Electrographic Seizure Activity Research Articles

The electro-responsive nanoliposome as an on-demand drug delivery platform for epilepsy treatment

Nano-based drug delivery systems are regarded as a promising tool for efficient epilepsy treatment and seizure medication with the least general side effects and socioeconomic challenges. In the current study, we have designed a smart nanoscale drug delivery platform and applied it in the kindling model of epilepsy that is triggered rapidly by epileptic discharges and releases anticonvulsant drugs in situ, such as carbamazepine (CBZ). The CBZ-loaded electroactive ferrocene nanoliposomes had an average diameter of 100.6 nm, a surface charge of −7.08 mV, and high drug encapsulation efficiency (85.4 %). A significant increase in liposome size was observed in response to direct current (50–500 μA) application. This liposome-based drug delivery system can release CBZ at a fast rate in response to both direct current and pulsatile electrical stimulation in vitro. The CBZ-liposome can release the anticonvulsant drug upon epileptiform activity in the kindled rat model and can decline electrographic and behavioral seizure activity in response to electrical stimulation of the hippocampus with an initially subconvulsive current. With satisfactory biosafety results, this “smart” nanocarrier has promising potential as an effective and safe drug delivery system to improve the therapeutic index of antiepileptic drugs.

Testing of putative antiseizure medications in a preclinical Dravet syndrome zebrafish model.

Dravet syndrome is a severe genetic epilepsy primarily caused by de novo mutations in a voltage-activated sodium channel gene (SCN1A). Patients face life-threatening seizures that are largely resistant to available anti-seizure medications. Preclinical Dravet syndrome animal models are a valuable tool to identify candidate anti-seizure medications for these patients. Among these, scn1lab mutant zebrafish, exhibiting spontaneous seizure-like activity, are particularly amenable to large-scale drug screening. Thus far, we have screened more than 3000 drug candidates in scn1lab zebrafish mutants, identifying valproate, stiripentol, and fenfluramine e.g. Food and Drug Administration-approved drugs, with clinical application in the Dravet syndrome population. Successful phenotypic screening in scn1lab mutant zebrafish is rigorous and consists of two stages: (i) a locomotion-based assay measuring high-velocity convulsive swim behaviour and (ii) an electrophysiology-based assay, using in vivo local field potential recordings, to quantify electrographic seizure-like events. Historically, nearly 90% of drug candidates fail during translation from preclinical models to the clinic. With such a high failure rate, it becomes necessary to address issues of replication and false positive identification. Leveraging our scn1lab zebrafish assays is one approach to address these problems. Here, we curated a list of nine anti-seizure drug candidates recently identified by other groups using preclinical Dravet syndrome models: 1-Ethyl-2-benzimidazolinone, AA43279, chlorzoxazone, donepezil, lisuride, mifepristone, pargyline, soticlestat and vorinostat. First-stage locomotion-based assays in scn1lab mutant zebrafish identified only 1-Ethyl-2-benzimidazolinone, chlorzoxazone and lisuride. However, second-stage local field potential recording assays did not show significant suppression of spontaneous electrographic seizure activity for any of the nine anti-seizure drug candidates. Surprisingly, soticlestat induced frank electrographic seizure-like discharges in wild-type control zebrafish. Taken together, our results failed to replicate clear anti-seizure efficacy for these drug candidates highlighting a necessity for strict scientific standards in preclinical identification of anti-seizure medications.

Prevalence of nonconvulsive seizures and nonconvulsive status epilepticus in dogs and cats with a history of cluster seizures: A retrospective study.

Nonconvulsive seizures (NCS) and nonconvulsive status epilepticus (NCSE) are frequently observed in human patients. Diagnosis of NCS and NCSE only can be achieved by the use of electroencephalography (EEG). Electroencephalographic monitoring is rare in veterinary medicine and consequently there is limited data on frequency of NCS and NCSE. Determine the prevalence of NCS and NCSE in dogs and cats with a history of cluster seizures. Twenty-six dogs and 12 cats. Retrospective study. Medical records of dogs and cats with cluster seizures were reviewed. Electroencephalography was performed in order to identify electrographic seizure activity after the apparent cessation of convulsive seizure activity. Nonconvulsive seizures were detected in 9 dogs and 2 cats out of the 38 patients (29%). Nonconvulsive status epilepticus was detected in 4 dogs and 2 cats (16%). Five patients had both NCS and NCSE. A decreased level of consciousness was evident in 6/11 patients with NCS, 3/6 also had NCSE. Mortality rate for patients with NCS (73%) and NCSE (67%) was much higher than that for patients with no seizure activity on EEG (27%). Prevalence of NCS and NCSE is high in dogs and cats with a history of cluster seizures. Nonconvulsive seizures and NCSE are difficult to detect clinically and are associated with higher in hospital mortality rates. Results indicate that prompt EEG monitoring should be performed in dogs and cats with cluster seizures.

