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Objective: To establish the utility of long-term electroencephalogram (EEG) in forecasting epilepsy onset in children with autism spectrum disorder (ASD)., Study Design: A single-institution, retrospective analysis of children with ASD, examining long-term overnight EEG recordings collected over a period of 15 years, was conducted. Clinical EEG findings, patient demographics, medical histories, and additional Autism Diagnostic Observation Schedule data were examined. Predictors for the timing of epilepsy onset were evaluated using survival analysis and Cox regression., Results: Among 151 patients, 17.2% (n = 26) developed unprovoked seizures (Sz group), while 82.8% (n = 125) did not (non-Sz group). The Sz group displayed a higher percentage of interictal epileptiform discharges (IEDs) in their initial EEGs compared with the non-Sz group (46.2% vs 20.0%, P = .01). The Sz group also exhibited a greater frequency of slowing (42.3% vs 13.6%, P < .01). The presence of IEDs or slowing predicted an earlier seizure onset, based on survival analysis. Multivariate Cox proportional hazards regression revealed that the presence of any IEDs (HR 3.83, 95% CI 1.38-10.65, P = .01) or any slowing (HR 2.78, 95% CI 1.02-7.58, P = .046 significantly increased the risk of developing unprovoked seizures., Conclusion: Long-term EEGs are valuable for predicting future epilepsy in children with ASD. These findings can guide clinicians in early education and potential interventions for epilepsy prevention., Competing Interests: Declaration of Competing Interest A.D. is supported by Uehara Memorial Foundation, and SENSHIN Medical Research Foundation to research abroad. H.N. is supported by the National Institute of Neurological Disorders and Stroke (NINDS) K23NS128318, the Sudha Neelakantan & Venky Harinarayan Charitable Fund, the Elsie and Isaac Fogelman Endowment, and the UCLA Children's Discovery and Innovation Institute (CDI) Junior Faculty Career Development Grant (#CDI-TTCF-07012021). R.S. serves on scientific advisory boards and speakers bureaus and has received honoraria and funding for travel from Eisai, Greenwich Biosciences, UCB Pharma, Sunovion, Supernus, Lundbeck Pharma, Liva Nova, West Therapeutics (advisory only); receives royalties from the publication of Pellock's Pediatric Neurology (Demos Publishing, 2016) and Epilepsy: Mechanisms, Models, and Translational Perspectives (CRC Press, 2011). S.H. has received research support from the John C. Hench Foundation, the CJDA Foundation, the Mohammed F. Alibrahim Endowment, the Elsie and Isaac Fogelman Endowment, the Epilepsy Therapy Project, the Milken Family Foundation, Paul Hughes Family Foundation, the Pediatric Epilepsy Research Foundation, Eisai, Bio-Pharm, Lundbeck, Insys, GW Pharmaceuticals, UCB Biopharma, Zogenix, Marinus, and the NIH. He has received compensation for service as a consultant to Amzell, Aquestive Therapeutics, Equilibre Biopharmaceuticals, Insys, GW Pharmaceuticals, Mallinckrodt, Marinus, MGC Pharmaceuticals, Radius, Shennox, UCB Biopharma, Upsher-Smith Laboratories, West Therapeutic Development, and Zogenix. The other authors declare no conflicts of interest. The funder/sponsor did not participate in the work., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Epilepsy has a peak incidence during the neonatal to early childhood period. These early onset epilepsies may be severe conditions frequently associated with comorbidities such as developmental deficits and intellectual disability and, in a significant percentage of patients, may be medication-resistant. The use of adult rodent models in the exploration of mechanisms and treatments for early life epilepsies is challenging, as it ignores significant age-specific developmental differences. More recently, models developed in immature animals, such as rodent pups, or in three-dimensional organoids may more closely model aspects of the immature brain and could result in more translatable findings. Although models are not perfect, they may offer a more controlled screening platform in studies of mechanisms and treatments, which cannot be done in pediatric patient cohorts. On the other hand, more simplified models with higher throughput capacities are required to deal with the large number of epilepsy candidate genes and the need for new treatment options. Therefore, a combination of different modeling approaches will be beneficial in addressing the unmet needs of pediatric epilepsy patients. In this review, we summarize the discussions on this topic that occurred during the XVI Workshop on Neurobiology of Epilepsy, organized in 2022 by the Neurobiology Commission of the International League Against Epilepsy. We provide an overview of selected models of early onset epilepsies, discussing their advantages and disadvantages. Heterologous expression models provide initial functional insights, and zebrafish, rodent models, and brain organoids present increasingly complex platforms for modeling and validating epilepsy-related phenomena. Together, these models offer valuable insights into early onset epilepsies and accelerate hypothesis generation and therapy discovery., (© 2024 International League Against Epilepsy.)

Epilepsy's myriad causes and clinical presentations ensure that accurate diagnoses and targeted treatments remain a challenge. Advanced neurotechnologies are needed to better characterize individual patients across multiple modalities and analytical techniques. At the XVIth Workshop on Neurobiology of Epilepsy: Early Onset Epilepsies: Neurobiology and Novel Therapeutic Strategies (WONOEP 2022), the session on "advanced tools" highlighted a range of approaches, from molecular phenotyping of genetic epilepsy models and resected tissue samples to imaging-guided localization of epileptogenic tissue for surgical resection of focal malformations. These tools integrate cutting edge research, clinical data acquisition, and advanced computational methods to leverage the rich information contained within increasingly large datasets. A number of common challenges and opportunities emerged, including the need for multidisciplinary collaboration, multimodal integration, potential ethical challenges, and the multistage path to clinical translation. Despite these challenges, advanced epilepsy neurotechnologies offer the potential to improve our understanding of the underlying causes of epilepsy and our capacity to provide patient-specific treatment., (© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: This study aimed to explore sensitive detection methods for pathological high-frequency oscillations (HFOs) to improve seizure outcomes in epilepsy surgery., Methods: We analyzed interictal HFOs (80-500 Hz) in 15 children with medication-resistant focal epilepsy who underwent chronic intracranial electroencephalogram via subdural grids. The HFOs were assessed using the short-term energy (STE) and Montreal Neurological Institute (MNI) detectors and examined for spike association and time-frequency plot characteristics. A deep learning (DL)-based classification was applied to purify pathological HFOs. Postoperative seizure outcomes were correlated with HFO-resection ratios to determine the optimal HFO detection method., Results: The MNI detector identified a higher percentage of pathological HFOs than the STE detector, but some pathological HFOs were detected only by the STE detector. HFOs detected by both detectors had the highest spike association rate. The Union detector, which detects HFOs identified by either the MNI or STE detector, outperformed other detectors in predicting postoperative seizure outcomes using HFO-resection ratios before and after DL-based purification., Conclusions: HFOs detected by standard automated detectors displayed different signal and morphological characteristics. DL-based classification effectively purified pathological HFOs., Significance: Enhancing the detection and classification methods of HFOs will improve their utility in predicting postoperative seizure outcomes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: To characterize ictal EEG change in the centromedian (CM) and anterior nucleus (AN) of the thalamus, using stereoelectroencephalography (SEEG) recordings., Methods: Forty habitual seizures were analyzed in nine patients with pediatric-onset neocortical drug-resistant epilepsy who underwent SEEG (age 2-25 y) with thalamic coverage. Both visual and quantitative analysis was used to evaluate ictal EEG signal in the cortex and thalamus. The amplitude and cortico-thalamic latencies of broadband frequencies at ictal onset were measured., Results: Visual analysis demonstrated consistent detection of ictal EEG changes in both the CM nucleus and AN nucleus with latency to thalamic ictal EEG changes of less than 400 ms in 95% of seizures, with low-voltage fast activity being the most common ictal pattern. Quantitative broadband amplitude analysis showed consistent power changes across the frequency bands, corresponding to ictal EEG onset, while while ictal EEG latency was variable from -18.0 seconds to 13.2 seconds. There was no significant difference between detection of CM and AN ictal activity on visual or amplitude analysis. Four patients with subsequent thalamic responsive neurostimulation (RNS) demonstrated ictal EEG changes consistent with SEEG findings., Conclusions: Ictal EEG changes were consistently seen at the CM and AN of the thalamus during neocortical seizures., Significance: It may be feasible to use a closed-loop system in the thalamus to detect and modulate seizure activity for neocortical epilepsy., (Copyright © 2023 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective. Intracranially-recorded interictal high-frequency oscillations (HFOs) have been proposed as a promising spatial biomarker of the epileptogenic zone. However, HFOs can also be recorded in the healthy brain regions, which complicates the interpretation of HFOs. The present study aimed to characterize salient features of physiological HFOs using deep learning (DL). Approach. We studied children with neocortical epilepsy who underwent intracranial strip/grid evaluation. Time-series EEG data were transformed into DL training inputs. The eloquent cortex (EC) was defined by functional cortical mapping and used as a DL label. Morphological characteristics of HFOs obtained from EC (ecHFOs) were distilled and interpreted through a novel weakly supervised DL model. Main results. A total of 63 379 interictal intracranially-recorded HFOs from 18 children were analyzed. The ecHFOs had lower amplitude throughout the 80-500 Hz frequency band around the HFO onset and also had a lower signal amplitude in the low frequency band throughout a one-second time window than non-ecHFOs, resembling a bell-shaped template in the time-frequency map. A minority of ecHFOs were HFOs with spikes (22.9%). Such morphological characteristics were confirmed to influence DL model prediction via perturbation analyses. Using the resection ratio (removed HFOs/detected HFOs) of non-ecHFOs, the prediction of postoperative seizure outcomes improved compared to using uncorrected HFOs (area under the ROC curve of 0.82, increased from 0.76). Significance. We characterized salient features of physiological HFOs using a DL algorithm. Our results suggested that this DL-based HFO classification, once trained, might help separate physiological from pathological HFOs, and efficiently guide surgical resection using HFOs., (© 2022 IOP Publishing Ltd.)

