Ongoing Seizure Activity Research Articles

Outpatient management of prolonged seizures and seizure clusters to prevent progression to a higher-level emergency: Consensus recommendations of an expert working group.

The management of prolonged seizures (PS) and seizure clusters (SC) is impeded by the lack of international, evidence-based guidance. We aimed to develop expert recommendations regarding consensus definitions of PS, SC, and treatment goals to prevent progression to higher-level emergencies such as status epilepticus (SE). An expert working group, comprising 12 epileptologists, neurologists, and pharmacologists from Europe and North America, used a modified Delphi consensus methodology to develop and anonymously vote on statements. Consensus was defined as ≥75% voting "Agree"/"Strongly agree." All group members strongly agreed that termination of an ongoing seizure in as short a time as possible is the primary goal of rapid and early seizure termination (REST) and that an ideal medication for REST would start to act within 2 min of administration to terminate ongoing seizure activity. Consensus was reached on the terminology defining PS (with proposed thresholds of 5 min for prolonged focal seizures and 2 min for prolonged absence seizures and the convulsive phase of bilateral tonic-clonic seizures) and SC (an abnormal increase in seizure frequency compared with the individual patient's usual seizure pattern). All group members strongly agreed or agreed that patients who have experienced a PS should be offered a REST medication, and all patients who have experienced a SC should be offered an acute cluster treatment (ACT). Further, when prescribing a REST medication or ACT, a seizure action plan should be agreed upon in consultation with the patient and caregiver. The expert working group had a high level of agreement on the recommendations for defining and managing PS and SC. These recommendations will complement the existing guidance for the management of acute seizures, with the possibility of treating them earlier to potentially avoid progression to more severe seizures, including SE.

Emergency cesarean section of a patient with refractory status epilepticus: A case report of challenges during anesthesia.

Maternal epilepsy is a critical condition that can significantly affect mothers and fetuses. Notably, the admission of a laboring mother with uncontrolled refractory status epilepticus (RSE) to the operating room presents a challenging scenario for anesthesiologists. A 30-year-old primigravida was transferred to the operating room for an emergency cesarean section. Cesarean section was performed after a provisional diagnosis of preeclampsia was made. Cesarean section was performed under general anesthesia. During the postoperative period, the patient exhibited no seizure activity in the brain; however, she experienced mild cognitive dysfunction for up to 6 months postdelivery. The neonate were discharged without any complications. Inducing anesthesia in pregnant women with ongoing seizure activity are challenging; however, anesthesiologists provide judgment based on the balance between the safety of the mother and fetus and the balance between patient monitoring and the progression of anesthesia. This challenge can be addressed through multidisciplinary collaboration.

Cognitive Impairment is Associated with Longitudinal Disability in LGI-1-IgG Encephalitis (S22.007)