Remote Monitoring for Seizures During Therapeutic Hypothermia in Neonates With Hypoxic-Ischemic Encephalopathy

Neonates with hypoxic-ischemic encephalopathy (HIE) undergoing therapeutic hypothermia (TH) frequently experience seizures, which are associated with adverse outcomes. Efforts to rapidly identify seizures and reduce seizure burden may positively change neurologic and neurodevelopmental outcomes. To describe the onset, treatment, and evolution of seizures in a large cohort of newborns with HIE during TH assisted by a telehealth model and remote neuromonitoring approach. This was a prospective, observational, multicenter cohort study performed between July 2017 and December 2021 in 32 hospitals in Brazil. Participants were newborns with HIE meeting eligibility criteria and receiving TH. Data were analyzed from November 2022 to April 2023. Infants with HIE receiving TH were remotely monitored with 3-channel amplitude-integrated electroencephalography (aEEG) including raw tracing and video imaging, and bedside clinicians received assistance from trained neonatologists and neurologists. Data on modified Sarnat examination, presence, timing and seizure type, aEEG background activity, sleep-wake cycling, and antiepileptic drugs used were collected. Descriptive statistical analysis was used with independent t test, χ2, Mann-Whitney test, and post hoc analyses applied for associations. A total of 872 cooled newborns were enrolled; the median (IQR) gestational age was 39 (38-40) weeks, 518 (59.4%) were male, and 59 (6.8%) were classified as having mild encephalopathy by modified Sarnat examination, 504 (57.8%) as moderate, and 180 (20.6%) as severe. Electrographic seizures were identified in 296 newborns (33.9%), being only electrographic in 213 (71.9%) and clinical followed by electroclinical uncoupling in 50 (16.9%). Early abnormal background activity had a significant association with seizures. Infants with flat trace had the highest rate of seizures (58 infants [68.2%]) and the greatest association with the incidence of seizures (odds ratio [OR], 12.90; 95% CI, 7.57-22.22) compared with continuous normal voltage. The absence of sleep-wake cycling was also associated with a higher occurrence of seizures (OR, 2.22; 95% CI, 1.67-2.96). Seizure onset was most frequent between 6 and 24 hours of life (181 infants [61.1%]); however, seizure occurred in 34 infants (11.5%) during rewarming. A single antiepileptic drug controlled seizures in 192 infants (64.9%). The first line antiepileptic drug was phenobarbital in 294 (99.3%). In this cohort study of newborns with HIE treated with TH, electrographic seizure activity occurred in 296 infants (33.9%) and was predominantly electrographic. Seizure control was obtained with a single antiepileptic drug in 192 infants (64.9%). These findings suggest neonatal neurocritical care can be delivered at remote limited resource hospitals due to innovations in technology and telehealth.

Sex Differences in Organophosphate Model of Benzodiazepine-Refractory Status Epilepticus and Neuronal Damage.

