Seizure Termination Research Articles

Investigating the role of gap junctions in seizure wave propagation.

The effect of gap junctions as well as the biological mechanisms behind seizure wave propagation is not completely understood. In this work, we use a simple neural field model to study the possible influence of gap junctions specifically on cortical wave propagation that has been observed in vivo preceding seizure termination. We consider a voltage-based neural field model consisting of an excitatory and an inhibitory population as well as both chemical and gap junction-like synapses. We are able to approximate important properties of cortical wave propagation previously observed in vivo before seizure termination. This model adds support to existing evidence from models and clinical data suggesting a key role of gap junctions in seizure wave propagation. In particular, we found that in this model gap junction-like connectivity determines the propagation of one-bump or two-bump traveling wave solutions with features consistent with the clinical data. For sufficiently increased gap junction connectivity, wave solutions cease to exist. Moreover, gap junction connectivity needs to be sufficiently low or moderate to permit the existence of linearly stable solutions of interest.

Effect of a novel prolonged febrile seizure model on GABA associated ion channels.

Prolonged febrile seizures are usually modelled in animals using hyperthermia as an inducer. In this study, a modified simple febrile seizure model using a combination of lipopolysaccharide (LPS) and kainic acid (KA) was used to develop a prolonged febrile seizure animal model, which we used to assess effects on the expression of the sodium- potassium-chloride cotransporter 1 (NKCC1) and potassium-chloride cotransporter 2 (KCC2) and their possible role in seizure exacerbation. At post-natal day (PND) 14, rat pups were divided into a saline (S), simple febrile seizure (FSA-), prolonged febrile seizure (FSB-), saline A (SA+) and saline B (SB+) groups. SA+ and SB+ groups received different concentrations of KA (1.75mg/kg, 1.83μg/kg respectively) but no LPS. Changes in temperature, seizure activity and duration were recorded. Gene and protein expression of NKCC1, KCC2 and KCC2 phosphorylated serine (KCC2 ser) 940 were measured 1h post seizure termination and on PND 15 using RT- PCR and western blot. There was an initial increase in temperature that was immediately followed by a temperature decrease and an increase in seizure severity and duration in the FSB- group. There was a decrease in KCC2 ser 940 protein expression. NKCC1 protein expression was increased in both FS groups suggesting decreased GABA receptor functionality. Therefore, the novel FSB- model resulted in more severe and sustained seizure activity by altering cotransporter gene and protein expression. This suggests that this model can be used to mimic prolonged febrile seizures and hence can be used to investigate the physiological changes accompanying this condition.

Acute metabolic effects of tonic-clonic seizures.

ObjectiveTonic‐clonic seizures (TCS) lead to metabolic stress and changes in related blood markers. Such markers may indicate harmful conditions but can also help to identify TCS as a cause of transient loss of consciousness. In this study, we hypothesized that the alterations of circulating markers of metabolic stress depend on the clinical features of TCS.MethodsNinety‐one adults undergoing video‐EEG monitoring participated in this prospective study. Electrolytes, renal parameters, creatine kinase (CK), prolactin (PRL), lactate, ammonia, glucose, and other parameters were measured at inclusion and different time points after TCS.ResultsA total of 39 TCS were recorded in 32 patients (six generalized onset tonic‐clonic seizures in 6 and 33 focal to bilateral tonic‐clonic seizures in 26 patients). Shortly after TCS, mean lactate, ammonia, and PRL levels were significantly increased 8.7‐fold, 2.6‐fold, and 5.1‐fold, respectively, with levels of more than twofold above the upper limits of the normal (ULN) in 90%, 71%, and 70% of the TCS and returned to baseline levels within 2 hours. Only postictal lactate levels were significantly correlated with the total duration of the tonic‐clonic phase. In contrast, CK elevations above the ULN were found in three TCS (~10%) only with a peak after 48 hours. Immediately after the TCS, hyperphosphatemia occurred in one third of the patients, whereas hypophosphatemia was observed in one third 2 hours later. TCS led to subtle but significant alterations of other electrolytes, creatinine, and uric acid, whereas glucose levels were moderately increased.SignificanceLactate is a robust metabolic marker of TCS with elevations found in ~90% of cases within 30 minutes after seizure termination, whereas ammonia rises in ~ 70%, similarly to PRL. Phosphate levels show an early increase and a decrease 2 hours after TCS in a third of patients. CK elevations are rare after video‐EEG‐documented TCS, challenging its value as a diagnostic marker.

