher after PSs than interictal or control subjects' levels. CSF concentrations of norepinephrine and its intraneuronal metabolite, dihydroxyphenylglycol, were highly correlated, both interictally and following SGTCs, whereas correlations between serum and CSF levels of these catechols generally were not statistically significant. The results indicate that seizures are associated with release of catecholamines in the central nervous system.

We examined the seizure records of 13 patients (nine men and four women, ages 27-50 years) with intractable partial epilepsy, maintained with steady anti-epileptic drug dosages. Patients recorded daily seizure frequency on calendars. Periods of outpatient observation ranged from 99 to 1,710 days and the number of observed seizures ranged from 18 to over 400, with daily seizure rates of 0.1-4.3 per day. We used the quasi-likelihood regression model to examine the following four departures of the daily seizure counts from a Poisson (random) model: (1) linear increasing or decreasing time trends in expected seizure rates; (2) clustering, where the expected seizure rate on a given day depends on the number of seizures observed on the immediate prior days; (3) monthly cyclicity; and (4) increased variability (overdispersion). Linear time trends were seen in six patients (four increasing and two decreasing), clustering was seen in 10 patients, and a near-monthly cycle appeared in four patients (two of nine men and two of four women). A significant amount of extra variation (overdispersion) relative to a Poisson distribution was observed in all but one of the 13 patients. Departures from a Poisson (random) model appear more common in this population of patients with medically intractable epilepsy than is commonly recognized, and have clinical importance as well as implications for the design of clinical studies.

We performed a randomized, double-blind, three-period cross-over study of felbamate (FBM, 2-phenyl-1,3-propanediol dicarbamate: Carter-Wallace 554) in patients with complex partial seizures. Patients continued carbamazepine (CBZ) throughout the study and were observed in the hospital for the entire trial period. The entry criteria required at least six seizures in a 3-week baseline period (and no more than 1 week with a single seizure) with CBZ alone. Thirty subjects were randomized. Two left the study after randomization, 1 owing to seizure exacerbation, and 1 owing to hyponatremia, which may have been related to CBZ therapy. The daily dosage of 50 mg/kg (maximum 3,000 mg) FBM per day was well tolerated by all 28 patients who completed the study. Only mild adverse experience were observed during the trial. FBM reduced CBZ level (p less than 0.0001; 95% confidence interval -28%, -20%). There was no significant difference in seizure frequency between placebo and FBM periods (one-sided p = 0.172), but when a correction was made for the lower CBZ level noted during FBM periods, the data suggested a strong antiseizure effect of FBM.

We studied the effects of valproate (VPA) on local cerebral glucose metabolism (LCMRglc) in eight patients with partial seizure disorders and two with primary generalized epilepsy. Each patient had two positron-emission tomography (PET) scans with 18F-2-deoxyglucose (FDG), with, and without, VPA (mean level 52 mg/dl, range 30-127 mg/dl). Patients continued carbamazepine (CBZ) for both scans: serum concentrations were not significantly changed by VPA (CBZ range 5.4-12 mg/dl). Seven patients had the "without-VPA" scan first. Mean interval between PET scans was 75 days. Global CMRglc was decreased by 22% by addition of VPA (7.2 +/- 1.8 mg/100 g/min without VPA, 5.6 +/- 1.1 g/min with VPA, p less than 0.05, corrected). Thirteen regions of interest (ROIs) were analyzed in each hemisphere in each PET scan. Metabolic rates were significantly lower in 15 of 26 ROIs with VPA (p less than 0.05, corrected). VPA depresses cerebral metabolism to a greater degree than do CBZ and phenytoin (PHT) but less than does phenobarbital (PB). The metabolic effect may be related to the mechanism of action and have neuropsychological implications.

Felbamate (FBM) is a novel antiepileptic drug (AED) currently undergoing clinical evaluation in the United States. During a controlled clinical trial conducted at the National Institutes of Health Clinical Center, FBM was added to constant carbamazepine (CBZ) monotherapy. CBZ total concentrations were reduced during active FBM treatment (mean reduction 25%, range 10-42%, p less than 0.001). The effect was evident after the first week of treatment and reached a plateau in 2-4 weeks. To clarify the interaction mechanism, free and total concentrations of CBZ and its plasma metabolites were determined by high-performance liquid chromatography (HPLC) and ultrafiltration in four patients. In these patients, FBM treatment reduced CBZ concentrations and increased CBZ-epoxide (CBZ-E) concentrations (p less than 0.01). Free fractions of all compounds were unmodified. FBM appears to be capable of inducing CBZ metabolism. CBZ-FBM interaction may be clinically relevant.

Using PET with [18-F]-2-deoxyglucose (FDG), we studied the effects of antiepileptic drugs on cerebral glucose metabolism. Serial scans were performed before and after the test drug was added to or removed from the patient's regimen. At least 3 weeks elapsed after achieving steady-state plasma levels when drugs were added, or after plasma levels were undetectable when drugs were tapered, before repeat scans were obtained. Only a single drug was changed between scans. In the phenobarbital (PB) study, the "on-drug" scan was performed first in each case. In this instance, a mean of 14 weeks elapsed between the time blood levels were undetectable and repeat scanning in order to avoid the possibility of withdrawal effects. Scanning in each group was performed 30 min after injection of 5 mCi of FDG, with EEG monitoring to exclude ictal activity. Regional glucose metabolic rates were calculated in 8 to 20 regions of interest. PB reduced LCMRglu in seven of eight regions studied, with a mean reduction over all regions of 37 +/- 3%. Phenytoin (PHT) reduced LCMRglu in only two of 10 regions (mean = 13%). We studied the effect of PHT on cerebellar metabolism in 42 patients using unpaired scans. Cerebellar LCMRglu was lower when patients were taking PHT at the time of scan, as well as in those who were taking PHT for 5 years or more, but the differences were not significant. There was a weak inverse correlation between PHT serum level and cerebellar LCMRglu in patients taking the drug at the time of scan (r = -0.36; 0.05 less than p less than 0.1).(ABSTRACT TRUNCATED AT 250 WORDS)

Seventy-four patients with intractable seizures were followed up 6 to 57 months (mean 25 months) after intensive monitoring. At discharge from the hospital, 59% of the patients had at least a 50% reduction in seizure frequency and 63% had decreased antiepileptic drug toxicity. The findings at follow-up compared with those at admission showed reduced seizure frequency in 55% of the patients, diminished medication toxicity in 54%, and improved social adjustment in 38%. A change in the seizure diagnosis was the best predictor of a favorable outcome. Patients with impaired mental status were not less likely to improve. The relationship between seizure type and outcome was not significant, although patients with complex partial seizures tended to be less likely to improve. Intensive monitoring can lead to significant long-lasting improvement of patients with severe epilepsy.