<h3>Objective:</h3> To determine predictors of longitudinal clinical outcomes in leucine-rich glioma inactivated-1 immunoglobulin G (LGI-1)-IgG autoimmune encephalitis (AE). <h3>Background:</h3> Longitudinal studies prognosticating outcomes in LGI-1-IgG AE are needed to identify key drivers of disability. We examine disability utilizing modified Rankin Scale (mRS) and an AE specific scale, the clinical assessment scale in AE (CASE). <h3>Design/Methods:</h3> A retrospective observational study of seropositive LGI-1-IgG AE patients was conducted between 2013–2022. Clinical predictors included demographics, clinical and paraclinical data, magnetic resonance imaging (MRI), and Montreal Cognitive Assessment (MoCA). Clinical outcomes included mRS and CASE scores. Logistic and linear regressions were used for modeling mRS and CASE, respectively. Baseline clinical characteristics were included as independent variables in the regression models. <h3>Results:</h3> Thirty patients (60% male, median age=69.5; IQR=63.0–76.0) were included, with a median follow-up time of 8.7 months (IQR=4.3–24.1). Seizures (29, [96.7%]), and cognitive impairment (CI) (30, [100%]) were present in the majority. Median initial MoCA was 23/30 (IQR=21.0–25.0). The majority received acute immunotherapy (27, [90%]), and maintenance immunotherapy, (26 [86.7%]). Baseline mRS (median=2.0, IQR=2.0–3.0) and CASE (mean=4.3, SD=3.7) correlated with each other (<i>r</i>=0.58, <i>P</i>&lt;.001) and with initial MoCA score (mRS <i>r</i>=−0.60, <i>P</i>=.009, CASE <i>r</i>=−0.51, <i>P</i>=.031). After 12 months from symptom onset, mRS (OR=0.88, [CI=0.82–0.94], <i>P</i>&lt;.001) and CASE (β=−0.03, [SE=0.01], <i>P</i>&lt;.001) decreased significantly. Temporal lobe(s) Fluid Attenuation Inversion Recovery (FLAIR) hyperintensity correlated with higher mRS longitudinally (OR=17.49, [CI=2.37, 129.05], <i>P</i>=.005). Higher initial MOCA was associated with lower mRS (OR=0.66, [CI=0.45–0.98], <i>P</i>=.04) and CASE (β=−0.24, [SE=0.13], <i>P</i>=.061) longitudinally. At last follow-up, most patients had ongoing cognitive symptoms (25, [83.3%]), while few had ongoing seizure activity (3, [10%]). <h3>Conclusions:</h3> CI is associated with disability at baseline and long-term follow up, underscoring cognition as an important determinant of disability outcomes in LGI-1-IgG AE. Severity of CI on baseline MoCA may offer prognostic information on long-term disability. <b>Disclosure:</b> Dr. Aboseif has a non-compensated relationship as a AAN Autoimmune Neurology Section -- Education Workgroup with AAN that is relevant to AAN interests or activities. Ms. Li has nothing to disclose. Dr. Amin has nothing to disclose. Brittany Lapin has received personal compensation for serving as an employee of Cleveland Clinic. Brittany Lapin has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Quality of Life Research. Brittany Lapin has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Anesthesia and Analgeisa. Dr. Abbatemarco has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for EMD Serono. Dr. Abbatemarco has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Horizon. Dr. Abbatemarco has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech . The institution of Dr. Abbatemarco has received research support from Horizon. Dr. Rae-Grant has received publishing royalties from a publication relating to health care. Dr. Rae-Grant has received publishing royalties from a publication relating to health care. Dr. Punia has nothing to disclose. Rachel Galioto has nothing to disclose. Dr. Kunchok has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech. Dr. Kunchok has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Horizon therapeutics . Dr. Kunchok has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Neurology.

Treatment of status epilepticus: Physiology, pharmacology, and future directions.

The review presents retrospective, present views and future perspectives on the treatment of status epilepticus (SE). First, presynaptic, postsynaptic, and extrasynaptic mechanisms underlying sustaining ongoing seizure activity are highlighted. Next, mechanism-based choices of antiseizure medications capable of promptly arresting SE are introduced. Finally, challenges associated with translating the advances in laboratory research in clinical practice are discussed.

A novel genetically modified mouse seizure model for evaluating anticonvulsive and neuroprotective efficacy of an A1 adenosine receptor agonist following soman intoxication

