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ObjectiveWe examined whether posttraumatic epilepsy (PTE) is associated with measurable perturbations in gut microbiome.MethodsAdult Sprague Dawley rats were subjected to lateral fluid percussion injury (LFPI). PTE was examined 7months 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 1week, 1 month, and 7months 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.ResultsAlpha 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.SignificanceWhereas 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.

Objective Traumatic brain injury (TBI) may lead to the disruption of the intestinal barrier (IB), and to the escape of products of commensal gut bacteria, including lipopolysaccharide (LPS), into the bloodstream. We examined whether lateral fluid percussion injury (LFPI) and post-traumatic epilepsy (PTE) are associated with the increased intestinal permeability and endotoxemia, and whether these events in turn are associated with PTE. Methods LFPI was delivered to adult male Sprague-Dawley rats. Before, 1 week, and 7 months after LFPI, the IB permeability was examined by measuring plasma concentration of fluorescein isothiocyanate-labeled dextran (FD4) upon its enteral administration. Plasma LPS concentration was measured in the same animals, using enzyme-linked immunosorbent assay. PTE was examined 7 months after LFPI, with use of video-EEG (electroencephalography) monitoring. Results One week after LFPI, the IB disruption was detected in 14 of 17 and endotoxemia - in 10 of 17 rats, with a strong positive correlation between FD4 and LPS levels, and between plasma levels of each of the analytes and the severity of neuromotor deficit. Seven months after LFPI, IB disruption was detected in 13 of 15 and endotoxemia in 8 of 15 rats, with a strong positive correlation between plasma levels of the two analytes. Five of 15 LFPI rats developed PTE. Plasma levels of both FD4 and LPS were significantly higher in animals with PTE than among the animals without PTE. The analysis of seven rats, which were examined repeatedly at 1 week and at 7 months, confirmed that late IB disruption and endotoxemia were not due to lingering of impairments occurring shortly after LFPI. Significance LFPI leads to early and remote disruption of IB and a secondary endotoxemia. Early and late perturbations may occur in different subjects. Early changes reflect the severity of acute post-traumatic motor dysfunction, whereas late changes are associated with PTE.

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

ObjectiveTo investigate the diagnostic utility of high frequency oscillations (HFOs) via scalp electroencephalogram (EEG) in infantile spasms.MethodsWe retrospectively analyzed interictal slow-wave sleep EEGs sampled at 2,000Hz recorded from 30 consecutive patients who were suspected of having infantile spasms. We measured the rate of HFOs (80-500Hz) and the strength of the cross-frequency coupling between HFOs and slow-wave activity (SWA) at 3-4Hz and 0.5-1Hz as quantified with modulation indices (MIs).ResultsTwenty-three patients (77%) exhibited active spasms during the overnight EEG recording. Although the HFOs were detected in all children, increased HFO rate and MIs correlated with the presence of active spasms (p&nbsp

A series of relatively small studies collectively suggest that zonisamide may be effective in the treatment of infantile spasms. Using a large single‐center cohort of children with infantile spasms, we set out to evaluate the efficacy and safety of zonisamide. We retrospectively identified all patients with infantile spasms who were treated with zonisamide at our center. For each patient, we recorded dates of birth, infantile spasms onset, response (if any), and most recent follow‐up. To quantify zonisamide exposure, we recorded daily dosage and patient weight at each sequential encounter so as to allow calculation of peak and weighted‐average weight‐based dosage. We identified 87 children who were treated with zonisamide, of whom 78 had previously been treated with hormonal therapy or vigabatrin. Peak and weighted‐average zonisamide dosage were 7.1 (interquartile range 3.6, 10.2) and 5.4 (interquartile range 3.0, 8.9) mg/kg/day, respectively. Whereas five (6%) patients exhibited resolution of epileptic spasms, only two (2%) patients exhibited video‐EEG confirmed resolution of both epileptic spasms and hypsarrhythmia (electroclinical response). Importantly, both electroclinical responders had not previously been treated with hormonal therapy or vigabatrin; in contrast, none of the 78 children with prior failure of hormonal therapy or vigabatrin subsequently responded to zonisamide. Zonisamide was well tolerated, and there were no deaths. This study suggests that zonisamide exhibits favorable tolerability but very limited efficacy among patients who do not respond to first‐line therapy.

To investigate spatial correlation between interictal HFOs and neuroimaging abnormalities, and to determine if complete removal of prospectively identified interictal HFOs correlates with post-surgical seizure-freedom.Interictal fast ripples (FRs: 250-500 Hz) in 19 consecutive children with pharmacoresistant focal epilepsy who underwent extra-operative electrocorticography (ECoG) recording were prospectively analyzed. The interictal FRs were sampled at 2000 Hz and were visually identified during 10 min of slow wave sleep. Interictal FRs, MRI and FDG-PET were delineated on patient-specific reconstructed three-dimensional brain MRI.Interictal FRs were observed in all patients except one. Thirteen out of 18 patients (72%) exhibited FRs beyond the extent of neuroimaging abnormalities. Fifteen of 19 children underwent resective surgery, and survival analysis with log-rank test demonstrated that complete resection of cortical sites showing interictal FRs correlated with longer post-operative seizure-freedom (p 0.01). Complete resection of seizure onset zones (SOZ) also correlated with longer post-operative seizure-freedom (p = 0.01), yet complete resection of neuroimaging abnormalities did not (p = 0.43).Prospective visual analysis of interictal FRs was feasible, and it seemed to accurately localize epileptogenic zones.Topological extent of epileptogenic region may exceed what is discernible by multimodal neuroimaging.

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.

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.