It has been well established that traumatic brain injury (TBI) modifies the composition of gut microbiome. Epilepsy, which represents one of the common sequelae of TBI, has been associated with dysbiosis. Earlier study showed that the risk of post-traumatic epilepsy (PTE) after lateral fluid percussion injury (LFPI) in rats can be stratified based on pre-existing (i.e., pre-TBI) gut microbiome profile. In the present study, we examined whether fecal microbiota transfer (FMT) from naïve rats with different prospective histories of PTE would affect the trajectory of PTE in recipients. Fecal samples were collected from naïve adult male Sprague-Dawley rats, followed by LFPI. Seven months later, upon four weeks of vide-EEG monitoring (vEEG), the rats were categorized as those with and without PTE. Recipients were subjected to LFPI, followed by FMT from donors with and without impending PTE. Control groups included auto-FMT and no-FMT subjects. Seven month after LFPI, recipients underwent four-week vEEG to detect spontaneous seizures. After completing vEEG, rats of all groups underwent kindling of basolateral amygdala. Fecal microbiota transfer from donors with impending PTE exerted mild-to-moderate pro-epileptic effects in recipients, evident as marginal increase in multiple spontaneous seizure incidence, and facilitation of kindling. Analysis of fecal samples in selected recipients and their respective donors confirmed that FMT modified microbiota in recipients along the donors' lines, albeit without full microbiome conversion. The findings provide further evidence that gut microbiome may actively modulate the susceptibility to epilepsy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interest or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

This study assessed the effectiveness of genetic testing in shortening the time to diagnosis of late infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease. Individuals who received epilepsy gene panel testing through Behind the Seizure ® , a sponsored genetic testing program (Cohort A), were compared to children outside of the sponsored testing program during the same period (Cohort B). Two cohorts were analyzed: children aged ≥24 to ≤60 months with unprovoked seizure onset at ≥24 months between December 2016 and January 2020 (Cohort 1) and children aged 0 to ≤60 months at time of testing with unprovoked seizure onset at any age between February 2019 and January 2020 (Cohort 2). The diagnostic yield in Cohort 1A (n = 1814) was 8.4% (n = 153). The TPP1 diagnostic yield within Cohort 1A was 2.9-fold higher compared to Cohort 1B (1.0%, n = 18/1814 vs. .35%, n = 8/2303; p = .0157). The average time from first symptom to CLN2 disease diagnosis was significantly shorter than previously reported (9.8 vs. 22.7 months, p < .001). These findings indicate that facilitated access to early epilepsy gene panel testing helps to increase diagnostic yield for CLN2 disease and shortens the time to diagnosis, enabling earlier intervention., (© 2022 Invitae Corporation. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: We examined whether posttraumatic epilepsy (PTE) is associated with measurable perturbations in gut microbiome., Methods: Adult Sprague Dawley rats were subjected to lateral fluid percussion injury (LFPI). PTE was examined 7 months after LFPI, during 4-week continuous video-electroencephalographic monitoring. 16S ribosomal RNA gene sequencing was performed in fecal samples collected before LFPI/sham-LFPI and 1 week, 1 month, and 7 months thereafter. Longitudinal analyses of alpha diversity, beta diversity, and differential microbial abundance were performed. Short-chain fatty acids (SCFAs) were measured in fecal samples collected before LFPI by liquid chromatography with tandem mass spectrometry., Results: Alpha diversity changed over time in both LFPI and sham-LFPI subjects; no association was observed between alpha diversity and LFPI, the severity of post-LFPI neuromotor impairments, and PTE. LFPI produced significant changes in beta diversity and selective changes in microbial abundances associated with the severity of neuromotor impairments. No association between LFPI-dependent microbial perturbations and PTE was detected. PTE was associated with beta diversity irrespective of timepoint vis-à-vis LFPI, including at baseline. Preexistent fecal microbial abundances of four amplicon sequence variants belonging to the Lachnospiraceae family (three enriched and one depleted) predicted the risk of PTE, with area under the curve (AUC) of .73. Global SCFA content was associated with the increased risk of PTE, with AUC of .722, and with 2-methylbutyric (depleted), valeric (depleted), isobutyric (enriched), and isovaleric (enriched) acids being the most important factors (AUC = .717). When the analyses of baseline microbial and SCFA compositions were combined, AUC to predict PTE increased to .78., Significance: Whereas LFPI produces no perturbations in the gut microbiome that are associated with PTE, the risk of PTE can be stratified based on preexistent microbial abundances and SCFA content., (© 2022 International League Against Epilepsy.)