Recently a novel humanized mouse strain has been successfully generated, in which serum carboxylesterase (CES) knock out (KO) mice (Es1−/−) were further genetically modified by knocking in (KI), or adding, the gene that encodes the human form of acetylcholinesterase (AChE). The resulting human AChE KI and serum CES KO (or KIKO) mouse strain should not only exhibit organophosphorus nerve agent (NA) intoxication in a manner more similar to humans, but also display AChE-specific treatment responses more closely mimicking those of humans to facilitate data translation to pre-clinic trials. In this study, we utilized the KIKO mouse to develop a seizure model for NA medical countermeasure investigation, and then applied it to evaluate the anticonvulsant and neuroprotectant (A/N) efficacy of a specific A1 adenosine receptor (A1AR) agonist, N-bicyclo-(2.2.1)hept-2-yl-5′-chloro-5′-deoxyadenosine (ENBA), which has been shown in a rat seizure model to be a potent A/N compound. Male mice surgically implanted with cortical electroencephalographic (EEG) electrodes a week earlier were pretreated with HI-6 and challenged with various doses (26 to 47 μg/kg, SC) of soman (GD) to determine a minimum effective dose (MED) that induced sustained status epilepticus (SSE) activity in 100% of animals while causing minimum lethality at 24 h. The GD dose selected was then used to investigate the MED doses of ENBA when given either immediately following SSE initiation (similar to wartime military first aid application) or at 15 min after ongoing SSE seizure activity (applicable to civilian chemical attack emergency triage). The selected GD dose of 33 μg/kg (1.4 x LD50) generated SSE in 100% of KIKO mice and produced only 30% mortality. ENBA at a dose as little as 10 mg/kg, IP, caused isoelectric EEG activity within minutes after administration in naïve un-exposed KIKO mice. The MED doses of ENBA to terminate GD-induced SSE activity were determined to be 10 and 15 mg/kg when treatment was given at the time of SSE onset and when seizure activity was ongoing for 15 min, respectively. These doses were much lower than in the non-genetically modified rat model, which required an ENBA dose of 60 mg/kg to terminate SSE in 100% GD-exposed rats. At MED doses, all mice survived for 24 h, and no neuropathology was observed when the SSE was stopped. The findings confirmed that ENBA is a potent A/N for both immediate and delayed (i.e., dual purposed) therapy to victims of NA exposure and serves as a promising neuroprotective antidotal and adjunctive medical countermeasure candidate for pre-clinical research and development for human application.

DISSEMINATED LISTERIOSIS: A DEADLY TRIPLICATE

DISSEMINATED LISTERIOSIS: A DEADLY TRIPLICATE

Suspected benzodiazepine withdrawal-associated seizures in 3 young dogs undergoing mechanical ventilation.

To describe new onset of generalized seizures in 3 young dogs following cessation of a benzodiazepine-containing sedation protocol to facilitate mechanical ventilation (MV) for hypoxemia. Three dogs under 5 months of age underwent MV due to severe hypoxemia. All 3 dogs were sedated with a constant rate infusion of benzodiazepines as part of their sedation protocol to facilitate MV. All 3 dogs had an acute onset of generalized seizures within 36hours of sedation cessation and weaning from MV. All 3 dogs' seizures were successfully managed with a slow, tapering course of benzodiazepines. One dog was additionally treated with levetiracetam at the time of initial seizure activity, which was discontinued 1year following discharge and absence of ongoing seizure activity. All 3 dogs were discharged successfully with no reports of ongoing seizures or neurologic deficits after discharge. Young dogs managed with benzodiazepines to facilitate MV may have acute onset of generalized seizures following cessation, which can be successfully managed with short-term benzodiazepine therapy. The 3 cases in this series demonstrated a positive outcome and were successfully managed following acute onset of generalized seizure activity post-MV.

Abstract TP171: Acute Magnetic Resonance Imaging Findings In Patients With Sturge Weber Syndrome

Sturge-Weber syndrome (SWS) is a neurovascular disorder characterized by facial Port-wine stain and intracranial capillary malformations. Patients can have multiple neurological complications including seizures, headaches, and stroke-like episodes, often leading to multiple hospital presentations. Published reports have shown conflicting results on whether patients with SWS with acute neurological complaints have positive imaging findings. Small case reports have described acute ischemic or hemorrhagic changes in SWS patients, whereas larger case series have not identified such imaging findings. Our aim was to report imaging findings in a cohort of SWS patients who presented with acute neurological complaints. We performed a retrospective analysis on all MRI studies performed on SWS patients presenting to our institution with acute neurological symptoms between August 1999 and July 2018. Imaging studies were initially evaluated by the radiologists on-call, and subsequently reviewed by a separate neuroradiologist to confirm the diagnoses. Only studies that were interpreted as having acute findings by both radiologists were counted as positive. During the study period, 23 patients with SWS presented to our institution with acute neurological complaints, of which 13 (56.5%) were male, median age 3 years, with 50 MRI obtained. Seizures were the most common indication for acute imaging (58%), followed by stroke-like episodes (32%), headache (6%), lethargy (2%) and vomiting (2%). Acute changes on MRI were found in 8 studies (16%), with restricted diffusion in 5 patients (of which 4 were presumed to be due to stroke and 1 due to ongoing seizure activity), brain edema in 2 patients and a subdural fluid collection in 1 patient. Of the patients with acute imaging findings, 4 presented with seizures, 3 with stroke-like episodes, and 1 with lethargy. In conclusion, SWS patients with acute neurological complaints can have acute findings on MRI consistent with stroke or other acute injuries. Imaging appears to be an important tool in the management of acute episodes in SWS patients. Restricted diffusion in SWS patients may represent venous congestion or other hemodynamic changes leading to acute injury.