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 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.

Objective The objective of this study was to evaluate long-term safety and tolerability outcomes in two open-label extension (OLE) studies of adjunctive eslicarbazepine acetate (ESL) in children with focal seizures. Methods Safety data from patients aged 4–17 years in OLEs of Studies 2093-208 and -305 were pooled and analyzed. Studies 208 and 305 were randomized, double-blind, placebo-controlled studies of adjunctive treatment with ESL in children with focal seizures refractory to treatment with 1–2 antiseizure drugs; patients could continue into uncontrolled OLEs (up to 5 years total duration). The OLEs evaluated the safety and tolerability of ESL (10–30 mg/kg/day; maximum 1200 mg/day). Results The 1-year OLE and post-1-year OLE safety populations comprised 337 and 177 ESL-treated patients, respectively. The overall incidence of treatment-emergent adverse events (TEAEs) with ESL was 64.1% during the 1-year OLE and 52.5% during the post-1-year OLE. Nasopharyngitis, partial seizures, vomiting, pyrexia, headache, somnolence, and respiratory tract infection were the most frequently reported TEAEs during the 1-year OLE. The overall incidence of serious adverse events (AEs) was 8.9% during the 1-year OLE and 10.2% during the post-1-year OLE. Partial seizures (1.2%) and pneumonia (1.2%) were the most frequently reported serious AEs during the 1-year OLE. The overall incidence of TEAEs leading to discontinuation was 4.2% during the 1-year OLE and 0.6% during the post-1-year OLE. Partial seizures (1.5%) was the most frequently reported TEAE leading to discontinuation during the 1-year OLE. Conclusions Overall, long-term treatment with ESL was generally well tolerated in pediatric patients aged 4–17 years with focal seizures. TEAEs were comparable to those observed in adults with no new events of concern.

Seizures are common in term infants with hypoxic-ischemic encephalopathy (HIE) undergoing therapeutic hypothermia. Although phenobarbital (PHB) is generally considered first-line therapy, some centers have embraced third-generation antiepileptic drugs (AEDs) such as levetiracetam (LEV) given the impression of comparable efficacy and superior tolerability. We set out to compare the efficacy of PHB and LEV in a large single-center cohort.We retrospectively identified consecutive newborns with HIE who were monitored with continuous video-electroencephalogram (VEEG) for the duration of therapeutic hypothermia. After identification of seizures, infants were treated with PHB or LEV at the discretion of treating physicians. We assessed time to seizure freedom as a function of AED choice, with adjustment for HIE severity and initial seizure frequency using the Kaplan-Meier procedure and multivariate Cox proportional hazards regression.We identified 78 infants with HIE. Among 44 (56%) patients who had VEEG-confirmed seizures, 34 became seizure-free during monitoring, and the remaining 10 died. Initial treatment with LEV, in comparison with PHB, predicted a shorter interval to seizure freedom in a univariate analysis (Hazard ratio (HR) = 2.58, P = 0.007), even after adjustment for initial seizure frequency and an unbiased ad hoc measure of HIE severity (adjusted HR = 2.57, P = 0.010). This effect was recapitulated in an analysis in which patients with treatment crossover were excluded. As expected, severity of HIE was an independent predictor of longer duration to seizure freedom (HR = 0.16, P 0.001) and remained a significant predictor after adjustment for initial seizure burden and treatment agent.Despite a relatively small sample size and retrospective design, this study suggests that LEV is a viable alternative to PHB in the treatment of neonatal seizures associated with HIE. A large-scale randomized controlled trial is needed to confirm these findings.

We report a 10-month-old boy with treatment-resistant infantile spasms associated with hypothalamic hamartoma (HH). Electroencephalography before surgical treatment showed modified hypsarrhythmia. Transventricular endoscopic resection and disconnection resulted in immediate and enduring disappearance of the epileptic spasms and improvement in the postoperative electroencephalography. After 8 years of treatment, the patient has nondisabling gelastic seizures associated with a small amount of residual HH but no other seizure types. He is not taking any antiepilepsy drugs. He is academically and socially successful. We are not aware of any prior reports of surgical treatment of HH with concurrent infantile spasms as an uncontrolled seizure type. The immediate disappearance of infantile spasms demonstrates that the HH lesion itself is an active and necessary component within the epileptic network responsible for spasms in this particular condition. This case contributes to the recognition that focal pathologies can be responsible for infantile spasms with hypsarrhythmia and respond successfully to surgical intervention.

In the surgical management of epilepsy, the resection of cortex exhibiting interictal fast ripples (250–500 Hz) on electrocorticography has been linked to postoperative seizure-freedom. Although fast ripples appear to accurately identify the epileptogenic zone—the minimum tissue that must be removed at surgery to achieve seizure-freedom—it has not been established that fast ripples are a superior biomarker in comparison with multimodal presurgical neuroimaging and other electrocorticography abnormalities. Hence, in the prediction of postoperative seizure-freedom, we compared the value of fast ripples with other intraoperative electocorticography abnormalities including focal slowing, paroxysmal fast activity, intermittent spike discharges, continuous epileptiform discharges, focal attenuation, and intraoperative seizures, as well as complete resection of the lesion defined by MRI and other neuroimaging. In a cohort of 60 children with lesional epilepsy and median postsurgical follow-up exceeding 4 years, who underwent resective epilepsy surgery with intraoperative electrocorticography, we evaluated the extent to which removal of each intraoperative electrocorticography abnormality impacts time to first postoperative seizure using the Kaplan-Meier method and Cox proportional hazards regression. Secondly, we contrasted the predictive value of resection of each competing electrocorticography abnormality using standard test metrics (sensitivity, specificity, positive predictive value, and negative predictive value). In contrast with all other intraoperative electrocorticography abnormalities, fast ripples demonstrated the most favorable combination of positive predictive value (100%) and negative predictive value (76%) in the prediction of postoperative seizures. Among all candidate electrocorticography features, time to first postoperative seizure was most strongly associated with incomplete resection of fast ripples (hazard ratio = 19.8, p