Sex differences are common in human epilepsy. Although men are more susceptible to seizure than women, the mechanisms underlying sex-specific vulnerabilities to seizure are unclear. The organophosphate (OP) diisopropylfluorophosphate (DFP) is known to cause neurotoxicity and status epilepticus (SE), a serious neurologic condition that causes prolonged seizures and brain damage. Current therapies for OP poisoning and SE do not consider neuronal variations between male and female brains. Therefore, we investigated sex-dependent differences in electrographic seizure activity and neuronal injury using the DFP model of refractory SE in rats. Electroencephalogram recordings were used to monitor DFP-induced SE, and the extent of brain injury was determined using fluoro-jade-B staining to detect cellular necrosis. After DFP exposure, we observed striking sex-dependent differences in SE and seizure activity patterns as well as protective responses to midazolam treatment. Following acute DFP exposure, male animals displayed more severe SE with intense epileptiform spiking and greater mortality than females. In contrast, we observed significantly more injured cells and cellular necrosis in the hippocampus and other brain regions in females than in males. We also observed extensive neuronal injury in the somatosensory cortex of males. The anticonvulsant effect of midazolam against SE was limited in this model and found to be similar in males and females. However, unlike males, females exhibited substantially more protection against neuronal damage after midazolam treatment. Overall, these results demonstrate significant sex-dependent differences in DFP-induced refractory SE and neuronal damage patterns, suggesting that it may be possible to develop sex-specific neuroprotective strategies for OP intoxication and refractory SE. SIGNIFICANCE STATEMENT: Sex-dependent differences in neurotoxicity and status epilepticus (SE) are key biological variables after organophosphate (OP) exposure. Here, we investigated sex-dependent differences in SE and brain injury after acute diisopropylfluorophosphate exposure. Male rats had more severe SE and less survival than females, while females had more neuronal damage. Females had more neuroprotection to midazolam than males, while both sexes had similar but partial anticonvulsant effects. These findings suggest that a sex-specific therapeutic approach may prevent neurological complications of OP-induced SE.

Expert and deep learning model identification of iEEG seizures and seizure onset times.

Hundreds of 90-s iEEG records are typically captured from each NeuroPace RNS System patient between clinic visits. While these records provide invaluable information about the patient's electrographic seizure and interictal activity patterns, manually classifying them into electrographic seizure/non-seizure activity, and manually identifying the seizure onset channels and times is an extremely time-consuming process. A convolutional neural network based Electrographic Seizure Classifier (ESC) model was developed in an earlier study. In this study, the classification model is tested against iEEG annotations provided by three expert reviewers board certified in epilepsy. The three experts individually annotated 3,874 iEEG channels from 36, 29, and 35 patients with leads in the mesiotemporal (MTL), neocortical (NEO), and MTL + NEO regions, respectively. The ESC model's seizure/non-seizure classification scores agreed with the three reviewers at 88.7%, 89.6%, and 84.3% which was similar to how reviewers agreed with each other (92.9%-86.4%). On iEEG channels with all 3 experts in agreement (83.2%), the ESC model had an agreement score of 93.2%. Additionally, the ESC model's certainty scores reflected combined reviewer certainty scores. When 0, 1, 2 and 3 (out of 3) reviewers annotated iEEG channels as electrographic seizures, the ESC model's seizure certainty scores were in the range: [0.12-0.19], [0.32-0.42], [0.61-0.70], and [0.92-0.95] respectively. The ESC model was used as a starting-point model for training a second Seizure Onset Detection (SOD) model. For this task, seizure onset times were manually annotated on a relatively small number of iEEG channels (4,859 from 50 patients). Experiments showed that fine-tuning the ESC models with augmented data (30,768 iEEG channels) resulted in a better validation performance (on 20% of the manually annotated data) compared to training with only the original data (3.1s vs 4.4s median absolute error). Similarly, using the ESC model weights as the starting point for fine-tuning instead of other model weight initialization methods provided significant advantage in SOD model validation performance (3.1s vs 4.7s and 3.5s median absolute error). Finally, on iEEG channels where three expert annotations of seizure onset times were within 1.5 s, the SOD model's seizure onset time prediction was within 1.7 s of expert annotation.

Sex and estrous cycle stage shape left-right asymmetry in chronic hippocampal seizures in mice.