Lessons from the Established Status Epilepticus Treatment Trial

Convulsive status epilepticus (SE) is a relatively common emergency condition affecting individuals of all ages. The primary goal of treatment is prompt termination of seizures. Where first-line treatment with benzodiazepine has failed to achieve this, a condition known as established SE (ESE), there is uncertainty about which agent to use next. The Established Status Epilepticus Treatment Trial (ESETT) is a 3-arm (valproate (VPA), fosphenytoin (FOS), levetiracetam (LEV)), phase III, double-blind randomized comparative effectiveness study in patients aged 2 years and above with established convulsive SE. Enrollment was completed in January 2019, and the results are expected later this year. We discuss lessons learnt during the conduct of the study in relation to the following: ethical considerations; trial design and practical implementation in emergency settings, including pediatric and adult populations; quality assurance; and outcome determination where treating emergency clinicians may lack specialist expertise. We consider that the ESETT is already informing both clinical practice and future trial design.This article is part of the Special Issue “Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures"

Status epilepticus: Management and prognosis

Status epilepticus is one of the most common neurological emergencies. Its incidence in adults is 36.1/100.000 per year (Leitinger et al. Epilepsia 2019). Less than half of the patients had previous seizures. Mortality varies according to the type of SE: case fatality is lower in awake patients (8.2%) compared with patients with impaired consciousness (33%) (Leitinger et al. Epilepsia 2019). SE is defined as “a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms, which lead to abnormally, prolonged seizures (after time point t1). It is a condition, which can have long-term consequences (after time point t2), including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures”. (Trinka et al. Epilepsia 2015). It is a highly dynamic condition, which requires early diagnosis and treatment to prevent long term consequences. About 60% of patients in Convulsive SE (CSE) will be controlled by first line treatment (Trinka et al. Expert Opin Pharmacother. 2016). Recent studies suggest, that there is significant undertreatment in the early stages of status: Up to 80% receive not the recommended dose of Benzodiazepines (Kellinghaus et al. Ann Neurol 2019). If treatment is delayed, or the patient does not respond to adequate Benzodiazepines the stage of refractory SE (RSE) is reached, where anaesthetic treatments are necessary. The causes of SE must be identified by all means [8]. Common causes should be established in the first hours and treated appropriately, if causes cannot be identified the term NORSE (New Onset RSE) is used. At this stage extensive investigations are necessary to identify (and treat) the cause. In nearly 50% of cases, the probable cause of NORSE can eventually be determined. (Gaspard et al. Neurology 2015). The most commonly identified etiologies include autoimmune (19%) and paraneoplastic encephalitis (18%) or infection-related (8%). Once the patient is under general anaesthesia, major complications, such as pneumonia, immunosuppression, acidosis, metabolic derangements, cardiac suppression, gastric paresis, and others have to be managed appropriately. Overall RSE and super-refractory SE (SRSE), which does not respond to > 24h of general anaesthesia, is rare (7.2 and 1.2 / 100.000 / year), but mortality is highest in this group (Leitinger et al. Epilepsia 2019). One of the main diagnostic challenges at this stage, which is still unsolved, is the distinction between coma due to SE and coma with SE like EEG patterns (Trinka and Bauer Epilepsia 2009). This presentation will give an up to date overview on management and prognosis of SE.[1Bauer G. Trinka E. Nonconvulsive status epilepticus and coma.Epilepsia. 2010; 51: 177-190Google Scholar, 2Gaspard N. Foreman B.P. Alvarez V. Cabrera Kang C. Probasco J.C. Jongeling A.C. Meyers E. Espinera A. Haas K.F. Schmitt S.E. Gerard E.E. Gofton T. Kaplan P.W. Lee J.W. Legros B. Szaflarski J.P. Westover B.M. LaRoche S.M. Hirsch L.J. Critical Care EEG Monitoring Research Consortium (CCEMRC). New-onset refractory status epilepticus: Etiology, clinical features, and outcome.Neurology. 2015; 85: 1604-1613Google Scholar, 3Hirsch L.J. Gaspard N. van Baalen A. Nabbout R. Demeret S. Loddenkemper T. Navarro V. Specchio N. Lagae L. Rossetti A.O. Hocker S. Gofton T.E. Abend N.S. Gilmore E.J. Hahn C. Khosravani H. Rosenow F. Trinka E. Proposed consensus definitions for new-onset refractory status epilepticus (NORSE), febrile infection-related epilepsy syndrome (FIRES), and related conditions.Epilepsia. 2018; 59: 739-744Google Scholar, 4Kellinghaus C. Rossetti A.O. Trinka E. Lang N. May T.W. Unterberger I. Rüegg S. Sutter R. Strzelczyk A. Tilz C. Uzelac Z. Rosenow F. Factors predicting cessation of status epilepticus in clinical practice: Data from a prospective observational registry (SENSE).Ann Neurol. 2019; 85: 421-432Google Scholar, 5Leitinger M. Trinka E. Giovannini G. Zimmermann G. Florea C. Rohracher A. Kalss G. Neuray C. Kreidenhuber R. Höfler J. Kuchukhidze G. Granbichler C. Dobesberger J. Novak H.F. Pilz G. Meletti S. Siebert U. Epidemiology of status epilepticus in adults: A population-based study on incidence, causes, and outcomes.Epilepsia. 2019; 60: 53-62Google Scholar, 6Trinka E. Cock H. Hesdorffer D. Rossetti A.O. Scheffer I.E. Shinnar S. Shorvon S. Lowenstein D.H. A definition and classification of status epilepticus--Report of the ILAE Task Force on Classification of Status Epilepticus.Epilepsia. 2015; 56: 1515-1523Google Scholar, 7Trinka E. Höfler J. Leitinger M. Rohracher A. Kalss G. Brigo F. Pharmacologic treatment of status epilepticus.Expert Opin Pharmacother. 2016; 17: 513-534Google Scholar, 8Trinka E. Höfler J. Zerbs A. Causes of status epilepticus.Epilepsia. 2012; 53: 127-138Google Scholar]