This study examined whether toll-like receptors 2 (TLR2) contribute to the rapid kindling epileptogenesis. A TLR2 agonist, lipoteichoic acid (LTA), LTA antibody (LTA-A) or normal saline (control) were administered daily over three consecutive days, unilaterally into ventral hippocampus of adult male Wistar rats. Thirty minutes after the last injection, the animals were subjected to rapid kindling procedure. The ictogenesis was gauged by comparing afterdischarge threshold (ADT) and afterdischarge duration (ADD) before the treatments, after the treatments prior to kindling, and 24 h after kindling. Kindling progression and retention were analyzed using video recording. The results showed that before kindling, LTA produced an ADT reduction. Neither LTA, nor LTA-A affected baseline ADD. On kindling progression, LTA accelerated occurrence of generalized seizures while LTA-A delayed this effect. The treatment with LTA-A reduced the number of secondary generalized complex partial seizures. Twenty four hours after kindling, the rats of both saline and LTA groups showed the increased hippocampal excitability as compared with pre-kindling parameters. Administration of LTA-A prevented kindling-induced increase of hippocampal excitability. The immunostaining revealed that LTA-A attenuated the inflammatory response produced by seizures. These findings suggest that the activation of TLR2 in the hippocampus may facilitate limbic epileptogenesis.

Purpose Limited data suggest that cannabidiol (CBD) may be effective for treatment of refractory infantile spasms (IS). This study was designed to more rigorously evaluate the efficacy and safety of synthetic CBD in the treatment of IS. Methods Children six to 36 months of age with IS that failed treatment with both adrenocorticotropic hormone (ACTH) and vigabatrin (VGB) were eligible for enrollment. Children receiving clobazam were excluded. After baseline overnight video-electroencephalography (vEEG) to confirm diagnosis and ascertain hypsarrhythmia, patients were treated with synthetic CBD oral solution (20 mg/kg/day). Overnight video-EEG was repeated after 14 days, and both baseline and repeat video-EEGs were completely de-identified and reviewed in a pairwise fashion by an independent, blinded pediatric electroencephalographer. The primary efficacy endpoint was freedom from spasms and hypsarrhythmia on day 14. Results Nine patients were enrolled, comprising an older (median age = 23 months) cohort with long-standing IS (median duration = 13 months) and numerous prior treatment failures (median = 6). One patient responded to therapy and eight patients exhibited neither clinical nor electrographic response. Conclusions The immediate but temporary response in a single patient suggests that CBD oral solution is not particularly effective in highly refractory cases, but may, nevertheless, be effective in younger patients with shorter durations of IS. Further study, examining both short- and long-term outcomes, is warranted to further evaluate the efficacy and safety of CBD oral solution in the treatment of IS.

Objective Molecular genetic etiologies in epilepsy have become better understood in recent years, creating important opportunities for precision medicine. Building on these advances, detailed studies of the complexities and outcomes of genetic testing for epilepsy can provide useful insights that inform and refine diagnostic approaches and illuminate the potential for precision medicine in epilepsy. Methods We used a multi‐gene next‐generation sequencing (NGS) panel with simultaneous sequence and exonic copy number variant detection to investigate up to 183 epilepsy‐related genes in 9769 individuals. Clinical variant interpretation was performed using a semi‐quantitative scoring system based on existing professional practice guidelines. Results Molecular genetic testing provided a diagnosis in 14.9%‐24.4% of individuals with epilepsy, depending on the NGS panel used. More than half of these diagnoses were in children younger than 5 years. Notably, the testing had possible precision medicine implications in 33% of individuals who received definitive diagnostic results. Only 30 genes provided 80% of molecular diagnoses. While most clinically significant findings were single‐nucleotide variants, ~15% were other types that are often challenging to detect with traditional methods. In addition to clinically significant variants, there were many others that initially had uncertain significance; reclassification of 1612 such variants with parental testing or other evidence contributed to 18.5% of diagnostic results overall and 6.1% of results with precision medicine implications. Significance Using an NGS gene panel with key high‐yield genes and robust analytic sensitivity as a first‐tier test early in the diagnostic process, especially for children younger than 5 years, can possibly enable precision medicine approaches in a significant number of individuals with epilepsy.

Background There is ongoing debate regarding the comparative effectiveness of adrenocorticotropic hormone and prednisolone in the treatment of infantile spasms. With a large cohort and extended follow-up, we set out to evaluate a protocol in which adrenocorticotropic hormone is reserved for prednisolone nonresponders. Methods The following standardized hormonal therapy protocol was adopted. Patients initially receive prednisolone (8 mg/kg/day [maximum 60 mg/day], divided in three daily doses for 14 days). Prednisolone responders taper it over 14 days, whereas prednisolone nonresponders immediately transition to natural adrenocorticotropic hormone (150 U/m2/day, divided in two daily doses for 14 days). We evaluated short-term response, defined as video-electroenecphaloagraphy-confirmed resolution of both epileptic spasms and hypsarrhythmia on day 14, without relapse for 28 additional days. We then evaluated long-term relapse and calculated the rates of sustained response at six, 12, and 18 months. Results We identified 102 children with infantile spasms who were treated with prednisolone. Prior exposure to hormonal therapy and vigabatrin was observed among 12% and 35% of patients, respectively. Sixty (59%) patients responded to prednisolone, and 13 (33%) prednisolone nonresponders then responded to adrenocorticotropic hormone. Cumulative response to prednisolone and adrenocorticotropic hormone (if needed) was higher among treatment-naive patients (84%) than among patients with prior exposure to first-line treatment (51%), with P Conclusion Short-term response to prednisolone was favorable and higher among treatment-naive patients. These data suggest that prednisolone is a reasonable approach to initial therapy and that adrenocorticotropic hormone exhibits substantial efficacy after prednisolone failure.