Lateralization of hippocampal function is indicated by varied outcomes of patients with neurological disorders that selectively affect one hemisphere of this structure, such as temporal lobe epilepsy (TLE). The intrahippocampal kainic acid (IHKA) injection model of TLE allows for targeted damage to the left or right hippocampus, enabling systematic comparison of effects of left-right asymmetry on seizure and non-seizure outcomes. Although varying non-seizure phenotypic outcomes based on injection side in dorsal hippocampus were recently evaluated in this model, differences in chronic seizure patterns in left- (IHKA-L) vs. right-injected (IHKA-R) IHKA animals have yet to be evaluated. Here, we assessed hippocampal seizure incidence in male and female IHKA-L and IHKA-R mice. Females displayed increased electrographic seizure activity compared to males at both 2 and 4 months post-injection. In addition, IHKA-L females showed higher seizure frequency than IHKA-R on diestrus and estrus at 2 months post-injection, but seizure duration and percent time in seizures were only higher in IHKA-L females on diestrus. These cycle stage-associated changes, however, did not persist to 4 months post-injection. Furthermore, this lateralized difference in seizure burden was not observed in males. These results indicate for the first time that the side of IHKA injection can shape chronic electrographic seizure burden. Overall, these results demonstrate a female-specific left-right asymmetry in hippocampal function can interact with estrous cycle stage to shape chronic seizures in mice with epilepsy, with implications for neural activity and behavior in both normal and disease states.Significance StatementSeizures in temporal lobe epilepsy often originate in the hippocampus, and patient outcomes can depend on whether the seizures initiate in the left or right hippocampus. Although rodent brain function appears less lateralized than in humans, emerging evidence indicates stronger lateralization of hippocampal function in mice than previously thought. Here, we systematically compared chronic epilepsy profiles in mice based on whether left or right hippocampus is the main site of seizure generation. Males did not show a left-right asymmetry in epilepsy severity, but females showed effects of seizure initiation side that varied with estrous cycle stage. These results thus suggest a female-specific lateralization of hippocampal function can interact with the estrous cycle to shape chronic seizures in mice with epilepsy.

Efficacy of the FDA-approved cannabidiol on the development and persistence of temporal lobe epilepsy and complex focal onset seizures

Presently there is no drug therapy for curing epilepsy. Despite many advancements in epilepsy research, nearly 30% of people with epilepsy remain refractory to current antiseizure medications (ASM). Cannabidiol (CBD) has recently been approved as an ASM for pediatric refractory seizures, but it has not been widely tested for adult epileptogenesis and focal onset seizures. In this study, we investigated the efficacy of the FDA-approved CBD in controlling epileptogenesis and complex focal onset seizures using the mouse kindling model of human temporal lobe epilepsy. We also tested combination regimens of CBD with other ASMs. The two primary outcome measures were disease modification and suppression of generalized seizures. In the epileptogenesis study, CBD had a striking effect in attenuating kindling development, with a dose-dependent decrease in behavioral and electrographic seizure activity. In the retention study, mice previously treated with CBD had significantly reduced overall seizure burden, suggesting disease modification. In a fully-kindled seizure study, CBD produced rapid and atypical U-shaped dose-dependent protection against generalized seizures (ED50, 52 mg/kg, i.p.). In a time-course study, CBD showed a maximal protective effect within 1 h of injection, and it declined within 4 h with a biphasic response. In the combination study, CBD produced synergistic/ additive protection when given with midazolam and ganaxolone but not with tiagabine, indicating its strong potential as an adjunct ASM. Finally, the protective effects of CBD were not associated with motor and functional impairments. These preclinical findings demonstrate the potential of adjunct CBD for controlling adult complex focal onset seizure conditions.

Pathway-specific inhibition of critical projections from the mediodorsal thalamus to the frontal cortex controls kindled seizures.

There is a large unmet need for improved treatment for temporal lobe epilepsy (TLE); circuit-specific manipulation that disrupts the initiation and propagation of seizures is promising in this regard. The midline thalamus, including the mediodorsal nucleus (MD) is a critical distributor of seizure activity, but its afferent and efferent pathways that mediate seizure activity are unknown. Here, we used chemogenetics to silence input and output projections of the MD to discrete regions of the frontal cortex in the kindling model of TLE in rats. Chemogenetic inhibition of the projection from the amygdala to the MD abolished seizures, an effect that was replicated using optogenetic inhibition. Chemogenetic inhibition of projections from the MD to the prelimbic cortex likewise abolished seizures. By contrast, inhibition of projections from the MD to other frontal regions produced partial (orbitofrontal cortex, infralimbic cortex) or no (cingulate, insular cortex) attenuation of behavioral or electrographic seizure activity. These results highlight the particular importance of projections from MD to prelimbic cortex in the propagation of amygdala-kindled seizures.

Clemizole and trazodone are effective antiseizure treatments in a zebrafish model of STXBP1 disorder.