Lateral fluid percussion injury (LFPI) in rats is used to model post-traumatic epilepsy (PTE), with spontaneous seizures occurring in up to ½ of the subjects. Using the kindling paradigm, we examined whether animals without detectable seizures had an altered seizure susceptibility. Male Sprague Dawley rats were subjected to LFPI. Seven-nine months later, spontaneous seizures were monitored for two weeks. Afterward, the animals underwent kindling of basolateral amygdala. For kindling outcomes, the animals were categorized based on the 95% confidence intervals of mean number trials to kindling (ie 3 consecutive stage 4-5 seizures). Spontaneous seizures were detected in 7 out of 24 rats. There was no correlation between the severity of LFPI and either baseline afterdischarge properties, or kindling rates. Six LFPI rats kindled at a rate comparable to those in sham-LFPI (n = 10) and in naïve (n = 7) subjects. Ten LFPI rats kindled faster and 8-slower than controls. None of slow-kindling rats had spontaneous seizures during the prekindling monitoring. During the same period, six fast-kindling and three normal-kindling rats had been seizure-free. Thus, kindling reveals a diversity to seizure susceptibility after LFPI beyond an overt seizure symptomatology, ranging from the increased susceptibility to the increased resistance., (© 2021 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Purpose: Epileptic spasms are often preceded by focal (or multifocal) seizures. Based on a series of case reports suggesting that carbamazepine and oxcarbazepine may induce epileptic spasms, we set out to rigorously evaluate the potential association between exposure to voltage-gated sodium channel blockade and latency to epileptic spasms., Methods: We identified 50 cases (children with focal seizures and evolution to epileptic spasms) and 50 controls (children with focal seizures without evolution to epileptic spasms). For each patient, we reviewed all sequential neurology encounters between onset of epilepsy and emergence of epileptic spasms. For each encounter we recorded seizure-frequency and all anti-seizure therapy exposures. Using multivariable Cox proportional hazards regression, we evaluated the association between voltage-gated sodium channel exposure (carbamazepine, oxcarbazepine, lacosamide, or phenytoin) and latency to epileptic spasms onset, with adjustment for etiology and seizure-frequency., Results: Latency to epileptic spasms onset was independently associated with exposure to sodium channel blockade (hazard ratio = 2.4; 95% CI 1.1-5.2; P = 0.03) and high-risk etiology (hazard ratio = 2.8; 95% CI 1.5-5.1; P = 0.001). With assessment for interaction between sodium channel blockade and etiology, we identified an estimated 7-fold increased risk of epileptic spasms with the combination of sodium channel blockade and high-risk etiology (hazard ratio = 7.0, 95% CI 2.5-19.8; P < 0.001)., Conclusion: This study suggests that voltage-gated sodium channel blockade may induce epileptic spasms among children at risk on the basis of etiology. Further study is warranted to replicate these findings, ascertain possible drug- and dose-specific risks, and identify potential mechanisms of harm., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Several small case series provide conflicting impressions of the efficacy of felbamate for treatment of epileptic spasms. Using a large single-center cohort of children with epileptic spasms, we retrospectively evaluated the efficacy and safety of felbamate. We identified all patients with video-EEG confirmed epileptic spasms who were treated with felbamate at our center. We quantified felbamate exposure by calculating peak and weighted-average weight-based dose. Clinical response was defined as resolution of epileptic spasms for at least 28 days, beginning not more than 3 months after felbamate initiation. Electroclinical response was defined as clinical response accompanied by overnight video-EEG demonstrating freedom from epileptic spasms and hypsarrhythmia. Among a cohort of 476 infants, we identified 62 children who were treated with felbamate, of whom 58 had previously failed treatment with hormonal therapy or vigabatrin. Median peak and weighted-average felbamate dosages were 47 and 40 mg/kg/day, respectively. Five (8%) children were classified as clinical responders and two (3%) children were classified as electroclinical responders. Among 17 patients with latency from epileptic spasms onset to felbamate initiation of less than 12 months, we observed 4 (24%) clinical responders. This study suggests that felbamate may be efficacious for treatment of epileptic spasms and that further rigorous study is warranted., Competing Interests: Declaration of Competing Interest Dr. Hussain has received research support from the Epilepsy Therapy Project, the Milken Family Foundation, the Hughes Family Foundation, the Elsie and Isaac Fogelman Endowment, Eisai, Lundbeck, Insys, GW Pharma, UCB Biopharma, Zogenix, and the NIH (R34MH089299). He has received honoraria for service on the scientific advisory boards of Mallinckrodt, Upsher-Smith Laboratories, Insys, UCB Biopharma, and Zogenix; as a consultant to UCB, Mallinckrodt, Insys, GW Pharma, West Therapeutic Development, Aquestive Therapeutics, Shennox, and Amzell; and on the speaker’s bureau for Mallinckrodt and GW Pharmaceuticals. Dr. Rajaraman has received research support from Marinus and the International CDKL5 Research Foundation. Dr. Shrey has received research support from the Lennox-Gastaut Syndrome Foundation, UCB Biopharma, and Mallinckrodt, as well as the CHOC Children’s Physician Subspecialty Faculty Tithe Fund and the CHOC Children’s Physician Scientist Scholars Program. Dr. Sankar serves on scientific advisory boards or serves on the speaker’s bureau for and has received honoraria and funding for travel from Eisai, UCB Pharma, Sunovion, Supernus, Greenwich Biosciences, LivaNova, and on the advisory boards for Aquestive Therapeutics, West Therapeutic Development, Insys Development Company, and Zogenix; receives royalties from the publication of Pellock’s Pediatric Epilepsy, 4th ed. (Demos Publishing, 2016) and Epilepsy: Mechanisms, Models, and Translational Perspectives (CRC Press, 2011); serves on speakers’ bureaus for and has received speaker honoraria from Eisai, UCB, GlaxoSmithKline, LivaNova, Supernus, and BioMarin. He has received research support from SK Life Sciences and Insys Development Company, Inc. The remaining authors report no conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The brain is a complex system composed of networks of interacting elements, from genes to circuits, whose function (and dysfunction) is not derivable from the superposition of individual components. Epilepsy is frequently described as a network disease, but to date, there is no standardized framework within which network concepts applicable to all levels from genes to whole brain can be used to generate deeper insights into the pathogenesis of seizures or the associated morbidities. To address this shortcoming, the Neurobiology Commission of the International League Against Epilepsy dedicated a Workshop on Neurobiology of Epilepsy (XIV WONOEP 2017) with the aim of formalizing network concepts as they apply to epilepsy and to critically discuss whether and how such concepts could augment current research endeavors. Here, we review concepts and strategies derived by considering epilepsy as a disease of different network hierarchies that range from genes to clinical phenotypes. We propose that the concept of networks is important for understanding epilepsy and is critical for developing new study designs. These approaches could ultimately facilitate the development of novel diagnostic and therapeutic strategies., (Wiley Periodicals, Inc. © 2018 International League Against Epilepsy.)

Objectives: We aim to establish that interictal fast ripples (FR; 250-500 Hz) are detectable on scalp EEG, and to investigate their association to epilepsy., Methods: Scalp EEG recordings of a subset of children with tuberous sclerosis complex (TSC)-associated epilepsy from two large multicenter observational TSC studies were analyzed and compared to control children without epilepsy or any other brain-based diagnoses. FR were identified both by human visual review and compared with semi-automated review utilizing a deep learning-based FR detector., Results: Seven out of 7 children with TSC-associated epilepsy had scalp FR compared to 0 out of 4 children in the control group (p = 0.003). The automatic detector has a sensitivity of 98% and false positive rate with average of 11.2 false positives per minute., Conclusions: Non-invasive detection of interictal scalp FR was feasible, by both visual and semi-automatic detection. Interictal scalp FR occurred exclusively in children with TSC-associated epilepsy and were absent in controls without epilepsy. The proposed detector achieves high sensitivity of FR detection; however, expert review of the results to reduce false positives is advised., Significance: Interictal FR are detectable on scalp EEG and may potentially serve as a biomarker of epilepsy in children with TSC., (Copyright © 2018 International Federation of Clinical Neurophysiology. All rights reserved.)

Anxiety is one of the most common comorbidities of epilepsy, which has major detrimental effects on the quality of life. Generalized anxiety disorder (GAD) associated with epilepsy has been receiving most attention. However, several other forms of anxiety reportedly present in patients with epilepsy, including panic disorder (PD). In this study, using an animal model of limbic epilepsy, we examined the interplay between epilepsy and panic-like behavior (PLB). Further, considering the high degree of comorbidity between depression on the one hand, and both epilepsy and PD on the other hand, we studied whether and how the presence of PLB in animals with epilepsy would affect their performance in depression-relevant tests. Fifty-day-old male Wistar rats were subjected to repeated alternating electrical stimulations of the basolateral amygdala (BLA) to induce kindling of limbic seizures, and the dorsal periaqueductal gray (DPAG) to induce panic-like episodes. Seizure susceptibility and panic reaction threshold were examined before the first and 24h after the last stimulation. At the end of the stimulations, the rats were examined in depression-relevant tests: saccharin preference test (SPT) for anhedonia and forced swimming test (FST) for despair/hopelessness. With regard to kindling, BLA+DPAG stimulation induced more profound increase of seizure susceptibility than BLA stimulation alone (evident as the reduction of the afterdischarge threshold and the increase of the afterdischarge duration). With regard to PLB, the BLA+DPAG stimulation exacerbated the severity of panic-like episodes, as compared with the DPAG stimulation alone. Basolateral amygdala stimulation alone had no effects on panic-like reactions, and DPAG stimulation alone did not modify kindling epileptogenesis. Combined stimulation of BLA and DPAG induced depressive-like behavioral impairments. This is the first experimental study showing bidirectional, mutually exacerbating effect of epilepsy and PLB, and the precipitation of depressive-like state by the epilepsy-PLB comorbidity., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The objective was to determine whether the depression comorbid with epilepsy could be predicted based on inherent premorbid patterns of monoaminergic transmission. In male Wistar rats, despair-like and anhedonia-like behaviors were examined using forced swimming and taste preference tests, respectively. Serotonergic raphe nucleus (RN)-prefrontal cortex (PFC) and dopaminergic ventral tegmental area (VTA)-nucleus accumbens (NAcc) pathways were interrogated by fast scan cyclic voltammetry (FSCV). The assays were performed before and 2 months after pilocarpine status epilepticus. In a subset of naive rats, FSCV, coupled with the intensity-dependent stimulation paradigm, detected specific deviations in each pathway (six rats for RN-PFC and seven rats for VTA-NAcc, with overlap in two, of 19 total subjects) in the absence of behavioral impairments. During epilepsy, animals with preexisting deviations in RN-PFC invariably developed despair, and rats with deviations in VTA-NAcc developed anhedonia. Serotonergic and dopaminergic pathways, respectively, showed signs of explicit deterioration. We suggest that epilepsy triggers decompensations in the already vulnerable depression-relevant neuronal circuits, which culminate in depression. The established connection between the identified specific signatures in monoamine transmission in naive rats and specific symptoms of epilepsy-associated depression may help in understanding causes of comorbidity and in developing its early biomarkers., (Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.)