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.

PURPOSE Extracorporeal membrane oxygenation (ECMO) is a life-saving heart and lung bypass procedure that can cause substantial EEG artifact. Continuous EEG monitoring is nonetheless a helpful neuromonitoring tool for patients receiving ECMO therapy because neurologic complications are frequent, but factors such as sedation, neuromuscular blockade, and hemodynamic instability limit clinical and radiographic evaluation. We examined whether using conductive plastic electrodes in place of conventional gold electrodes reduces artifact in clinical EEG studies of pediatric ECMO patients. METHODS Four masked electroencephalographers assessed artifact and its impact on overall EEG interpretation in samples from 21 consecutive EEGs recorded during ECMO therapy (14 gold and 7 plastic). A spectral power analysis then quantified 50- to 70-Hz artifact in a larger group of 14 gold and 34 plastic electrode studies during ECMO and 4 non-ECMO gold electrode studies. RESULTS The masked electroencephalographers identified less artifact (P < 0.001) and indicated greater confidence in the accuracy of EEG interpretation (P < 0.001) among studies recorded with plastic electrodes. In quantitative analyses, ECMO was associated with greater 50- to 70-Hz power among studies using gold electrodes (P < 0.001) and gold electrodes exhibited greater 50- to 70-Hz power than plastic electrodes (P < 0.001). Contrasting studies in which most of the electroencephalographers believed that interpretation was (n = 12; 7 gold and 5 plastic) or was not (n = 7; all gold) compromised by artifact, 50- to 70-Hz power was similarly higher among the compromised studies (P < 0.001). CONCLUSION Plastic electrodes substantially reduce the burden of electrical artifact in EEG studies performed on pediatric ECMO patients and improve confidence in EEG interpretation.

Purpose Numerous studies have suggested that the ketogenic diet is effective in the treatment of epileptic spasms, even in refractory cases. However, there has been very limited demonstration of prompt and complete (video-EEG confirmed) response. We set out to describe our center's experience with the ketogenic diet in the treatment of children with highly refractory epileptic spasms, with rigorous seizure outcome assessment. Method Children treated with the ketogenic diet for epileptic spasms between April, 2010 and June, 2014 were retrospectively identified. Seizure burden was tabulated at baseline and after 1, 3, 6, and 12-months of ketogenic diet exposure. Adverse events were similarly ascertained. Results We identified a cohort of 22 consecutive patients who received ketogenic diet therapy, with median age of onset of epileptic spasms of 5.2 (IQR 2.0–9.0) months, with diet initiation beginning a median of 26.4 (12.5–38.7) months after onset, and following a median of 7 (IQR 5–7) treatment failures. Only 2 patients exhibited a complete response during ketogenic diet exposure, and response was more reasonably attributed to alternative therapies in both cases. A modest early reduction in seizure frequency was not sustained beyond 1 month of diet exposure. The diet was well tolerated, and continued in 6 patients with subjective and/or partial response. Conclusion In contrast to prior studies reporting substantial efficacy of the ketogenic diet, our findings suggest limited efficacy, albeit in a highly refractory cohort. Prospective studies in both refractory and new-onset populations, with both video-EEG confirmation of response and rigorous cognitive outcome assessment, would be of great value to more clearly define the utility of the ketogenic diet in the treatment of epileptic spasms.

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.

Summary High‐frequency oscillations (HFOs), including ripples (Rs) and fast ripples (FRs), are promising biomarkers of epileptogenesis, but their clinical utility is limited by the lack of a standardized approach to identification. We set out to determine whether electroencephalographers experienced in HFO analysis can reliably identify and quantify interictal HFOs. Two blinded raters independently reviewed 10 intraoperative electrocorticography (ECoG) samples from epilepsy surgery cases, and 10 scalp EEG samples from epilepsy monitoring unit evaluations. HFOs were visually marked using bandpass filters (R, 80–250 Hz; FR, 250–500 Hz) with a sampling frequency of 2,000 Hz. There was agreement as to the presence or absence of epileptiform discharges (EDs), Rs, and FRs, in 17, 18, and 18 cases, respectively. Interrater reliability (IRR) was favorable with κ = 0.70, 0.80, and 0.80, respectively, and similar for ECoG and scalp electroencephalography (EEG). Furthermore, interclass correlation for rates of Rs (0.99, 95% confidence interval [CI] 0.96–0.99) and FRs (0.77, 95% CI 0.41–0.91) were superior in comparison to EDs (0.37, 95% CI −0.60 to 0.75). Our data suggest that HFO identification and quantification are reliable among experienced electroencephalographers. Our findings support the reliability of utilizing HFO data in both research and clinical arenas.

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.