CRISPR‐Cas9–generated zebrafish carrying a 12 base‐pair deletion in stxbpb1b, a paralog sharing 79% amino acid sequence identity with human, exhibit spontaneous electrographic seizures during larval stages of development. Zebrafish stxbp1b mutants provide an efficient preclinical platform to test antiseizure therapeutics. The present study was designed to test antiseizure medications approved for clinical use and two recently identified repurposed drugs with antiseizure activity. Larval homozygous stxbp1b zebrafish (4 days postfertilization (dpf)) were agarose‐embedded and monitored for electrographic seizure activity using a local field recording electrode placed in midbrain. Frequency of ictal‐like events was evaluated at baseline and following 45 min of continuous drug exposure (1 mM, bath application). Analysis was performed on coded files by an experimenter blinded to drug treatment and genotype. Phenytoin (PHT), valproate (VPA), ethosuximide (ESX), levetiracetam (LEV), and diazepam (DZP) had no effect on the ictal‐like event frequency in stxbp1b mutant zebrafish. Clemizole and trazodone decreased ictal‐like event frequency in stxbp1b mutant zebrafish by 80% and 83%, respectively. These results suggest that repurposed drugs with serotonin receptor–binding affinities could be effective antiseizure treatments. Clemizole and trazodone were previously identified in a larval zebrafish model for Dravet syndrome. Based primarily on these preclinical zebrafish studies, compassionate‐use and double‐blind clinical trials with both drugs have progressed. The present study extends this approach to a preclinical zebrafish model representing STXBP1 (syntaxin‐binding protein 1)‐related disorders and suggests that future clinical studies may be warranted.

Status Epilepticus Diagnostic and Management Approach in Emergency Department

Status Epilepticus (SE) is a condition that arises from existing neurological disorders, including epilepsy syndromes. It refers to a state of incessant clinical and/or electrographic seizure activity, or recurrent seizure activity within 5 minutes during which the patient does not recover to a normal level of consciousness between seizures. It is also a medical emergency with a high complication rate. The Medline, PubMed, Embase, NCBI, and Cochrane databases were searched for studies of patient

Association Between Increased Seizures During Rewarming After Hypothermia for Neonatal Hypoxic Ischemic Encephalopathy and Abnormal Neurodevelopmental Outcomes at 2-Year Follow-up

Compared with normothermia, hypothermia has been shown to reduce death or disability in neonatal hypoxic ischemic encephalopathy but data on seizures during rewarming and associated outcomes are scarce. To determine whether electrographic seizures are more likely to occur during rewarming compared with the preceding period and whether they are associated with abnormal outcomes in asphyxiated neonates receiving hypothermia therapy. This prespecified nested cohort study of infants enrolled in the Optimizing Cooling (OC) multicenter Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network trial from December 2011 to December 2013 with 2 years' follow-up randomized infants to either 72 hours of cooling (group A) or 120 hours (group B). The main trial included 364 infants. Of these, 194 were screened, 10 declined consent, and 120 met all predefined inclusion criteria. A total of 112 (90%) had complete data for death or disability. Data were analyzed from January 2018 to January 2020. Serial amplitude electroencephalography recordings were compared in the 12 hours prior and 12 hours during rewarming for evidence of electrographic seizure activity by 2 central amplitude-integrated electroencephalography readers blinded to treatment arm and rewarming epoch. Odds ratios and 95% CIs were evaluated following adjustment for center, prior seizures, depth of cooling, and encephalopathy severity. The primary outcome was the occurrence of electrographic seizures during rewarming initiated at 72 or 120 hours compared with the preceding 12-hour epoch. Secondary outcomes included death or moderate or severe disability at age 18 to 22 months. The hypothesis was that seizures during rewarming were associated with higher odds of abnormal neurodevelopmental outcomes. A total of 120 newborns (70 male [58%]) were enrolled (66 in group A and 54 in group B). The mean (SD) gestational age was 39 (1) weeks. There was excellent interrater agreement (κ, 0.99) in detection of seizures. More infants had electrographic seizures during the rewarming epoch compared with the preceding epoch (group A, 27% vs 14%; P = .001; group B, 21% vs 10%; P = .03). Adjusted odd ratios (95% CIs) for seizure frequency during rewarming were 2.7 (1.0-7.5) for group A and 3.2 (0.9-11.6) for group B. The composite death or moderate to severe disability outcome at 2 years was significantly higher in infants with electrographic seizures during rewarming (relative risk [95% CI], 1.7 [1.25-2.37]) after adjusting for baseline clinical encephalopathy and seizures as well as center. Findings that higher odds of electrographic seizures during rewarming are associated with death or disability at 2 years highlight the necessity of electroencephalography monitoring during rewarming in infants at risk. ClinicalTrials.gov Identifier: NCT01192776.