A combined astrocyte – G-lymphatic model of epilepsy initiation, maintenance and termination

Although epilepsy afflicts numerous people worldwide, its dynamics are still controversial. Especially seizure termination is relatively unidentified. Here we suggest a coherent explanation to all stages of epilepsy, its genesis, seizure initiation and termination. We present biophysical features that could account for the phenomenon: all phases of epilepsy can be related to the brain’s “waste disposal” systems. Although problems in the astrocytic system have already been suggested as a major player in this malfunction, the termination phase is not really understood. Here it is assumed to arise from a G-lymphatic clearance system.Our biophysical mechanism provides a coherent explanation of the phenomenon, offers support for the previously published mathematical model, and can shed light on the conflicting results encountered in norepinephrine measurements in epilepsy treatment.

Isolated effective coherence analysis of epileptogenic networks in temporal lobe epilepsy using stereo-electroencephalography

Stereo-electroencephalography (SEEG) is widely used to record the electrical activity of patients' brain in clinical. The SEEG-based epileptogenic network can better describe the origin and the spreading of seizures, which makes it an important measure to localize epileptogenic zone (EZ). SEEG data from six patients with refractory epilepsy are used in this study. Five of them are with temporal lobe epilepsy, and the other is with extratemporal lobe epilepsy. The node outflow (out-degree) and inflow (in-degree) of information are calculated in each node of epileptic network, and the overlay between selected nodes and resected nodes is analyzed. In this study, SEEG data is transformed to bipolar montage, and then the epileptic network is established by using independent effective coherence (iCoh) method. The SEEG segments at onset, middle and termination of seizures in Delta, Theta, Alpha, Beta, and Gamma rhythms are used respectively. Finally, the K-means clustering algorithm is applied on the node values of out-degree and in-degree respectively. The nodes in the cluster with high value are compared with the resected regions. The final results show that the accuracy of selected nodes in resected region in the Delta, Alpha and Beta rhythm are 0.90, 0.88 and 0.89 based on out-degree values in temporal lobe epilepsy patients respectively, while the in-degree values cannot differentiate them. In contrast, the out-degree values are higher outside the temporal lobe in the patient with extratemporal lobe epilepsy. Based on the out-degree feature in low-frequency epileptic network, this study provides a potential quantitative measure for identifying patients with temporal lobe epilepsy in clinical.