Neurologic and psychiatric comorbidities are common in patients with epilepsy. Diagnostic, predictive, and pharmacodynamic biomarkers of such comorbidities do not exist. They may share pathogenetic mechanisms with epileptogenesis/ictogenesis, and as such are an unmet clinical need. The objectives of the subgroup on biomarkers of comorbidities at the XIII Workshop on the Neurobiology of Epilepsy (WONOEP) were to present the state-of-the-art recent research findings in the field that highlighting potential biomarkers for comorbidities in epilepsy. We review recent progress in the field, including molecular, imaging, and genetic biomarkers of comorbidities as discussed during the WONOEP meeting on August 31-September 4, 2015, in Heybeliada Island (Istanbul, Turkey). We further highlight new directions and concepts from studies on comorbidities and potential new biomarkers for the prediction, diagnosis, and treatment of epilepsy-associated comorbidities. The activation of various molecular signaling pathways such as the "Janus Kinase/Signal Transducer and Activator of Transcription," "mammalian Target of Rapamycin," and oxidative stress have been shown to correlate with the presence and severity of subsequent cognitive abnormalities. Furthermore, dysfunction in serotonergic transmission, hyperactivity of the hypothalamic-pituitary-adrenocortical axis, the role of the inflammatory cytokines, and the contributions of genetic factors have all recently been regarded as relevant for understanding epilepsy-associated depression and cognitive deficits. Recent evidence supports the utility of imaging studies as potential biomarkers. The role of such biomarker may be far beyond the diagnosis of comorbidities, as accumulating clinical data indicate that comorbidities can predict epilepsy outcomes. Future research is required to reveal whether molecular changes in specific signaling pathways or advanced imaging techniques could be detected in the clinical settings and correlate with epilepsy-associated comorbidities. A reliable biomarker will allow a more accurate diagnosis and improved treatment of epilepsy-associated comorbidities., (Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.)

The importance of comorbidities in determining the quality of life of individuals with epilepsy and their families has received increasing attention in the past decade. Along with it has come a recognition that in some individuals, certain comorbidities may have preexisted, and may have contributed to their developing epilepsy. Many mechanisms are capable of interconnecting different dysfunctions that manifest as distinct disorders, often diagnosed and managed by different specialists. We review the human data from the perspective of epidemiology as well as insights gathered from neurodiagnostic and endocrine studies. Animal studies are reviewed to refine our mechanistic understanding of the connections, because they permit the narrowing of variables, which is not possible when studying humans., (Copyright © 2016 Cold Spring Harbor Laboratory Press; all rights reserved.)

Maternal immune activation (MIA) results in the development of autism in the offspring via hyperactivation of IL-6 signaling. Furthermore, experimental studies showed that the MIA-associated activation of interleukin-1β (IL-1β) concurrently with IL-6 increases the rate and the severity of hippocampal kindling in mice, thus, offering an explanation for autism-epilepsy comorbidity. We examined whether epileptic phenotype triggered by prenatal exposure to IL-6 and IL-1β combination is restricted to kindling or whether it is reproducible in another model of epilepsy, whereby spontaneous seizures develop following kainic acid (KA)-induced status epilepticus. We also examined whether in mice prenatally exposed to IL-6 and IL-6+IL-1β, the presence of spontaneous seizures would exacerbate autism-like features. Between days 12 and 16 of pregnancy, C57BL/6J mice received daily injections of IL-6, IL-1β, or IL-6+IL-1β combination. At postnatal day 40, male offspring were examined for the presence of social behavioral deficit, and status epilepticus was induced by intrahippocampal KA injection. After 6weeks of monitoring for spontaneous seizures, sociability was tested again. Both IL-6 and IL-6+IL-1β offspring presented with social behavioral deficit. Prenatal exposure to IL-6 alleviated, while such exposure to IL-6+IL-1β exacerbated, the severity of KA-induced epilepsy. Increased severity of epilepsy in the IL-6+IL-1β mice correlated with the improvement of autism-like behavior. We conclude that complex and not necessarily agonistic relationships exist between epileptic and autism-like phenotypes in an animal model of MIA coupled with KA-induced epilepsy and that the nature of these relationships depends on components of MIA involved., (Copyright © 2015 Elsevier Inc. All rights reserved.)

There is a great need for safe and effective therapies for treatment of infantile spasms (IS) and Lennox-Gastaut syndrome (LGS). Based on anecdotal reports and limited experience in an open-label trial, cannabidiol (CBD) has received tremendous attention as a potential treatment for pediatric epilepsy, especially Dravet syndrome. However, there is scant evidence of specific utility for treatment of IS and LGS. We sought to document the experiences of children with IS and/or LGS who have been treated with CBD-enriched cannabis preparations. We conducted a brief online survey of parents who administered CBD-enriched cannabis preparations for the treatment of their children's epilepsy. We specifically recruited parents of children with IS and LGS and focused on perceived efficacy, dosage, and tolerability. Survey respondents included 117 parents of children with epilepsy (including 53 with IS or LGS) who had administered CBD products to their children. Perceived efficacy and tolerability were similar across etiologic subgroups. Eighty-five percent of all parents reported a reduction in seizure frequency, and 14% reported complete seizure freedom. Epilepsy was characterized as highly refractory with median latency from epilepsy onset to CBD initiation of five years, during which the patient's seizures failed to improve after a median of eight antiseizure medication trials. The median duration and the median dosage of CBD exposure were 6.8 months and 4.3mg/kg/day, respectively. Reported side effects were far less common during CBD exposure, with the exception of increased appetite (30%). A high proportion of respondents reported improvement in sleep (53%), alertness (71%), and mood (63%) during CBD therapy. Although this study suggests a potential role for CBD in the treatment of refractory childhood epilepsy including IS and LGS, it does not represent compelling evidence of efficacy or safety. From a methodological standpoint, this study is extraordinarily vulnerable to participation bias and limited by lack of blinded outcome ascertainment. Appropriately controlled clinical trials are essential to establish efficacy and safety., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Introduction: In treating refractory epilepsy, many clinicians are interested in methods used to transition patients receiving clonazepam to clobazam to maintain or increase seizure control, improve tolerability of patients' overall drug therapy regimens, and to enhance quality of life for patients and their families. However, no published guidelines assist clinicians in successfully accomplishing this change safely., Case Presentations: The following three case reports provide insight into the transition from clonazepam to clobazam. First, an 8-year-old Caucasian boy with cryptogenic Lennox-Gastaut syndrome beginning at 3.5 years of age, who was experiencing multiple daily generalized tonic-clonic, absence, myoclonic, and tonic seizures at presentation. Second, a 25-year-old, left-handed, White Hispanic man with moderate mental retardation and medically refractory seizures that he began experiencing at 1 year of age, secondary to tuberous sclerosis. When first presented to an epilepsy center, he had been receiving levetiracetam, valproate, and clonazepam, but reported having ongoing and frequent seizures. Third, a 69-year-old Korean woman who had been healthy until she had a stroke in 2009 with subsequent right hemiparesis; as a result, she became less physically and socially active, and had her first convulsive seizure approximately 4 months after the stroke., Conclusions: From these cases, we observe that a rough estimate of final clobazam dosage for each mg of clonazepam under substitution is likely to be at least 10-fold, probably closer to 15-fold for many patients, and as high as 20-fold for a few. Consideration and discussion of the pharmacokinetic, pharmacologic, and clinical properties of 1,4- and 1,5-benzodiazepine action provide a rationale on why and how these transitions were successful.

Attention deficit/hyperactivity disorder (ADHD) is encountered among patients with epilepsy at a significantly higher rate than in the general population. Mechanisms of epilepsy-ADHD comorbidity remain largely unknown. We investigated whether a model of chronic epilepsy in rats produces signs of ADHD, and thus, whether it can be used for studying mechanisms of this comorbidity. Epilepsy was induced in male Wistar rats via pilocarpine status epilepticus. Half of the animals exhibited chronic ADHD-like abnormalities, particularly increased impulsivity and diminished attention in the lateralized reaction-time task. These impairments correlated with the suppressed noradrenergic transmission in locus coeruleus outputs. The other half of animals exhibited depressive behavior in the forced swimming test congruently with the diminished serotonergic transmission in raphe nucleus outputs. Attention deficit/hyperactivity disorder and depressive behavior appeared mutually exclusive. Therefore, the pilocarpine model of epilepsy affords a system for reproducing and studying mechanisms of comorbidity between epilepsy and both ADHD and/or depression., (© 2013.)