Wearable Reduced-Channel EEG System for Remote Seizure Monitoring.

Epitel has developed Epilog, a miniature, wireless, wearable electroencephalography (EEG) sensor. Four Epilog sensors are combined as part of Epitel's Remote EEG Monitoring platform (REMI) to create 10 channels of EEG for remote patient monitoring. REMI is designed to provide comprehensive spatial EEG recordings that can be administered by non-specialized medical personnel in any medical center. The purpose of this study was to determine how accurate epileptologists are at remotely reviewing Epilog sensor EEG in the 10-channel “REMI montage,” with and without seizure detection support software. Three board certified epileptologists reviewed the REMI montage from 20 subjects who wore four Epilog sensors for up to 5 days alongside traditional video-EEG in the EMU, 10 of whom experienced a total of 24 focal-onset electrographic seizures and 10 of whom experienced no seizures or epileptiform activity. Epileptologists randomly reviewed the same datasets with and without clinical decision support annotations from an automated seizure detection algorithm tuned to be highly sensitive. Blinded consensus review of unannotated Epilog EEG in the REMI montage detected people who were experiencing electrographic seizure activity with 90% sensitivity and 90% specificity. Consensus detection of individual focal onset seizures resulted in a mean sensitivity of 61%, precision of 80%, and false detection rate (FDR) of 0.002 false positives per hour (FP/h) of data. With algorithm seizure detection annotations, the consensus review mean sensitivity improved to 68% with a slight increase in FDR (0.005 FP/h). As seizure detection software, the automated algorithm detected people who were experiencing electrographic seizure activity with 100% sensitivity and 70% specificity, and detected individual focal onset seizures with a mean sensitivity of 90% and mean false alarm rate of 0.087 FP/h. This is the first study showing epileptologists' ability to blindly review EEG from four Epilog sensors in the REMI montage, and the results demonstrate the clinical potential to accurately identify patients experiencing electrographic seizures. Additionally, the automated algorithm shows promise as clinical decision support software to detect discrete electrographic seizures in individual records as accurately as FDA-cleared predicates.

Phenotypic analysis of catastrophic childhood epilepsy genes

Genetic engineering techniques have contributed to the now widespread use of zebrafish to investigate gene function, but zebrafish-based human disease studies, and particularly for neurological disorders, are limited. Here we used CRISPR-Cas9 to generate 40 single-gene mutant zebrafish lines representing catastrophic childhood epilepsies. We evaluated larval phenotypes using electrophysiological, behavioral, neuro-anatomical, survival and pharmacological assays. Local field potential recordings (LFP) were used to screen ∼3300 larvae. Phenotypes with unprovoked electrographic seizure activity (i.e., epilepsy) were identified in zebrafish lines for 8 genes; ARX, EEF1A, GABRB3, GRIN1, PNPO, SCN1A, STRADA and STXBP1. We also created an open-source database containing sequencing information, survival curves, behavioral profiles and representative electrophysiology data. We offer all zebrafish lines as a resource to the neuroscience community and envision them as a starting point for further functional analysis and/or identification of new therapies.

Autistic-like behavior, spontaneous seizures, and increased neuronal excitability in a Scn8a mouse model.