Summary There has been growing interest in the role of intestinal microbiome in brain disorders. We examined whether dysbiosis can predispose to epilepsy. The study was performed in female and male Sprague‐Dawley rats. To induce dysbiosis, the rats were subjected to chronic restraint stress (two 2‐h long sessions per day, over 2 weeks). Cecal content from stressed and sham‐stressed donors was transplanted via oral gavage to recipients, in which commensal microbiota had been depleted by the antibiotics. The study included the following groups: (1) Sham stress, no microbiota transplant; (2) Stress, no microbiota transplant; (3) Sham‐stressed recipients transplanted with microbiota from sham‐stressed donors; (4) Stressed recipients transplanted with microbiota from sham‐stressed donors; (5) Sham‐stressed recipients transplanted with microbiota from stressed donors; and (6) Stressed recipients transplanted with microbiota from stressed donors. After microbiota transplant, all animals were subjected to kindling of the basolateral amygdala. Both chronic stress and microbiome transplanted from stressed to sham‐stressed subjects accelerated the progression and prolonged the duration of kindled seizures. Microbiome from sham‐stressed animals transplanted to chronically stressed rats, counteracted proepileptic effects of restraint stress. These findings directly implicate perturbations in the gut microbiome, particularly those associated with chronic stress, in the increased susceptibility to epilepsy.

Purpose Electrical status epilepticus in sleep (ESES) is an electrographic abnormality linked to language abnormalities and cognitive dysfunction and specifically associated with Landau–Kleffner syndrome (LKS), the syndrome of continuous spike and wave in slow-wave sleep (CSWS), and autistic regression with epileptiform EEG (AREE). As first-line therapies for treatment of ESES display inadequate efficacy and confer substantial risk, we set out to describe our center's experience with amantadine in the treatment of ESES. Methods Patients with video-EEG-confirmed ESES who received amantadine were retrospectively identified in a clinical EEG database. Spike–wave index, before and after amantadine exposure, was compared in a pairwise fashion. In an exploratory analysis, we cataloged reported changes in language functioning, cognition, and autistic features, which accompanied treatment. Results We identified 20 patients with ESES-associated syndromes. Median cumulative weighted average amantadine dosage was 2.1 mg/kg/d (interquartile range (IQR): 1.1, 4.5), and median duration of therapy was 11.5 months (IQR: 7.8, 26.6). In comparison with median baseline spike–wave index (76%), post-amantadine spike–wave index (53%) was reduced, with P = 0.01. Six (30%) patients exhibited complete (or nearly complete) resolution of ESES. A majority of patients exhibited subjective cognitive, linguistic, or behavioral benefit. Amantadine was generally well-tolerated despite substantial dosage and duration of therapy. Conclusions This study suggests that amantadine may be effective in the treatment of ESES-associated syndromes but warrants replication in a more rigorous study.

We present the case of a child with long-standing, super-refractory status epilepticus (SRSE) who manifested prompt and complete resolution of SRSE upon exposure to pure cannabidiol. SRSE emerged in the context of remote suspected encephalitis with previously well-controlled epilepsy. We discuss the extent to which response may be specifically attributed to cannabidiol, with consideration and discussion of multiple potential drug–drug interactions. Based on this case, we propose that adjunctive cannabidiol be considered in the treatment of SRSE., Highlights • Adjunctive cannabidiol may be effective in the treatment of super refractory status epilepticus

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.

Autism is a developmental disorder characterized by impairments in social and communication abilities, as well as by restricted and repetitive behaviors. Incidence of autism is higher than earlier estimates, and treatments have limited efficacy and are costly. Limited clinical and experimental evidence suggest that patients with autism may benefit from electroconvulsive therapy (ECT). We examined the therapeutic potential of ECT in BTBR T+ tf/j mice, which represent a validated model of autism. A series of 13 electroconvulsive shocks (ECS) delivered twice a day over 7 days reversed core autism-like behavioral abnormalities—impaired sociability, social novelty, and repetitive behavior—when the animals were tested 24 h after the last ECS. The effect lasted up to 2 weeks after ECT. Neither single ECS nor a series of 6 ECS modified animals’ behavior. Chronic infusion into the lateral brain ventricle of a preferential oxytocin receptor blocker (2S)-2-Amino-N-[(1S,2S,4R)-7,7-dimethyl-1-[[[4-(2-methylphenyl)-1-piperazinyl]sulfonyl]methyl]bicyclo[2.2.1]hept-2-yl]-4-(methylsulfonyl)butanamide hydrochloride abolished ECT-induced improvement of sociability and mitigated improvement of social novelty but did not affect ECT-induced reversal of repetitive behavior. These proof-of-principle experiments suggest that ECT may, indeed, be useful in the treatment of autism, and that its therapeutic effects may be mediated, in part, by central oxytocin signaling.

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.

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.

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.