Background: It is unclear if socioeconomic factors like type of insurance influence time to referral and developmental outcomes for pediatric patients undergoing epilepsy surgery., Objective: This study determined whether private compared with state government insurance was associated with shorter intervals of seizure onset to surgery and better developmental quotients for pediatric patients undergoing epilepsy surgery., Methods: A consecutive cohort (n = 420) of pediatric patients undergoing epilepsy surgery were retrospectively categorized into those with Medicaid (California Children's Services; n = 91) or private (Preferred Provider Organization, Health Maintenance Organization, Indemnity; n = 329) insurance. Intervals from seizure onset to referral and surgery and Vineland developmental assessments were compared by insurance type with the use of log-rank tests., Results: Compared with private insurance, children with Medicaid had longer intervals from seizure onset to referral for evaluation (log-rank test, P = .034), and from seizure onset to surgery (P = .017). In a subset (25%) that had Vineland assessments, children with Medicaid compared with private insurance had lower Vineland scores presurgery (P = .042) and postsurgery (P = .003). Type of insurance was not associated with seizure severity, types of operations, etiology, postsurgical seizure-free outcomes, and complication rate., Conclusion: Compared with Medicaid, children with private insurance had shorter intervals from seizure onset to referral and to epilepsy surgery, and this was associated with lower Vineland scores before surgery. These findings may reflect delayed access for uninsured children who eventually obtained state insurance. Reasons for the delay and whether longer intervals before epilepsy surgery affect long-term cognitive and developmental outcomes warrant further prospective investigations.

Objective: Maternal immune activation (MIA) triggered by infections has been identified as a cause of autism in offspring. Considering the involvement of perturbations in innate immunity in epilepsy, we examined whether MIA represents a risk factor for epilepsy as well. The role of specific MIA components interleukin (IL)-6 and IL-1β was also addressed., Methods: MIA was induced in C57BL/6 mice by polyinosinic-polycytidylic acid (PIC) injected during embryonic days 12 to 16. Beginning from postnatal day 40, the propensity of the offspring to epilepsy was examined using hippocampal kindling; autismlike behavior was studied using the sociability test. The involvement of IL-6 and IL-1β in PIC-induced effects was studied by the coadministration of the cytokine antibodies with PIC, and by delivering recombinant cytokines in lieu of PIC., Results: The offspring of PIC-exposed mice exhibited increased hippocampal excitability, accelerated kindling rate, prolonged increase of seizure susceptibility after kindling, and diminished sociability. Epileptic impairments were abolished by antibodies to IL-6 or IL-1β. Neither of the recombinant cytokines alone increased the propensity to seizures; however, when combined, they produced effects similar to those induced by PIC. PIC-induced behavioral deficits were abolished by IL-6 antibodies and were mimicked by recombinant IL-6; IL-1β was not involved., Interpretation: In addition to confirming the previously established critical role of IL-6 in the development of autismlike behavior following MIA, the present study shows that concurrent involvement of IL-6 and IL-1β is required for priming the offspring for epilepsy. These data shed light on mechanisms of comorbidity between autism and epilepsy., (© 2013 American Neurological Association.)

Objective: To identify clinical and nonclinical factors associated with time from epilepsy onset to surgical evaluation and treatment among a cohort of children having epilepsy surgery., Methods: Data were abstracted from records of 430 children (younger than 18 years) who had epilepsy neurosurgery at the University of California, Los Angeles from 1986 to 2010. Multivariable Cox proportional hazards models were used to analyze unique associations of clinical severity, pre-referral brain MRI, and sociodemographic characteristics with time to surgery., Results: Shorter time to surgery was associated with active (hazard ratio [HR] 5.67, 95% confidence interval [CI] 3.74-8.70) and successfully treated infantile spasms (HR 2.20, 95% CI 1.63-2.96); daily or more seizures (HR 2.09, 95% CI 1.58-2.76); MRI before referral regardless of imaging findings (HR 1.95, 95% CI 1.47-2.58); private insurance (HR 1.54, 95% CI 1.14-2.09); and Hispanic ethnicity (HR 1.38, 95% CI 1.01-1.87). There were race/ethnicity by insurance interactions (log-rank p = 0.049) with shortest time to surgery for Hispanic children with private insurance., Conclusions: Shorter intervals to surgical treatment were associated with greater epilepsy severity and insurance type, consistent with existing literature. However, associations of shorter times to treatment with having a brain MRI before referral and Hispanic ethnicity were unexpected and warrant further investigation. More knowledgeable referring providers and parents with greater help-seeking capability may explain obtaining an MRI before referral. Shorter intervals to surgery among Hispanic children may relate to the same factors yielding an increased volume of Hispanic children receiving surgery at the University of California, Los Angeles since 2000.

Object: Low income, government insurance, and minority status are associated with delayed treatment for neurosurgery patients. Less is known about the influence of referral location and how socioeconomic factors and referral patterns evolve over time. For pediatric epilepsy surgery patients at the University of California, Los Angeles (UCLA), this study determined how referral location and sociodemographic features have evolved over 25 years., Methods: Children undergoing epilepsy neurosurgery at UCLA (453 patients) were classified by location of residence and compared with clinical epilepsy and sociodemographic factors., Results: From 1986 to 2010, referrals from Southern California increased (+33%) and referrals from outside of California decreased (-19%). Over the same period, the number of patients with preferred provider organization (PPO) and health maintenance organization (HMO) insurance increased (+148% and +69%, respectively) and indemnity insurance decreased (-96%). Likewise, the number of Hispanics (+117%) and Asians (100%) increased and Caucasians/whites decreased (-24%). The number of insurance companies decreased from 52 carriers per 100 surgical patients in 1986-1990 to 19 per 100 in 2006-2010. Patients living in the Eastern US had a younger age at surgery (-46%), shorter intervals from seizure onset to referral for evaluation (-28%) and from presurgical evaluation to surgery (-61%) compared with patients from Southern California. The interval from seizure onset to evaluation was shorter (-33%) for patients from Los Angeles County compared with those living in non-California Western US states., Conclusions: Referral locations evolved over 25 years at UCLA, with more cases coming from local regions; the percentage of minority patients also increased. The interval from seizures onset to surgery was shortest for patients living farthest from UCLA but still within the US. Geographic location and race/ethnicity was not associated with differences in becoming seizure free after epilepsy surgery in children.

Background: It is unclear whether long-term seizure outcomes in children are similar to those in adult epilepsy surgery patients., Objective: To determine 5-year outcomes and antiepilepsy drug (AED) use in pediatric epilepsy surgery patients from a single institution., Methods: The cohort consisted of children younger than 18 years of age whose 5-year outcome data would have been available by 2010. Comparisons were made between patients with and without 5-year data (n = 338), patients with 5-year data for seizure outcome (n = 257), and seizure-free patients on and off AEDs (n = 137)., Results: Five-year data were available from 76% of patients. More seizure-free patients with focal resections for hippocampal sclerosis and tumors lacked 5-year data compared with other cases. Of those with 5-year data, 53% were continuously seizure free, 18% had late seizure recurrence, 3% became seizure free after initial failure, and 25% were never seizure free. Patients were more likely to be continuously seizure free if their surgery was performed during the period 2001 to 2005 (68%) compared with surgery performed from 1996 to 2000 (61%), 1991 to 1995 (36%), and 1986 to 1990 (46%). More patients had 1 or fewer seizures per month in the late seizure recurrence (47%) compared with the not seizure-free group (20%). Four late deaths occurred in the not seizure-free group compared with 1 in the seizure-free group. Of patients who were continuously seizure free, 55% were not taking AEDs, and more cortical dysplasia patients (74%) had stopped taking AEDs compared with hemimegalencephaly patients (18%)., Conclusion: In children, 5-year outcomes improved over 20 years of clinical experience. Our results are similar to those of adult epilepsy surgery patients despite mostly extratemporal and hemispheric operations for diverse developmental etiologies.

Depression represents a common comorbidity of epilepsy and is frequently resistant to selective serotonin reuptake inhibitors (SSRI). We tested the hypothesis that the SSRI resistance in epilepsy associated depression may be a result of a pathologically enhanced interleukin-1β (IL1-β) signaling, and consequently that the blockade of IL1-β may restore the effectiveness of SSRI. Epilepsy and concurrent depression-like impairments were induced in Wistar rats by pilocarpine status epilepticus (SE). The effects of the 2-week long treatment with fluoxetine, interleukin-1 receptor antagonist (IL-1ra), and their combination were examined using behavioral, biochemical, neuroendocrine, and autoradiographic assays. In post-SE rats, depression-like impairments included behavioral deficits indicative of hopelessness and anhedonia; the hyperactivity of the hypothalamo-pituitary-adrenocortical axis; the diminished serotonin output from raphe nucleus; and the upregulation of presynaptic serotonin 1-A (5-HT1A) receptors. Fluoxetine monotherapy exerted no antidepressant effects, whereas the treatment with IL-1ra led to the complete reversal of anhedonia and to a partial improvement of all other depressive impairments. Combined administration of fluoxetine and IL-1ra completely abolished all hallmarks of epilepsy-associated depressive abnormalities, with the exception of the hyperactivity of the hypothalamo-pituitary-adrenocortical axis, the latter remaining only partially improved. We propose that in certain forms of depression, including but not limited to depression associated with epilepsy, the resistance to SSRI may be driven by the pathologically enhanced interleukin-1β signaling and by the subsequent upregulation of presynaptic 5-HT1A receptors. In such forms of depression, the use of interleukin-1β blockers in conjunction with SSRI may represent an effective therapeutic approach.