Patients with SCN8A epileptic encephalopathy exhibit a range of clinical features, including multiple seizure types, movement disorders, and behavioral abnormalities, such as developmental delay, mild-to-severe intellectual disability, and autism. Recently, the de novo heterozygous SCN8A R1620L mutation was identified in an individual with autism, intellectual disability, and behavioral seizures without accompanying electrographic seizure activity. To date, the effects of SCN8A mutations that are primarily associated with behavioral abnormalities have not been studied in a mouse model. To better understand the phenotypic and functional consequences of the R1620L mutation, we used CRISPR/Cas9 technology to generate mice expressing the corresponding SCN8A amino acid substitution. Homozygous mutants exhibit tremors and a maximum lifespan of 22 days, while heterozygous mutants (RL/+) exhibit autistic-like behaviors, such as hyperactivity and learning and social deficits, increased seizure susceptibility, and spontaneous seizures. Current clamp analyses revealed a reduced threshold for firing action potentials in heterozygous CA3 pyramidal neurons and reduced firing frequency, suggesting that the R1620L mutation has both gain- and loss-of-function effects. In vivo calcium imaging using miniscopes in freely moving RL/+ mutants showed hyperexcitability of cortical excitatory neurons that is likely to increase seizure susceptibility. Finally, we found that oxcarbazepine and Huperzine A, a sodium channel blocker and reversible acetylcholinesterase inhibitor, respectively, were capable of conferring robust protection against induced seizures in RL/+ mutants. This mouse line will provide the opportunity to better understand the range of clinical phenotypes associated with SCN8A mutations and to develop new therapeutic approaches.

Zebrafish model of posttraumatic epilepsy

Posttraumatic epilepsy (PTE) is defined as recurrent and unprovoked seizures occurring >1week after traumatic brain injury (TBI). Animal studies of PTE are lengthy and expensive. In this study, we developed a cost-effective PTE animal model using zebrafish to bridge the gap between in vitro studies and low-throughput animal studies. We used two different sets of parameters (G1 and G2) to induce closed-head TBI in adult zebrafish using pulsed high-intensity focused ultrasound. Injured fish and naive controls were evaluated for behavioral deficits and spontaneous behavioral seizure activity up to 21 days postinjury (DPI). We also assessed behavioral seizure susceptibility to a subconvulsive dose of pentylenetetrazole (PTZ; 2.5mmol·L-1 ) and recorded electrophysiological signals to confirm seizure activity up to 40 DPI. In addition, we investigated injury-related changes in the blood-brain barrier and expression levels of various proteins altered in rodent and human TBI. The G2 parameters resulted in a more severe TBI, with a mortality rate of 25%, as well as motor dysfunction and heightened anxiety persisting at 21 DPI. One hundred percent of the G2 group showed spontaneous myocloniclike behavior, and 80% demonstrated tonic-clonic-like behavioral seizures by 21 DPI. Such activities were not detected in the naive group. After the application of 2.5mmol·L-1 PTZ, 100% of injured zebrafish had cloniclike seizures at 21 DPI, versus 30% of the naive group. We also demonstrated electrographic seizure activity at 40 DPI, which was not detected in the naive controls. Lastly, we observed acute blood-brain barrier dysfunction and increased levels of HMGB1 and ratios of phosphorylated/total Akt and tau through 21 DPI. Together, the results indicate that severe TBI in the adult zebrafish leads to similar behavioral and physiological changes to those of more traditional models, including the development of PTE, and suggest this may be a useful model that can accelerate research in TBI/PTE.

INNV-38. RATE OF EEG IN GLIOMA PATIENTS: SHOULD THIS BE PART OF STANDARD OF CARE FOR NEW BRAIN TUMOR PATIENTS?

Abstract Current guidelines recommend antiepileptic drug (AED) therapy for glioma patients only in patients who have experienced a seizure. There is no current recommendation in regards to performing EEG monitoring in glioma patients. Thus, typically only clinical seizures have prompted AED therapy in glioma patients. Our purpose was to investigate the rate of EEG monitoring in glioma patients entered into our glioma registry, along with seizure and AED rates. Using our glioma registry to date, of 167 glioma patients, 119 patients had EEGs performed during their clinical course. Of those 119 patients, 104 glioma patients had either clinical or electrographic seizure activity and all 104 were on AEDs. This observation indicates that baseline eeg monitoring might be considered in all newly diagnosed glioma patients to reduce seizure incidence, potentially, starting AED prophylaxis if epileptiform activity is seen on EEG prior to clinical seizure activity to potentially reduce morbidity and healthcare costs related to clinical seizure activity. This warrants further prospective study.