FULL-LENGTH ORIGINAL RESEARCH Risk of vigabatrin-associated brain abnormalities on MRI in the treatment of infantile spasms is dose-dependent *Shaun A. Hussain, *Jackie Tsao, †Menglu Li, ‡Madeline D. Schwarz, *Raymond Zhou, *Joyce Y. Wu, §Noriko Salamon, and *¶Raman Sankar Epilepsia, 58(4):674–682, 2017 doi: 10.1111/epi.13712 S UMMARY Dr. Hussain is the Director of the UCLA Infantile Spasms Program, David Geffen School of Medicine and Mattel Children’s Hospital UCLA, Los Angeles, California. Objective: Although the link between vigabatrin (VGB) and retinotoxicity is well known, little attention has been focused on the risk of VGB-associated brain abnormal- ities on magnetic resonance imaging (MRI) (VABAM), namely reversible—and largely asymptomatic—signal changes in the thalami, basal ganglia, brainstem tegmentum, and cerebellar nuclei. Using a large infantile spasms cohort, we set out to identify pre- dictors of these phenomena. Methods: Children with infantile spasms were retrospectively identified. Brain MRI reports were serially reviewed without knowledge of VGB exposure. Upon VABAM discovery, records were systematically reviewed to ascertain presence of symptoms attributable to VGB. Separately, progress notes were sequentially reviewed to identify and quantify VGB exposure. Results: We identified 507 brain MRI studies among 257 patients with infantile spasms. VGB treatment was documented in 143 children, with detailed exposure data available for 104, of whom 45 had at least one MRI study during VGB treatment. Among the lim- ited subset of asymptomatic children who underwent MRI (n = 40), 6 exhibited VABAM. Risk of asymptomatic VABAM was dose-dependent, as peak (but not cumula- tive) VGB dosage was strongly associated with asymptomatic VABAM (p = 0.0028). In an exploratory analysis, we encountered 4 children with symptomatic VABAM among 104 patients with detailed VGB exposure data. Risk of symptomatic VABAM was seemingly dose-independent, and potentially associated with concomitant hormonal therapy (i.e., prednisolone and adrenocorticotropic hormone [ACTH]) (p = 0.039). Significance: We have demonstrated dose-dependent risk of asymptomatic VABAM and uncovered a possible association between symptomatic VABAM and concomitant hormonal therapy. Caution should be exercised in the use of high VGB dosage (i.e., >175 mg/kg/day), and further study is warranted to confirm the potential impact of hormonal therapy. KEY WORDS: West syndrome, Epileptic spasms, Toxicity, Neuroimaging. Accepted January 25, 2017; Early View publication February 23, 2017. *Division of Pediatric Neurology, David Geffen School of Medicine and Mattel Children’s Hospital UCLA, Los Angeles, California, U.S.A.; †School of Medicine and Health Sciences, George Washington University, Washington, District of Columbia, U.S.A.; ‡School of Medicine, University of California, San Francisco, San Francisco, California, U.S.A.; Departments of §Radiology, and ¶Neurology, David Geffen School of Medicine and Mattel Children’s Hospital UCLA, Los Angeles, California, U.S.A. Address correspondence to Shaun A. Hussain, UCLA Pediatric Neurol- ogy, 10833 Le Conte Ave, Room 22-474, Los Angeles, CA 90095-1752, U.S.A. E-mail: shussain@mednet.ucla.edu Wiley Periodicals, Inc. © 2017 International League Against Epilepsy Infantile spasms (also known as epileptic spasms in the most recently proposed International League Against Epi- lepsy (ILAE) classification scheme 1 ) is an often devastating form of epilepsy with onset in the first year of life; is fre- quently attributed to one of many structural, genetic, or metabolic disorders; and is usually accompanied by neu- rodevelopmental arrest or regression. 2 Infantile spasms is characterized by clusters of brief seizures termed spasms and a spectrum of severe electroencephalographic abnormalities including hypsarrhythmia. 3 A lack of prompt and successful treatment is associated with adverse long-term

Summary Objective Hypsarrhythmia is the classic interictal electroencephalographic pattern associated with infantile spasms, and characterized by high voltage, disorganization, and multifocal independent epileptiform discharges. Given this seemingly simple definition, one might expect excellent interrater reliability (IRR) in the identification of this pattern. Alternatively, it may be argued that assessments of voltage and disorganization are fairly subjective, and thus quite challenging in borderline cases. We sought to test the IRR of hypsarrhythmia assessment in a systematic fashion. Methods Six blinded pediatric electroencephalographers from four centers reviewed 22 electroencephalography (EEG) samples from patients with infantile spasms. Each sample was 5 min in duration and included only wakefulness. Raters determined if each EEG was abnormal and if hypsarrhythmia was present/absent, and characterized relevant features: voltage, organization, epileptiform discharges, slowing, interictal attenuations, symmetry, and synchrony. In addition, raters indicated their level of confidence for each assessment. Multirater kappa statistics (κ) were calculated for the assessment of hypsarrhythmia and each feature. Results Although IRR was favorable in determining whether a study was normal or abnormal (κ = 0.89), reliability was unfavorable for assessment of hypsarrhythmia (κ = 0.40), modified hypsarrhythmia (κ = 0.47), high voltage (κ = 0.37), disorganization (κ = 0.22), multifocal epileptiform discharges (κ = 0.68), interictal voltage attenuations (κ = 0.21), slowing (κ = 0.20), asymmetry (κ = 0.26), and asynchrony (κ = 0.08). Despite generally unsatisfactory interrater agreement, raters consistently reported high confidence in assessments. Significance This study contradicts the view that hypsarrhythmia assessment is straightforward. Even small variability in the identification of hypsarrhythmia has potentially deleterious consequences for clinical care, as its presence or absence impacts decisions to pursue high-risk and high-cost therapies. These inconsistencies may similarly confound studies in which abolition of hypsarrhythmia is an outcome measure. There is a great need for practical, reliable, and unbiased measures of hypsarrhythmia.

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.