High incidence of status epilepticus and ongoing seizures on arrival to the hospital due to high prevalence of febrile seizures in Izumo, Japan: A questionnaire-based study

ObjectivesTo determine the incidence of prolonged febrile seizures and status epilepticus in the first three years of life. MethodsA questionnaire was sent to 1560 families between April 2016 and March 2017 before their child attended a routine health check at three years of age in Izumo, Shimane prefecture, Japan. The questionnaire included an overview of febrile seizures, including the age at which febrile seizures occurred, the duration, and how the condition was managed. ResultsWe received 1089 (69.8%) responses and these showed that 134 (12.3%) children had a history of febrile seizures. Fourteen children with febrile seizures (10.4%) had prolonged seizures lasting 10–30 min and six children (4.5%) had status epilepticus. Ongoing febrile seizures that did not terminate on arrival to the hospital were observed in 11 children (8.2%) with febrile seizures. The incidence rates of status epilepticus, prolonged febrile seizures including status epilepticus and ongoing febrile seizures were 184, 612 and 337 per 100,000 children aged 36 months or less, respectively. ConclusionsThere was a greater incidence of status epilepticus than previously thought, possibly due to the high prevalence of febrile seizures in Japan. Eight percent of children with febrile seizures were seizing on arrival to the hospital. These ongoing seizures requiring emergency interventions were almost twice more than status epilepticus. Thus, it is necessary to develop an early intervention for the termination of prolonged febrile seizures.

Prevention, Treatment, and Monitoring of Seizures in the Intensive Care Unit.

The diagnosis and management of seizures in the critically ill patient can sometimes present a unique challenge for practitioners due to lack of exposure and complex patient comorbidities. The reported incidence varies between 8% and 34% of critically ill patients, with many patients often showing no overt clinical signs of seizures. Outcomes in patients with unidentified seizure activity tend to be poor, and mortality significantly increases in those who have seizure activity longer than 30 min. Prompt diagnosis and provision of medical therapy are crucial in order to attain successful seizure termination and prevent poor outcomes. In this article, we review the epidemiology and pathophysiology of seizures in the critically ill, various seizure monitoring modalities, and recommended medical therapy.

Comparison of intranasal midazolam versus intravenous lorazepam for seizure termination and prevention of seizure clusters in the adult epilepsy monitoring unit

ObjectiveThe objective of the study was to compare the performance of intravenous (IV) lorazepam (IVL) and intranasal midazolam (INM) for seizure termination and prevention of seizure clusters in adults admitted to the epilepsy monitoring unit (EMU) in whom seizures were captured on continuous video-electroencephalogram. MethodsRetrospective cohort of consecutive adults (≥18 years) with epilepsy admitted to the EMU at a single tertiary academic center, who experienced epileptic seizures (confirmed electroencephalographically) and required rescue therapy. The study spanned from January 2015 until December 2016, which included one year before and one year after transitioning from IVL to INM as the standard rescue therapy at our institution. ResultsA total of 50 subjects received rescue therapy and were included in the analysis. In the first year, out of 216 patients with epilepsy admitted to the EMU, 27 (13%) received IVL; in the second year, 23/217 (11%) received INM. There were no differences in baseline characteristics and markers of epilepsy severity, the median duration of index seizure (1.7 min [interquartile range (IQR): 1.1–2.7] in IVL vs. 2.0 min [IQR: 1.5–2.6] in INM group, p = 0.20), or in the number of subjects requiring repeat benzodiazepine administrations (IVL 8/27 [29.6%] vs. INM 7/23 [30.4%], p = 0.95). There were no differences in the median number of recurrent seizures in 24 h (1 [IQR: 1–3] in IVL vs. 2 [IQR: 1–4] in INM, p = 0.27), occurrence of status epilepticus (IVL 4/27 [14.8%] subjects vs. INM 1/23 [4.3%] subjects, p = 0.36), incidence of seizure clusters (IVL 8/27 [29.6%] subjects vs. INM 7/23 [30.4%] subjects, p = 0.95), need for transfer to an intensive care unit (ICU), or other adverse events. SignificanceIn our retrospective study, INM was comparable with IVL for seizure termination and prevention of seizure clusters in the adult EMU. Intranasal midazolam circumvents the need for IV access to be maintained throughout hospitalization and is an attractive alternative to IVL as a rescue therapy in this setting. Ideally, future large, prospective, randomized, and double blind studies are needed to confirm these findings.