Retigabine [RTG (international nonproprietary name); ezogabine (EZG; U.S. adopted name)] is a first-in-class antiepileptic drug (AED) that reduces neuronal excitability by enhancing the activity of KCNQ (K(v)7) potassium (K(+)) channels. RTG/EZG has recently been approved by the European Medicines Agency and the U.S. Food and Drug Administration as adjunctive therapy in adults with partial-onset seizures. In this review we discuss the activity that RTG/EZG has demonstrated across a broad spectrum of in vitro/in vivo animal models of seizures, including generalized tonic-clonic, primary generalized (absence), and partial seizures, in addition to the compound's ability to resist and block the occurrence of seizures induced by a range of stimuli across different regions of the brain. The potency of RTG/EZG in models refractory to several conventional AEDs and the work done to assess antiepileptogenesis and neuroprotection are discussed. Studies that have evaluated the central nervous system side effects of RTG/EZG in animals are reviewed in order to compare these effects with adverse events observed in patients with epilepsy. Based on its demonstrated effect in a number of animal epilepsy models, the synergistic and additive activity of RTG/EZG with other AEDs supports its potential use in therapeutic combinations for different seizure types. The distinct mechanism of action of RTG/EZG from those of currently available AEDs, along with its broad preclinical activity, underscores the key role of KCNQ (K(v)7) K(+) channels in neuronal excitability, and further supports the potential efficacy of this unique molecule in the treatment of epilepsy., (Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.)

The pharmacologic profile of retigabine [RTG (international nonproprietary name); ezogabine, EZG (U.S. adopted name)], is different from all currently approved antiepileptic drugs (AEDs). Its primary mechanism of action (MoA) as a positive allosteric modulator of KCNQ2-5 (K(v) 7.2-7.5) ion channels defines RTG/EZG as the first neuronal potassium (K(+)) channel opener for the treatment of epilepsy. KCNQ2-5 channels are predominantly expressed in neurons and are important determinants of cellular excitability, as indicated by the occurrence of human genetic mutations in KCNQ channels that underlie inheritable disorders including, in the case of KCNQ2/3, the syndrome of benign familial neonatal convulsions. In vitro pharmacologic studies demonstrate that the most potent action of RTG/EZG is at KCNQ2-5 channels, particularly heteromeric KCNQ2/3. Furthermore, mutagenesis and modeling studies have pinpointed the RTG/EZG binding site to a hydrophobic pocket near the channel gate, indicating how RTG/EZG can stabilize the open form of KCNQ2-5 channels; the absence of this site in KCNQ1 also provides a clear explanation for the inbuilt selectivity RTG/EZG has for potassium channels other than the KCNQ cardiac channel. KCNQ channels are active at the normal cell resting membrane potential (RMP) and contribute a continual hyperpolarizing influence that stabilizes cellular excitability. The MoA of RTG/EZG increases the number of KCNQ channels that are open at rest and also primes the cell to retort with a larger, more rapid, and more prolonged response to membrane depolarization or increased neuronal excitability. In this way, RTG/EZG amplifies this natural inhibitory force in the brain, acting like a brake to prevent the high levels of neuronal action potential burst firing (epileptiform activity) that may accompany sustained depolarizations associated with the initiation and propagation of seizures. This action to restore physiologic levels of neuronal activity is thought to underlie the efficacy of RTG/EZG as an anticonvulsant in a broad spectrum of preclinical seizure models and in placebo-controlled trials in patients with partial epilepsy. In this article, we consider the pharmacologic characteristics of RTG/EZG at the receptor, cellular, and network levels as a means of understanding the novel and efficacious MoA of this new AED as defined in both preclinical and clinical research., (Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.)

The successful pharmacologic treatment of intractable childhood epilepsy is predicated upon an accurate classification of the epilepsy syndrome. The selection of an antiepileptic drug is facilitated by the knowledge of syndrome-specific efficacy, the anticipation of potential side effects, and a careful risk-benefit assessment tailored to each patient. As such, the identification of comorbidities and careful monitoring for treatment-emergent adverse events, especially cognitive and behavioral effects, is of utmost importance. Especially in refractory cases, polypharmacy may increase the likelihood of side effects, but carefully chosen combinations can result in synergistic benefit. For most epilepsy syndromes, newer antiepileptic drugs typically yield equivalent efficacy and superior tolerability. Nevertheless, continued research is needed to further contrast the syndrome-specific efficacy and tolerability of available drugs and to foster the development of new agents with superior efficacy and side effect profiles., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Depression is a common comorbidity of temporal lobe epilepsy and has highly negative impact on patients' quality of life. We previously established that pilocarpine-induced status epilepticus (SE) in rats, concurrently with chronic epilepsy leads to depressive impairments, and that the latter may stem from the dysregulation of hypothalamo-pituitary-adrenocortical (HPA) axis and/or diminished raphe-hippocampal serotonergic transmission. We examined possible involvement of presynaptic and postsynaptic serotonin 1A (5-HT1A) receptors in epilepsy-associated depression. Based on their performance in the forced swim test (FST), post-SE animals were classified as those with moderate and severe depressive impairments. In moderately impaired rats, the activity of the HPA axis (examined using plasma corticosterone radioimmunoassay) was higher than in naive subjects, but the functional capacity of presynaptic 5-HT1A receptors (measured in raphe using autoradiography) remained unaltered. In severely depressed animals, both the activity of the HPA axis and the function of presynaptic 5-HT1A receptors were increased as compared with naive and moderately depressed rats. Pharmacological uncoupling of the HPA axis from raphe nucleus exerted antidepressant effects in severely impaired rats, but did not modify behavior in both naive and moderately depressed animals. Further, the function of postsynaptic 5-HT1A receptors was diminished in the hippocampus of post-SE rats. Pharmacological activation of postsynaptic 5-HT1A receptors improved depressive deficits in epileptic animals. We suggest that under the conditions of chronic epilepsy, excessively hyperactive HPA axis activates presynaptic 5-HT1A receptors, thus shifting the regulation of serotonin release in favor of autoinhibition. Downregulation of postsynaptic 5-HT1A receptors may further exacerbate the severity of epilepsy-associated depression.

In many experimental systems, proinflammatory stimuli exhibit proconvulsant properties. There are also accumulating data suggesting that inflammation may contribute to epileptogenesis in experimental models as well as in humans. Using two different models (Lithium-pilocarpine induced-status epilepticus (SE) and rapid kindling), we address this issue in the developing brain. Using P14 Wistar rat pups, we showed that inflammation induced by LPS results, after SE, into a more severe disease in adulthood. The main histological feature was an active gliosis that was observed only when inflammation and SE was combined. The use of a kindling model at P14, a model where seizure progress without any neurodegeneration, permits to show that systemic inflammation is responsible of an enhancement of epileptogenesis. The role of inflammation should be further explored in immature brain to identify therapeutic targets that may be relevant to clinical practice where the association of inflammation and epileptic events is common., ((c) 2010 Elsevier Inc. All rights reserved.)

This study examined the relationship between suicidal ideation and frontotemporal volumes, particularly orbital frontal gyrus volume, in 51 subjects with epilepsy with a mean age of 9.8 (2.1) years. Structured psychiatric interviews of the children and parents provided information on suicidal behavior and DSM-IV diagnoses. Tissue of 1.5-T MRI scans was segmented, and total brain, frontal lobe, frontal parcellations, and temporal lobe volumes were computed. The 11 subjects with epilepsy with suicidal ideation had significantly smaller right orbital frontal gyrus white matter volumes and larger left temporal lobe gray matter volumes than the 40 children without suicidal thoughts. Given the role of the orbital frontal gyrus in both emotional regulation and epilepsy, these findings highlight the biological underpinnings of suicidal ideation in pediatric epilepsy., (Copyright 2010. Published by Elsevier Inc.)