It has been long recognized that there is more to epilepsy than seizures. The prevalence of such neurobehavioral abnormalities as cognitive and mood disorders, autism spectrum disorder, and attention deficit and hyperactivity disorder (ADHD) is significantly higher among patients with epilepsy than in the general population. A long-held view that comorbidities of epilepsy represent mere epiphenomena of seizures has undergone substantial transformation during the past decade, as emerging clinical evidence and experimental evidence suggest the involvement of specific neurobiological mechanisms in the evolution of neurobehavioral deficits in patients with epilepsy. Developmental aspects of both epilepsy and its comorbidities, as well as the frequently reported reciprocal connection between these disorders, both add other dimensions to the already complex problem. In light of progress in effective seizure management in many patients with epilepsy, the importance of neurobehavioral comorbidities has become acute, as the latter are frequently more detrimental to patients' quality of life compared with seizures. This calls for a serious increase in efforts to effectively predict, manage, and ideally cure these comorbidities. Coordinated multicenter clinical, translational, and basic research studies focusing on epidemiology, neuropsychology, neurophysiology, imaging, genetics, epigenetics, and pharmacology of neurobehavioral comorbidities of epilepsy are absolutely instrumental for ensuring tangible progress in the field. Clinical research should focus more on new-onset epilepsy and put particular emphasis on longitudinal studies in large cohorts of patients and groups at risk, while translational research should primarily focus on the development of valid preclinical systems which would allow investigating the fundamental mechanism of epilepsy comorbidities. The final goal of the described research efforts would lie in producing an armamentarium of evidence-based diagnostic tools and therapeutic interventions which would at minimum mitigate and at maximum prevent or abolish neurobehavioral comorbidities of epilepsy and, thus, improve the quality of life of those patients with epilepsy who suffer from the said comorbidities.

Refractory status epilepticus carries significant morbidity and mortality. Recent reports have promoted the use of the ketogenic diet as an effective treatment for refractory status epilepticus. We describe our recent experience with instituting the ketogenic diet for 4 critically ill children in refractory status epilepticus, ranging in age from 9 weeks to 13.5 years after failure of traditional treatment. The ketogenic diet allowed these patients to be weaned off continuous infusions of anesthetics without recurrence of status epilepticus, though delayed ketosis and persistently elevated glucose measurements posed special challenges to effective initiation, and none experienced complete seizure cessation. The ease of sustaining myocardial function with fatty acid energy substrates compares favorably over the myocardial toxicity posed by anesthetic doses of barbiturates and contributes to the safety profile of the ketogenic diet. The ketogenic diet can be implemented successfully and safely for the treatment of refractory status epilepticus in pediatric patients.

Objective—Maternal immune activation (MIA) triggered by infections, has been identified as a cause of autism in the 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-6 and interleukin-1β was also addressed. Methods—MIA was induced in C57BL/6 mice by polyinosinic–polycytidylic acid (PIC) injected during embryonic days 12–16. Beginning from postnatal day 40, the propensity of the offspring to epilepsy was examined using hippocampal kindling; autism-like behavior was studied using the sociability test. The involvement of interleukin-6 and interleukin-1β in PIC-induced effects was studied by the co-administration 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 interleukin-6 or interleukin-1β . Neither of the recombinant cytokines alone increased the propensity to seizures; however when combined, they produced effects similar to the ones induced by PIC. PIC- induced behavioral deficits were abolished by interleukin-6 antibodies and were mimicked by recombinant interleukin-6; interleukin-1β was not involved. Interpretation—In addition to confirming previously established critical role of interleukin-6 in the development of autism-like behavior following MIA, the present study shows that concurrent involvement of interleukin-6 and interleukin-1β is required for priming the offspring for epilepsy. These data shed light on mechanisms of comorbidity between autism and epilepsy.

Objective Fast ripples (FR, 250–500 Hz) are proposed biomarkers of the epileptogenic zone on the basis of several retrospective reports linking postoperative seizure freedom to their complete resection. There are no clinical trials or prospective reports validating the use of FR as characterized by electrocorticography (ECoG), to guide the scope of epilepsy surgery, and to inform prognosis thereafter. We set out to prospectively evaluate the utility of FR resection to predict postoperative epilepsy outcomes, and examine the feasibility of “live” intraoperative FR ascertainment. Methods FR were prospectively reviewed in 30 consecutive pediatric cases including 11 reviewed “live” during surgery. Intraoperative ECoG studies were recorded at 2000 Hz sampling rate, interpreted conventionally to guide surgical resection, and visually inspected for FR. Seizure outcome was tallied for all 30 children. Results Median age at surgery was 9.1 years (interquartile range [IQR] 4.7–13.2), median ECoG duration was 10.5 min (IQR 8.0–13.2), and median postoperative follow-up was 58.4 months (IQR 25.7–79.0). FR were identified in 24 of 30 ECoG studies. The incomplete resection of FR was strongly linked to postoperative seizures (hazard ratio 11.6, p = 0.005). “Live” ECoG review in the operating room to ascertain FR proved feasible and did not differ from conventional FR ascertainment. Significance: In a prospective fashion, including “live” review, FR were detected in 80% of pediatric ECoG studies, and incomplete resection of FR cortex predicted postoperative seizures. These findings extend the notion that interictal FR are surrogate markers of the epileptogenic zone, and that their intraoperative localization could be used to inform prognosis and guide surgical resections in children.

SummaryObjective There is scant evidence to guide the management of infantile spasms after successful response to initial therapies. There is significant risk of relapse, largely because effective pharmacologic treatments cannot be continued long term because of concern for significant adverse events. Zonisamide (ZNS) and topiramate (TPM) are commonly used to prevent relapse, and the purpose of this study was to specifically evaluate the efficacy of ZNS and TPM as agents for secondary prevention of infantile spasms. Methods Patients with video–electroencephalography (EEG) confirmed resolution of infantile spasms were retrospectively identified. Relevant clinical data were systematically collected, including lead time from onset of spasms to successful treatment response, etiology of infantile spasms, number of treatment failures prior to response, timing of relapse, and detailed exposure data for ZNS and TPM. Results We identified 106 patients with response to hormonal therapy (n = 58), vigabatrin (n = 25), or surgery (n = 23). To prevent relapse of infantile spasms, 37 patients received ZNS, 34 received TPM, 3 received both ZNS and TPM, and 38 patients received neither ZNS nor TPM. There were 44 relapses, occurring a median of 6.9 (3.2–10.8) months after initial response. Time to relapse was not affected by treatment with ZNS or TPM. Relapse was less likely among patients who were older (hazard ratio 0.97 [per month], p = 0.036) and those who responded to surgical resection (hazard ratio = 0.28, p = 0.017). Of note, we identified a relatively refractory cohort with multiple treatment failures and long lead time to initial response. Significance In this refractory cohort, neither ZNS nor TPM was successful in preventing relapse of infantile spasms, despite relatively high dosages. At this time, aside from surgical resection in eligible candidates, there is no known treatment that is efficacious in the prevention of relapse of infantile spasms.