Safety and efficacy of midazolam nasal spray in the outpatient treatment of patients with seizure clusters: An open‐label extension trial

To evaluate safety- and seizure-related outcomes with repeated intermittent use of a novel formulation of midazolam administered as a single-dose nasal spray (MDZ-NS) in the outpatient treatment of patients experiencing seizure clusters (SCs). In this open-label extension trial (ClinicalTrials.gov NCT01529034), patients aged ≥12years and on a stable regimen of antiepileptic drugs who completed the original phase III, randomized controlled trial were enrolled. Caregivers administered MDZ-NS 5mg when patients experienced SCs; a second dose could be given if seizures did not terminate within 10minutes or recurred within 10minutes-6hours. Patients were monitored for treatment-emergent adverse events (TEAEs) throughout, and the main seizure-related outcome was treatment success, defined as seizure termination within 10minutes and no recurrence 10minutes-6hours after drug administration. Of 175 patients enrolled, 161 (92.0%) received ≥1 MDZ-NS dose, for a total of 1998 SC episodes. Median time spent by patients in the trial was 16.8months (range = 1-55.7months). TEAEs were experienced by 40.4% of patients within 2days of drug administration and 57.1% overall. TEAEs reported by most patients (within 2days and overall) were nasal discomfort (12.4%) and somnolence (9.3%). One patient each discontinued due to treatment-related nasal discomfort and somnolence. There were no patients with treatment-related respiratory depression, and none with TEAEs indicative of drug abuse or dependence. Treatment success criteria were met in 55% (1108/1998) of SC episodes after administration of a single 5-mg dose and in 80.2% (617/769) with the second dose. Treatment success was consistent over treated episode number. Repeated, intermittent, acute treatment of patients experiencing SCs with MDZ-NS in the outpatient setting was well tolerated over an extended period, with maintenance of efficacy suggesting lack of development of tolerance.

Dynamic Neuromagnetic Network Changes of Seizure Termination in Absence Epilepsy: A Magnetoencephalography Study.

Objective: With increasing efforts devoted to investigating the generation and propagation mechanisms of spontaneous spike and wave discharges (SWDs), little attention has been paid to network mechanisms associated with termination patterns of SWDs to date. In the current study, we aimed to identify the frequency-dependent neural network dynamics during the offset of absence seizures.Methods: Fifteen drug-naïve patients with childhood absence epilepsy (CAE) were assessed with a 275-Channel Magnetoencephalography (MEG) system. MEG data were recorded during and between seizures at a sampling rate of 6,000 Hz and analyzed in seven frequency bands. Source localization was performed with accumulated source imaging. Granger causality analysis was used to evaluate effective connectivity networks of the entire brain at the source level.Results: At the low-frequency (1–80 Hz) bands, activities were predominantly distributed in the frontal cortical and parieto–occipito–temporal junction at the offset transition periods. The high-frequency oscillations (HFOs, 80–500 Hz) analysis indicated significant source localization in the medial frontal cortex and deep brain areas (mainly thalamus) during both the termination transition and interictal periods. Furthermore, an enhanced positive cortico–thalamic effective connectivity was observed around the discharge offset at all of the seven analyzed bands, the direction of which was primarily from various cortical regions to the thalamus.Conclusions: Seizure termination is a gradual process that involves both the cortices and the thalamus in CAE. Cortico–thalamic coupling is observed at the termination transition periods, and the cerebral cortex acts as the driving force.

Cross-Frequency Coupling Features of Postictal Generalized EEG Suppression State.

In patients with epilepsy, convulsive seizures are often followed by a postictal generalized EEG suppression (PGES) state characterized by reduced background activity. Recent studies found a correlation between seizure termination state and PGES duration, and suggested that PGES is the result of the cessation of neuronal activity. To test that assertion, we investigated ten seizure records obtained from intracranial EEG (iEEG) from six patients, four of which had Engel Class 1 surgical outcome. In each case expert neurologists identified the most likely seizure onset electrode. We found the iEEG equivalent of PGES and an artifact-free preictal quiescent state of the same window size. Using index of cross-frequency coupling (ICFC) we identified the degree of coupling and dominant frequency bands involved in PGES and preictal quiescent states, and quantified the areas of high ICFC. We found that there was an increase in the degree of coupling between the 0.5-1.5Hz with high gamma frequency bands in the PGES states. We found that among all of the patients, as well as in Engel Class 1 patients specifically, the change in the quantified area of high ICFC was significant (p <; 0.05) between PGES and preictal quiescent states. Furthermore, we were able to identify whether a recording was from a depth or subdural electrode, or whether it was from seizure onset zone or not using ICFC markers in PGES. This suggests that there are frequency coupling markers that successfully identify PGES and that there are underlying dynamics that occur in this seemingly quiet postictal state.