In this study the relationship between language skill and frontotemporal volumes was compared in 69 medically treated subjects with epilepsy and 34 healthy children, aged 6.1-16.6 years. Also, whether patients with linguistic deficits had abnormal volumes and atypical associations between volumes and language skills in these brain regions was determined. The children underwent language testing and MRI scans at 1.5 T. Brain tissue was segmented and frontotemporal volumes were computed. Higher mean language scores were significantly associated with larger inferior frontal gyrus, temporal lobe, and posterior superior temporal gyrus gray matter volumes in the epilepsy group and in the children with epilepsy with average language scores. Increased total brain and dorsolateral prefrontal gray and white matter volumes, however, were associated with higher language scores in the healthy controls. Within the epilepsy group, linguistic deficits were related to smaller anterior superior temporal gyrus gray matter volumes and there was a negative association between language scores and dorsolateral prefrontal gray matter volumes. These findings demonstrate abnormal development of language-related brain regions, and imply differential reorganization of brain regions subserving language in children with epilepsy with normal linguistic skills and in those with impaired language., ((c) 2010 Elsevier Inc. All rights reserved.)

The issues surrounding generic drug substitution in patients with epilepsy are complex. The substitution of one formulation of an antiepileptic drug (AED) for another is controversial. Well-reasoned and defensible cases can be made both for and against such substitution. Although regulatory agencies require that generic and proprietary drugs have similar pharmacokinetic bioequivalence data, their therapeutic efficacy may not necessarily be identical. The paroxysmal nature of epilepsy, the narrow therapeutic index of some AEDs, the need to individualize therapy to achieve seizure control, and the negative consequences of uncontrolled epilepsy distinguishes epilepsy from other clinical conditions. Epilepsy management with AEDs requires careful dose titration and consistent drug exposure at the optimal level for each patient, which can be altered if a different formulation of the AED is substituted. Unexpected variability in plasma concentrations could occur when a patient who has been receiving one formulation of an AED (generic or brand) receives an alternate formulation. Thus, no substitutions should be made for people with epilepsy without the knowledge and approval of the prescribing physician. Patients should be consulted about the substitution, with all risks and benefits carefully explained.

Depression is a frequent comorbidity of temporal lobe epilepsy (TLE); however, its mechanisms remain poorly understood and effective therapies are lacking. Augmentation of hippocampal interleukin-1beta (IL-1beta) signaling may be a mechanistic factor of both TLE and clinical depression. We examined whether pharmacological blockade of hippocampal interleukin-1 receptor exerts antidepressant effects in an animal model of comorbidity between TLE and depression, which developed in Wistar rats following pilocarpine status epilepticus (SE). In post-SE animals, depression-like state was characterized by behavioral equivalents of anhedonia and despair; dysregulation of the hypothalamo-pituitary-adrenocortical axis; compromised raphe-hippocampal serotonergic transmission. Two-week long bilateral intrahippocampal infusion of human recombinant Interleukin-1 receptor antagonist (IL-1ra) improved all of the examined depressive impairments, without modifying spontaneous seizure frequency and without affecting normal parameters in naïve rats. These findings implicate hippocampal IL-1beta in epilepsy-associated depression and provide a rationale for the introduction of IL-1beta blockers in the treatment of depression in TLE.

Purpose: This study examined the severity and range of linguistic impairments in young, intermediate, and adolescent youth with epilepsy and how these deficits were associated with illness effects, nonverbal intelligence, psychopathology, and reading., Methods: Tests of language, intelligence, achievement, and structured psychiatric interviews were administered to 182 epilepsy youth, aged 6.3-8.1, 9.1-11.7, and 13.0-15.2 years, as well as to 102 age- and gender-matched normal children. Parents provided demographic, seizure-related, and behavioral information on their children., Results: Significantly more epilepsy subjects had language scores 1 standard deviation (SD) below average than the age-matched control groups did. The intermediate and adolescent epilepsy groups also had significantly lower mean language scores compared to their matched controls. The older compared to the younger epilepsy groups had more language impairment and a wider range of linguistic deficits. Longer duration of illness, childhood absence epilepsy, psychiatric diagnosis, and socioeconomic status were associated with linguistic deficits in the young group. Prolonged seizures, lower Performance IQ, and minority status predicted low language scores in the intermediate epilepsy group. In the adolescent group, language impairment was associated with poor seizure control, decreased Performance IQ, and lower socioeconomic status. Linguistic and reading deficits were significantly related in each epilepsy group., Conclusions: The age-related increase in linguistic impairment, different profiles of predictors in each age group, and the relationship of linguistic deficits with poor reading skills have important clinical, developmental, theoretical, and academic implications.

This 24-week, multicenter, open-label trial was designed to evaluate the dosing, effectiveness, and safety of topiramate monotherapy for epilepsy and to identify patient and clinical characteristics predictive of optimally effective stabilized monotherapy doses. Of 406 randomized patients, 244 comprised the evaluable-for-efficacy population (12 weeks of treatment and stabilized topiramate dose during final 28 days); 213 were on topiramate monotherapy at the end of the trial. The mean stabilized daily dose of topiramate over the last 28 days of treatment (primary endpoint) was significantly lower for patients reporting one to three seizures (low seizure frequency, n=147) than for those reporting more than three seizures (high seizure frequency, n=66) during a 3-month retrospective baseline period (191 mg vs 239 mg, P=0.003). Patients in the low-seizure-frequency group reached a stable topiramate dose after a median of 36 days, compared with 53 days for patients in the high-seizure-frequency group. Linear and stepwise regression analyses showed baseline seizure frequency and lifetime seizure count to be significant (P<0.05) predictors of the stabilized dosage. Most treatment-emergent adverse events (TEAEs) were mild to moderate; those occurring with cumulative incidence rates >10% in either seizure frequency group were paresthesia, fatigue, anorexia, dizziness, somnolence, headache, and hypoesthesia; 18.2% of patients discontinued topiramate because of a TEAE, 5.1% reported serious TEAEs, and no deaths were reported during the study.

Recent findings on the clinical, electroencephalography (EEG), neuroimaging, and surgical outcomes are reviewed comparing patients with Palmini type I (mild) and type II (severe) cortical dysplasia. Resources include peer-reviewed studies on surgically treated patients and a subanalysis of the 2004 International League Against Epilepsy (ILAE) Survey of Pediatric Epilepsy Surgery. These sources were supplemented with data from University of California, Los Angeles (UCLA). Cortical dysplasia is the most frequent histopathologic substrate in children, and the second most common etiology in adult epilepsy surgery patients. Cortical dysplasia patients present with seizures at an earlier age than other surgically treated etiologies, and 33-50% have nonlocalized scalp EEG and normal magnetic resonance imaging (MRI) scans. 2-((18)F)Fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) is positive in 75-90% of cases. After complete resection, 80% of patients are seizure free compared with 20% with incomplete resections. Compared with type I, patients with type II cortical dysplasia present at younger ages, have higher seizure frequencies, and are extratemporal. Type I dysplasia is found more often in adult patients in the temporal lobe and is often MRI negative. These findings identify characteristics of patients with mild and severe cortical dysplasia that define surgically treated epilepsy syndromes. The authors discuss future challenges to identifying and treating medically refractory epilepsy patients with cortical dysplasia.

This exploratory study compared the responses of 20 Caucasian and 20 Hispanic mothers of children with epilepsy about possible obstacles to mental health care (MHC) for their children before and after they read a brochure on the neurobehavioral comorbidities of epilepsy. The intervention significantly increased the mothers' knowledge of the behavior and cognitive comorbidities of pediatric epilepsy and their treatment. Baseline differences in the attitude toward MHC and the stigma of epilepsy between Hispanic and Caucasian mothers were no longer apparent after the intervention. Irrespective of ethnicity, the mothers also became significantly more aware that their children did not want to have epilepsy-related behavior and learning difficulties. Efficient use of time spent in doctors' waiting rooms to educate parents about the neurobehavioral comorbidities of epilepsy can address the lack-of-knowledge barrier to MHC. However, the study's findings suggested a need to determine if there are specific obstacles to MHC in pediatric epilepsy.