Summary Objective Examine therapeutic potential of a selective serotonin reuptake inhibitor (SSRI) and a norepinephrine reuptake inhibitor (NERI) in an animal model of comorbidity between epilepsy, depression-like, and impulsive-like impairments. Methods Epilepsy was induced in male Wistar rats by LiCl and pilocarpine. An SSRI fluoxetine (FLX), and an NERI reboxetine (RBX) were administered either alone or as a combination over 1 week. Depressive-like and impulsive-like behaviors were examined using the forced swim test. Fast scan cyclic voltammetry was used to analyze serotonergic transmission in the raphe nucleus (RN)–prefrontal cortex (PFC) pathway, and noradrenergic transmission in locus coeruleus (LC)-PFC, and LC-RN projections. Monoamine levels in PFC were measured using high-performance liquid chromatography (HPLC). Functional capacities of 5-HT1A receptors and α2A adrenoreceptors in PFC were analyzed by autoradiography. Results Epileptic rats showed behavioral signs of depression and hyperimpulsivity, suppressed serotonergic and noradrenergic tones, decreased levels of serotonin (5-HT), and norepinephrine (NE); 5-HT1A receptor and α2A adrenoreceptors functions remained intact. FLX failed to improve behavioral deficits, but effectively raised 5-HT level and marginally improved RN-PFC serotonergic transmission. RBX reversed impulsive-like behavior, normalized content of NE and noradrenergic tone in LC-PFC and LC-RN. FLX-RBX combination fully reversed depressive-like behavior, and normalized RN-PFC serotonergic transmission. None of the treatment modified the function of 5-HT and NE receptors. Significance Depressive- and impulsive-like behaviors in the pilocarpine model of epilepsy stem respectively from dysfunctions of serotonergic and noradrenergic ascending pathways. At the same time, epilepsy-associated depression is SSRI resistant. The finding that an SSRI-NERI combination exerts antidepressant effect, along with RBX-induced improvement of LC-RN noradrenergic transmission point toward the involvement of LC-RN noradrenergic input in enabling therapeutic potential of FLX. Medications that improve serotonergic and noradrenergic transmission, such as serotonin–norepinephrine reuptake inhibitors may be effective in treating epilepsy-associated SSRI-resistant depression, as well as concurrent depression and attention-deficit/hyperactivity disorder (ADHD).

Objective: To evaluate potential development of tolerance to adjunctive clobazam in patients with Lennox-Gastaut syndrome. Methods: Eligible patients enrolled in open-label extension study OV-1004, which continued until clobazam was commercially available in the United States or for a maximum of 2 years outside the United States. Enrolled patients started at 0.5 mg·kg −1 ·d −1 clobazam, not to exceed 40 mg/d. After 48 hours, dosages could be adjusted up to 2.0 mg·kg −1 ·d −1 (maximum 80 mg/d) on the basis of efficacy and tolerability. Post hoc analyses evaluated mean dosages and drop-seizure rates for the first 2 years of the open-label extension based on responder categories and baseline seizure quartiles in OV-1012. Individual patient listings were reviewed for dosage increases ≥40% and increasing seizure rates. Results: Data from 200 patients were included. For patients free of drop seizures, there was no notable change in dosage over 24 months. For responder groups still exhibiting drop seizures, dosages were increased. Weekly drop-seizure rates for 100% and ≥75% responders demonstrated a consistent response over time. Few patients had a dosage increase ≥40% associated with an increase in seizure rates. Conclusions: Two-year findings suggest that the majority of patients do not develop tolerance to the antiseizure actions of clobazam. Observed dosage increases may reflect best efforts to achieve seizure freedom. It is possible that the clinical development of tolerance to clobazam has been overstated. ClinicalTrials.gov identifier: NCT00518713 and NCT01160770. Classification of evidence: This study provides Class III evidence that the majority of patients do not develop tolerance to clobazam over 2 years of treatment.

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.

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.

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.

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.

Depression represents one of the most common comorbidities of temporal lobe epilepsy (TLE), and has profound negative impact on the quality of life of patients with TLE. However, causes and mechanisms of depression in TLE remain poorly understood, and effective therapies are lacking. We examined whether a commonly used model of TLE in rats could be used as a model of comorbidity between epilepsy and depression suitable for both mechanistic studies and for the development of mechanism-based antidepressant therapies. We established that animals that had been subjected to lithium chloride and pilocarpine status epilepticus (SE) and developed spontaneous recurrent seizures, exhibited a set of impairments congruent with a depressive state: behavioral equivalents of anhedonia and despair, dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis, and compromised raphe-hippocampal serotonergic transmission. Pharmacologic studies have suggested that depressive impairments following SE develop as a result of enhanced interleukin-1beta signaling in the hippocampus, which leads to depression via inducing perturbations in the HPA axis and subsequent deficit in the raphe-hippocampal serotonergic transmission.

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.