Nonconvulsive Status Epilepticus: Current Status and Future Perspectives

AbstractIntroduction Nonconvulsive status epilepticus is defined as a state of impaired consciousness with subtle motor manifestations and ongoing seizure activity in the electroencephalogram (EEG) for at least 30 minutes.Objectives and Methods This study of nonconvulsive status epilepticus and its outcomes was a retrospective analysis of the continuous bedside EEG recordings of 100 patients over 2 years (Aug 2017–July 2019) at the Neurophysiology Department in Sir Ganga Ram Hospital, New Delhi. There were two groups of patients in the study comprising of adults (72) and children (28). A comparison between the two groups was made based on the clinical presentation, etiology, EEG, MRI findings, treatment, and the consequences.Results and Conclusions In adults, nonconvulsive status had a high mortality rate, while in children, the associated comorbidities dominated and contributed to residual neurological sequelae. Early diagnosis and treatment at any age is essential to prevent cognitive decline and psychomotor retardation. Presently, bedside and ambulatory EEG recordings are used to capture the dynamic and rhythmic features of the ictal EEG. Continuous EEG monitoring enables bedside assessment of the effectiveness of treatment.

Restarting propofol following successful management of propofol infusion syndrome: a case report

: Propofol infusion syndrome (PRIS) is a rare and potentially fatal complication seen in high-dose (>5 mg/kg/h) or prolonged (>48 h) propofol infusions. PRIS presents as a constellation of symptoms, including anion-gap metabolic acidosis, elevated lactate, cardiogenic shock, rhabdomyolysis, arrhythmia, among other biochemical abnormalities. The current standard of care focuses on early recognition, propofol cessation, and supportive management. Case reports have shown evidence for several novel therapeutic interventions, including plasmapheresis, dialysis, and extracorporeal membrane oxygenation. There has yet to be a documented case demonstrating a trial of reinitiating propofol following successful PRIS management. We present the case of a previously healthy 20-year-old male that presented to the emergency department with new-onset refractory status epilepticus, secondary to suspected autoimmune encephalitis. Despite multiple immunomodulators, anesthetic therapies, and anti-epileptic agents, he exhibited ongoing refractory seizure activity on continuous electroencephalogram monitoring. Propofol boluses were the only therapy to offer seizure burst suppression, prompting uptitration of the infusion. The patient subsequently developed hemodynamic instability and multiple biochemical abnormalities consistent with PRIS. He was managed with one round of plasmapheresis, later followed by a session of sustained-low efficiency dialysis (SLED). This therapeutic combination was successful in managing PRIS and restoring hemodynamic stability. After stopping the propofol infusion, he developed near constant electrographic seizures, with breakthrough clinical seizures despite multiple other therapeutic interventions. Propofol was later restarted for seizure control, with no further recurrence of PRIS. This case provides support for novel therapeutic modalities, plasmapheresis and SLED, when managing PRIS. This case also marks the first successful attempt at restarting propofol following PRIS.