Enaminone Modulators of Extrasynaptic α4β3δ γ-Aminobutyric AcidA Receptors Reverse Electrographic Status Epilepticus in the Rat After Acute Organophosphorus Poisoning.

Seizures induced by organophosphorus nerve agent exposure become refractory to treatment with benzodiazepines because these drugs engage synaptic γ-aminobutyric acid-A receptors (GABAARs) that rapidly internalize during status epilepticus (SE). Extrasynaptic GABAARs, such as those containing α4β3δ subunits, are a putative pharmacological target to comprehensively manage nerve agent-induced seizures since they do not internalize during SE and are continuously available for activation. Neurosteroids related to allopregnanolone have been tested as a possible replacement for benzodiazepines because they target both synaptic and extrasynaptic GABAARs receptors. A longer effective treatment window, extended treatment efficacy, and enhanced neuroprotection represent significant advantages of neurosteroids over benzodiazepines. However, neurosteroid use is limited by poor physicochemical properties arising from the intrinsic requirement of the pregnane steroid core structure for efficacy rendering drug formulation problematic. We tested a non-steroidal enaminone GABAAR modulator that interacts with both synaptic and extrasynaptic GABAARs on a binding site distinct from neurosteroids or benzodiazepines for efficacy to control electrographic SE induced by diisopropyl fluorophosphate or soman intoxication in rats. Animals were treated with standard antidotes, and experimental therapeutic treatment was given following 1 h (diisopropyl fluorophosphate model) or 20 min (soman model) after SE onset. We found that the enaminone 2-261 had an extended duration of seizure termination (>10 h) in the diisopropyl fluorophosphate intoxication model in the presence or absence of midazolam (MDZ). 2-261 also moderately potentiated MDZ in the soman-induced seizure model but had limited efficacy as a stand-alone anticonvulsant treatment due to slow onset of action. 2-261 significantly reduced neuronal death in brain areas associated with either diisopropyl fluorophosphate- or soman-induced SE. 2-261 represents an alternate chemical template from neurosteroids for enhancing extrasynaptic α4β3δ GABAAR activity to reverse SE from organophosphorous intoxication.

On the cause of sleep: Protein fragments, the concept of sentinels, and links to epilepsy

The molecular-level cause of sleep is unknown. In 2012, we suggested that the cause of sleep stems from cumulative effects of numerous intracellular and extracellular protein fragments. According to the fragment generation (FG) hypothesis, protein fragments (which are continually produced through nonprocessive cleavages by intracellular, intramembrane, and extracellular proteases) can be beneficial but toxic as well, and some fragments are eliminated slowly during wakefulness. We consider the FG hypothesis and propose that, during wakefulness, the degradation of accumulating fragments is delayed within natural protein aggregates such as postsynaptic densities (PSDs) in excitatory synapses and in other dense protein meshworks, owing to an impeded diffusion of the ∼3,000-kDa 26S proteasome. We also propose that a major function of sleep involves a partial and reversible expansion of PSDs, allowing an accelerated destruction of PSD-localized fragments by the ubiquitin/proteasome system. Expansion of PSDs would alter electrochemistry of synapses, thereby contributing to a decreased neuronal firing during sleep. If so, the loss of consciousness, a feature of sleep, would be the consequence of molecular processes (expansions of protein meshworks) that are required for degradation of protein fragments. We consider the concept of FG sentinels, which signal to sleep-regulating circuits that the levels of fragments are going up. Also discussed is the possibility that protein fragments, which are known to be overproduced during an epileptic seizure, may contribute to postictal sleep and termination of seizures. These and related suggestions, described in the paper, are compatible with current evidence about sleep and lead to testable predictions.

TSPO PET Using [18F]PBR111 Reveals Persistent Neuroinflammation Following Acute Diisopropylfluorophosphate Intoxication in the Rat.