Background: Although epilepsy is relatively common, only a limited number of specialized epilepsy centers exist in the United States. Therefore, epilepsy diagnosis and management frequently occur in the community setting. This can complicate patient management and suboptimal care is a potential concern. Delayed recognition and inadequate treatment increase the risk of subsequent seizures, brain damage, disability, and death from seizure-related injuries. To identify core elements of epilepsy management that should be offered to all patients, the Leadership in Epilepsy, Advocacy, and Development (LEAD) faculty assessed current practical issues and identified practices to improve patient care and outcomes., Scope: This paper presents a consensus opinion formed from a survey of 26 current LEAD faculty members, who answered 105 questions about epilepsy diagnosis and patient evaluation, treatment decisions, lifelong monitoring, and the management of special patient subgroups. Consensus agreement was concluded when >or=50% of the faculty provided the same answer. The results were compiled and areas of consensus are included in this report. The recommendations provided in this commentary are limited by the scope of the survey., Findings: Consensus was reached on several minimum standard patient management practices. Primary among these minimum standards of care is the need for diagnosis including a detailed medical history, neurological examination, discussions with caregivers, and diagnostic tests including electroencephalograms and magnetic resonance imaging. As the overall goals of therapy include seizure freedom, minimizing side effects, and improving quality of life and long-term safety, therapy decisions should consider parameters that affect these goals, including potential adverse effects of therapy. Antiepileptic drug selection should consider coexisting conditions for possible exacerbation of disease and potential drug-drug interactions., Conclusions: The core elements of epilepsy management identified here suggest minimum standards that can be used across all settings to improve consistency and quality of epilepsy diagnosis and care.

The aim of this study was to determine if volumes of frontotemporal regions associated with language were related to thought disorder in 42 children, aged 5-16 years, with cryptogenic epilepsy, all of whom had complex partial seizures (CPS). The children with CPS and 41 age- and gender-matched healthy children underwent brain MRI scans at 1.5 T. Tissue was segmented, and total brain, frontal lobe, and temporal lobe volumes were computed. Thought disorder measures, IQ, and seizure information were collected for each patient. The subjects with CPS had more thought disorder, smaller total gray matter and orbital frontal gray matter volumes, as well as larger temporal lobe white matter volumes than the control group. In the CPS group, thought disorder was significantly related to smaller orbital frontal and inferior frontal gray matter volumes, increased Heschl's gyrus gray matter volumes, and smaller superior temporal gyrus white matter volumes. However, significantly larger orbital frontal gyrus, superior temporal gyrus, and temporal lobe gray matter volumes and decreased Heschl's gyrus white matter volumes were associated with thought disorder in the control group. These findings suggest that thought disorder might represent a developmental disability involving frontotemporal regions associated with language in pediatric CPS.

Over the past decade, much progress has been made in understanding the mechanisms of ketogenic diet (KD) action. From the complex systemic and metabolic changes induced by the KD have emerged innovative hypotheses attempting to link biochemical adaptations to its clinical effects. Despite such developments, the fundamental question of how the KD works remains as elusive as ever. At present, it is unclear which of the many potential mechanisms proposed thus far are directly relevant to the clinical effects of the KD. It is unlikely that these numerous hypotheses can be unified into a single mechanism (or a final common pathway). Nevertheless, it may be instructive to consider each of these putative mechanisms in turn and ask the following question: if the mechanism or target in question is a critical determinant of the anticonvulsant efficacy of the KD, then would a similar intervention known to be based on that mechanism yield a comparable effect? Perhaps answering this question for each mechanistic speculation might help substantiate (or invalidate) that particular hypothesis. Can the KD be packaged into a pill? At present, the answer is likely "no." We have yet to discover a "magic bullet" that completely mirrors the anticonvulsant (and potential neuroprotective) effects of the KD. However, without a clearer understanding of the mechanistic elements comprising the complex metabolic puzzle posed by the KD, we would be left only with empiric observations, and to wonder curiously how a high-fat diet can exert such profound clinical effects.

Purpose: High-frequency oscillations (>100Hz) have been proposed as localized markers of epileptic networks, but require intracranial electroencephalographic (EEG) recordings. This study explored if beta- and gamma-frequency paroxysmal fast activity (PFA), recorded interictally during non-REM sleep, could be used as a scalp EEG marker of epileptogenesis in children., Methods: The presence and scalp location of PFA was visually identified in 681 patients with overnight video-EEG (age 0-18 years), and compared with ictal onset sites. The clinical features of patients with PFA were compared with patients without PFA along with evidence of PFA evolution in 35 patients who had multiple video-EEG records., Results: PFA was present in 16% of all patients and in 28% of those with seizures. PFA was more frequently observed in EEGs from patients 3 years of age or younger (>40%), and children with infantile spasms (85%). When present, PFA predicted if the patient had epilepsy with 97% accuracy, and was not found in individuals with non-epileptic events. PFA localized with EEG-ictal onset sites with 91% sensitivity and 82% accuracy. Ictal scalp EEG events began with beta- and gamma-frequencies in 80% of patients with PFA, and they had increased seizure frequencies compared with non-PFA cases. In patients with multiple video-EEG studies, PFA showed progression over increased numbers of electrodes in 74%, improvement in 15%, and remained unchanged in 12% and correlated with seizure evolution. PFA was not associated with other seizure types, anatomic location, type of antiepileptic drug, etiology, or histopathology., Conclusions: While relatively infrequent, interictal PFA was specific in identifying younger children with epilepsy, co-localized with the ictal onset sites on scalp video-EEG, and progressed and correlated with seizure severity. We propose that PFA is a scalp EEG marker of epileptic networks with the advantage of being recorded non-invasively during interictal non-REM sleep.

Purpose: To examine antiepileptogenic and antiictogenic potential of retigabine (RTG) under conditions of rapid kindling epileptogenesis during different stages of development., Methods: The experiments were performed in postnatal day 14 (P14), P21, and P35 male Wistar rats. After stereotaxic implantation of hippocampal stimulating and recording electrodes, the effects of RTG on baseline afterdischarge (AD) properties were studied. Next, the animals underwent rapid kindling (sixty 10 s trains, bipolar 20 Hz square wave pulses delivered every 5 min). The progression of seizures (kindling acquisition), and responses to test stimulations after kindling (retention) were compared between RTG and vehicle-treated rats. Additionally, the effects of RTG on the severity of seizures in previously kindled animals were examined., Results: When administered intraperitoneally in doses that induced only mild, or no motor deficits, RTG significantly dampened brain excitability, evident as the increase of AD threshold and shortening of AD duration. During kindling, RTG delayed the development of focal seizures in P14 rats, and prevented the occurrence of full limbic seizures at all three ages. At P14 and P21, but not at P35, pretreatment with RTG prevented the establishment of kindling-induced enhanced seizure susceptibility. Administration of RTG to kindled animals decreased the severity of seizures induced by test stimulation. The effect was most prominent at P14., Discussion: RTG exerted both antiepileptogenic and antiictogenic effects under conditions of rapid kindling model. These effects were apparent during postneonatal, early childhood, and adolescent stages of development.

In this study, focus groups were used to examine parents' attitudes toward mental health services, use of mental health and other services, as well as service-related and other challenges encountered by parents of children with epilepsy. Both quantitative and qualitative analytic approaches were used to analyze the transcripts of 36 parents grouped into six focus groups by socioeconomic status (SES) (high, low) and ethnicity (African-American, Caucasian, Hispanic). The quantitative analyses demonstrated that, irrespective of SES and ethnicity, the parents were highly aware of their children's behavioral, emotional, and cognitive difficulties and the lack of knowledge about epilepsy among medical, educational, and mental health professionals. The higher-SES parents were significantly more concerned about inadequate educational services and the need for medical services, but less concerned about mental health and medical service use than the lower-SES parents. Insufficient knowledge about epilepsy and about services, parent emotional difficulties, and use of educational services differed significantly by ethnicity. The qualitative analyses highlighted the parents' concerns regarding misconceptions about epilepsy and the stigma toward mental health care among the African-American and Hispanic parents. These findings suggest the need for accessible and better-quality mental health, educational, and medical services for children with epilepsy irrespective of SES and ethnicity. They also underscore the importance of educating parents, service providers, and the general public about epilepsy.

Eighteen pediatric neurologists and 18 pediatricians completed a 5-point Likert scale questionnaire on their knowledge of, attitudes toward, and management of the behavioral, cognitive, and psychosocial aspects of pediatric epilepsy, before and after a lecture on this topic. They also responded to questions about possible barriers to mental health care of children with epilepsy. The brief educational intervention modified the knowledge/attitudes of pediatricians compared with pediatric neurologists on the impact of epilepsy on behavior and cognition in children with epilepsy. However, there were no between-group differences in how providers perceived their competence to assess behavioral and cognitive comorbid conditions in pediatric epilepsy. Responses to open-ended questions suggested insufficient mental health coverage for and expertise on pediatric epilepsy, resistance of mental health clinicians to treat children with epilepsy, and the stigma of mental health as possible barriers to mental health care in children with epilepsy. In addition to the need for provider education about the behavioral and cognitive comorbid conditions of pediatric epilepsy, these findings emphasize the importance of examining alternative routes to increasing mental health care for children with epilepsy.