Case 1: An Infant with Arm Swelling and Nodules

A male neonate is born via spontaneous vaginal delivery to a 28-year-old primiparous woman at 39 2/7 weeks of gestation after an uncomplicated pregnancy. Labor is complicated by prolonged fetal heart rate decelerations, but the mother declines a cesarean section and vacuum extraction is initially unsuccessful. At birth the neonate is apneic but maintains a heart rate greater than 100 beats/min throughout the resuscitation. He requires intubation for persistent apnea 4 minutes after birth. His Apgar scores are 2, 3, 5, and 5 at 1, 5, 10, and 20 minutes, respectively. His physical examination on admission to the NICU is significant for diffuse hypotonia, lethargy, and absence of primitive reflexes. His arterial blood gas measurement 1.5 hours after birth shows a pH of 7.32, Pco2 of 32 mm Hg, and base deficit of 9. A blood culture specimen is collected and he starts empiric treatment with ampicillin and gentamicin. The infant is transferred to a tertiary care NICU for therapeutic hypothermia and has moderate encephalopathy on admission. He has a fluctuant, boggy mass over his occipital skull and undergoes noncontrast head computed tomography, which shows a large subgaleal hemorrhage, skull fracture, and small ventricles concerning for cerebral edema. A significant drop in his hematocrit is noted, and he receives transfusions of packed red blood cells and fresh frozen plasma. He requires a dopamine infusion and stress-dose hydrocortisone to maintain age-appropriate blood pressures. Electroencephalography (EEG) shows electrographic and clinical seizure activity, which is …

Continuous EEG Monitoring-The Neurologist's Crystal Ball.

Time to Epileptiform Activity and EEG Background Recovery Are Independent Predictors After Cardiac Arrest Westhall E, Rose I, Rundgren M, Bro-Jeppesen J, Kjaergaard J, Hassager C, Lindehammar H, Horn J, Ullen S, Nielsen N, Friberg H, Cronberg T. Clin Neurophysiol. 2018;129:1660-1668. doi:10.1016/j.clinph.2018.05.016Objective: To investigate the temporal development of electroencephalogram (EEG) and prognosis. Methods: Prospective observational substudy of the Target Temperature Management trial. Six sites performed simplified continuous EEG monitoring (cEEG) on comatose patients after cardiac arrest, blinded to treating physicians. We determined time points of recovery of a normal-voltage continuous background activity and the appearance of an epileptiform EEG, defined as abundant epileptiform discharges, periodic/rhythmic discharges, or electrographic seizure activity. Results: One hundred thirty-four patients were included, of which 65 had a good outcome. Early recovery of continuous background activity (within 24 hours) occurred in 72 patients and predicted good outcome since 55 (76%) had good outcome, increasing the odds for a good outcome 7 times compared to a late background recovery. Early appearance of an epileptiform EEG occurred in 38 patients and 34 (89%) had a poor outcome, increasing the odds for a poor outcome 6 times compared to a late debut. The time to background recovery and the time to epileptiform activity were highly associated with outcome and levels of neuron-specific enolase. Multiple regression analysis showed that both variables were independent predictors. Conclusions: Time to epileptiform activity and background recovery are independent prognostic indicators. SIGNIFICANCE: Patients with early background recovery combined with late appearance of epileptiform activity may have a good outcome.

The diagnostic value of continuous EEG for the detection of non-convulsive status epilepticus in neurosurgical patients – A prospective cohort study

ObjectiveTo prospectively compare the diagnostic yields of standard EEG and continuous EEG (cEEG) monitoring for the diagnosis of non-convulsive status epilepticus (NCSE) in neurosurgical patients in the intensive care unit. MethodsWe included 50 consecutive patients with clinical suspicion of NCSE due to unexplained coma or subtle clinical phenomena such as discrete myoclonus. The initial 30-minute EEG recording and the following cEEG were analyzed separately for seizure activity. Data were collected on neurosurgical diagnosis, previous diagnosis of epilepsy, current medication, level of consciousness, and outcome at discharge from the neurosurgical department. ResultsRecurrent electrographic seizure activity was detected in five patients. This was within the first 30 mins for three patients and on the following cEEG for two patients. Antiepileptic treatment had been initiated in three of these patients. Most of the 50 patients had severe newly acquired neurological disability at discharge. ConclusionsThe prospective finding of a 10% seizure incidence was lower than reports from retrospective studies. SignificanceUse of cEEG led to detection of seizure activity in 2 of 50 patients (4%) and was thus a low-yield method in neurosurgical patients with suspicion of NCSE. Specific markers for patient selection for cEEG are needed.