Acute intoxication with organophosphates (OPs) can trigger status epilepticus followed by persistent cognitive impairment and/or electroencephalographic abnormalities. Neuroinflammation is widely posited to influence these persistent neurological consequences. However, testing this hypothesis has been challenging, in part because traditional biometrics preclude longitudinal measures of neuroinflammation within the same animal. Therefore, we evaluated the performance of noninvasive positron emission tomography (PET), using the translocator protein (TSPO) radioligand [18F]PBR111 against classic histopathologic measures of neuroinflammation in a preclinical model of acute intoxication with the OP diisopropylfluorophosphate (DFP). Adult male Sprague Dawley rats administered pyridostigmine bromide (0.1 mg/kg, im) 30 min prior to administration of DFP (4 mg/kg, sc), atropine sulfate (2 mg/kg, im) and 2-pralidoxime (25 mg/kg, im) exhibited moderate-to-severe seizure behavior. TSPO PET performed prior to DFP exposure and at 3, 7, 14, 21, and 28 days postexposure revealed distinct lesions, as defined by increased standardized uptake values (SUV). Increased SUV showed high spatial correspondence to immunohistochemical evidence of neuroinflammation, which was corroborated by cytokine gene and protein expression. Regional SUV metrics varied spatiotemporally with days postexposure and correlated with the degree of neuroinflammation detected immunohistochemically. Furthermore, SUV metrics were highly correlated with seizure severity, suggesting that early termination of OP-induced seizures may be critical for attenuating subsequent neuroinflammatory responses. Normalization of SUV values to a cerebellar reference region improved correlations to all outcome measures and seizure severity. Collectively, these results establish TSPO PET using [18F]PBR111 as a robust, noninvasive tool for longitudinal monitoring of neuroinflammation following acute OP intoxication.

Cortico-striatal synchronization in human focal seizures.

Although a number of experimental and clinical studies have pointed out participation or an even more prominent role of basal ganglia in focal seizures, the mode of interaction between cortical and striatal signals remains unclear. In the present study, we took stereoelectroencephalographic (SEEG) recordings in drug-resistant epilepsy patients, to qualitatively and quantitatively analyse the ictal striatum activity as well as its synchronization with cerebral cortex. Eleven patients who underwent SEEG evaluation were prospectively included if they fulfilled two inclusion criteria: (i) at least one orthogonal intracerebral electrode contact explored the basal ganglia, in either their putaminal or caudate part; and (ii) at least two SEEG seizures were recorded. Cortical and subcortical regions of interest were defined and different periods of interest were analysed. SEEG was visually inspected and h2 non-linear correlation analysis performed to study functional connectivity between cortical region of interest and striatum. Six correlation indices were calculated. Two main patterns of striatal activation were recorded: the most frequent was characterized by an early alpha/beta activity that started within the first 5 s after seizure onset, sometimes concomitant with it. The second one was characterized by late, slower, theta/delta activity. A significant difference in h2 correlation indices was observed during the preictal and seizure onset period compared to background for global striatal index, mesio-temporal/striatal index, latero-temporal/striatal index, insular/striatal index, prefrontal/striatal index. In addition, a significant difference in h2 correlation indices was observed during the seizure termination period compared to all the other periods of interest for the six indices calculated. These results indicate that cortico-striatal synchronization can arise from the start of focal seizures. Depending on the ictal frequency pattern, desynchronization can occur later, but a late and terminal hypersynchronization progressively takes over. These changes in synchronization level between cortical and striatal activity might be part of an endogenous mechanism controlling the duration of abnormal oscillations within the striato-thalamo-cortical loop and thereby their termination. Pathophysiology of basal ganglia in focal seizures appears to be much more interlinked with the cortex than expected. Beyond the stereotypical features they could imprint to seizure semiology, their role in strengthening mechanisms underlying cessation of ictal propagation should inspire new rationales for deep brain stimulation in patients with intractable focal epilepsies.

Postictal EEG changes following focal seizures: Interrater agreement and comparison to frequency analysis

ObjectivesTo compare frequency analysis to human raters and determine the interrater agreement of postictal EEG changes after focal seizures. Methods24 focal seizures with and without impaired awareness recorded with scalp-EEG in the epilepsy monitoring unit were selected. Five board-certified neurophysiologists annotated seizure termination and end of postictal changes for all seizures. We assessed agreement using intraclass correlation, described the band-power changes by time-frequency analysis, and correlated these measures with the rater annotations. ResultsInterrater agreement on the duration of the postictal changes was moderate (0.64, 95% confidence interval: 0.36–0.82). The interrater agreement for seizure termination was excellent (1.00). Median duration of the postictal interval of seizures with impaired awareness was significantly shorter than for seizures with retained awareness (p = 0.0004). Mean postictal duration was 16.4 min. Seizure duration did not predict duration of the postictal changes. We found a strong correlation of 0.8 between the median human rater and the duration of the decrease in spectral edge frequency. ConclusionsThe agreement of neurophysiologists is moderate for duration of postictal changes and high for seizure termination. Rater determination of postictal duration is correlated with measures of EEG slowing. SignificanceDisagreement between neurophysiologists on postictal duration need to be considered.

Regional and temporal regulation and role of somatostatin receptor subtypes in the mouse brain following systemic kainate-induced acute seizures

Somatostatin reduces neuronal excitability via somatostatin receptors (Sst1-Sst5) and inhibits seizure activity. However, the expression status of the Sst subtypes in epileptic mice and their role in the antiepileptic effects of somatostatin remain unclear. Here, we show that the Sst subtypes are regulated differently by epileptic neuronal activity in mice. Systemic kainate injection rapidly and transiently elevated the Sst2 and Sst3 mRNA and reduced Sst1 and Sst4 mRNA in the hippocampus; however, among all the subtypes, only Sst2 mRNA was increased in the excitatory neurons of the basolateral amygdala, accompanied by a decrease in the level of Sst2 protein. Following kainate administration, recovery from seizure was delayed by reduced expression of Sst2 in the basolateral amygdala, but not in the dentate gyrus of the hippocampus; higher expression levels of Bdnf, a neuronal activity marker, were observed in both conditions. These results suggest that Sst2 contributes to seizure termination by feedback inhibition in the amygdala. This could be a potential therapeutic target for acute seizures.

Tonic electromyographic activity following bilateral tonic-clonic seizures is associated with periictal respiratory dysfunction and postictal generalized EEG suppression.

No biomarkers reliably predict risk for sudden unexpected death in epilepsy (SUDEP). Postictal generalized electroencephalography (EEG) suppression (PGES) is a possible biomarker for SUDEP risk. However, its utility in predicting SUDEP remains uncertain. We had observed that postictal tonic electromyography (PTEMG) activity follows some generalized convulsive seizures (GCS). PTEMG activity and PGES may have a common pathophysiologic basis. PGES is associated with periictal respiratory distress. There is evidence that tonic EMG occurs with brain hypoxia. Thus PTEMG activity may be related to seizure-associated hypoxemia. Pronounced variation occurs among expert clinicians in identifying PGES, thereby limiting its utility as a biomarker. Characteristics of PTEMG activity and its relationship to preceding GCS have not been explored. We studied PTEMG activity characteristics, its relationship to the preceding seizure and associated respiratory dysfunction. We reviewed 145 GCS in 66 patients undergoing video-EEG telemetry (VET). The presence of PTEMG activity was defined when tonic EMG occurred for at least 3seconds following seizure termination and was identified with filter settings at 5-200Hz. Duration of PTEMG activity, the seizure, PGES, seizure-associated peripheral capillary oxygen saturation (SpO2 ) change, and end-tidal CO2 were analyzed. We compared data from GCS with and without PTEMG activity. Ninety of 145 seizures with GCS had PTEMG activity. The remainder had postictal slowing without PTEMG activity, and cessation of activity was followed by EEG slowing. Duration of the initial PTEMG discharge was 39.1 (mean)±(standard deviation) 17.9seconds. SpO2 nadir was lower (P=0.005) in seizures with PTEMG activity than in those without (72% vs 77%). End-tidal CO2 was higher (P=0.05) in seizures with PTEMG activity than in those without (63 vs 56mm Hg). PGES duration was 35.6±22.2seconds and associated with duration of PTEMG activity (P<0.001). The novel finding is that PTEMG activity occurs following 62% of GCS and that seizures with PTEMG activity have greater severity of respiratory dysfunction than seizures without. PTEMG activity is readily discerned by visual analysis of VET at appropriate filter settings and has the potential of being a complementary or surrogate biomarker of PGES for assessing SUDEP risk.