WS1.11. EEG in the ICU: Status Epilepticus and the Ictal-Interictal Continuum

Epileptic seizures and nonconvulsive status (NCSE) are common in the critically ill, but non- epileptic movements and posturing are even more common. EEG can provide clarification when seizures are suspected. Different EEG patterns form a continuum of non-seizure to seizure activity, and over- interpretation of these patterns may lead to inappropriate advice and treatment. Recurrent seizures are easiest to recognise, with rhythmic discharges having spatiotemporal evolution in frequency (>4Hz), morphology and distribution. Periodic patterns are the most difficult. Generalised periodic discharges (GPDs) may or may not be ictal, and the specific EEG findings combined with the clinical context determines the approach. Severe myoclonic encephalopathy may occur after cardiac arrest, and the EEG may show burst suppression, unreactive GPDs separated by isoelectric intervals, ± electrographic seizures. The prognosis is extremely poor irrespective of treatment. Lateralised periodic discharges (i.e. PLEDs) may be an interictal finding in epilepsy and after any acute cerebral insult such as stroke or herpes encephalitis, and usually indicates a predisposition to seizures rather than ongoing seizure activity. Generalised triphasic waves are mainly seen with metabolic and toxic encephalopathies and are usually not an ictal finding. Whilst they can be sharply contoured, they are recognised by their other characteristics including morphology, state-dependent reactivity, and lag in phase and/or morphology changes from front to back. Triphasic waves (and almost all periodic patterns) are suppressed by benzodiazepines, along with consciousness and respiration. Such EEG suppression, in the absence of clinical improvement, does not diagnose NCSE. Ambiguous patterns can also be seen, with stimulus-induced rhythmic, periodic or evolving discharges. Whilst non-convulsive seizures and NCSE may be detected in comatose patients, prognosis is largely determined by the underlying aetiology and its complications. Unresolved questions include what particular EEG patterns should consistently prompt aggressive treatment. It is not always possible to be certain that an EEG pattern is ictal or non- ictal, and in the correct clinical context (especially patients presenting with seizures or with a history of epilepsy) a treatment trial may be indicated to see if temporally associated clinical improvement occurs. EEG interpretation needs to be made within the clinical context by an expert reporter.

The efficacy of fructose-1,6-bisphosphate in suppressing status epilepticus in developing rats

PurposeTreatment of pediatric status epilepticus (SE) remains challenging as up to 50 % of patients are refractory to conventional anti-seizure medications. The glycolytic intermediate, fructose-1,6-bisphosphate (FBP), has been reported to exert significant anticonvulsant effects in both adult animals and in in vitro models of seizures. This study aims to examine FBP efficacy in controlling seizures in a rat model of juvenile SE. MethodsSprague Dawley rats (P11-P17) were injected with pilocarpine (300 mg/kg, i.p.) to induce SE, which was monitored by video-electroencephalography (v-EEG). Thirty minutes into SE, FBP was administrated (500 or 1000 mg/kg, i.p.). v-EEG recording was continued for ∼60 additional minutes to assess the anticonvulsant effect of FBP, compared with vehicle (saline) treatment. ResultsSE consistently occurred in rat pups 10−15 min after pilocarpine injection and persisted over the 90-min recording period. Neither saline nor a lower dose of FBP (500 mg/kg) treatment stopped behavioral and electrographic seizures. At higher doses (1000 mg/kg), FBP terminated SE in ∼15 min in 60 % (6 of 10) of the rat pups. ConclusionThe endogenous glycolytic metabolite, FBP, promptly suppresses ongoing seizure activity and represents a potential alternative metabolic therapy to improve the treatment of SE in the juvenile age range.

2-Deoxyglucose terminates pilocarpine-induced status epilepticus in neonatal rats.

Neonatal status epilepticus (SE) is a life-threatening medical emergency. Unfortunately, up to 50% of neonates with SE are resistant to current antiseizure drugs, highlighting the need for better treatments. This study aims to explore a novel metabolic approach as a potential alternative treatment to control neonatal SE, using the glycolytic inhibitor 2-deoxyglucose (2-DG). SE was induced by pilocarpine (300mg/kg, intraperitoneally [ip]) in neonatal Sprague Dawley rats (postnatal day 10 [P10]-P17) and was monitored by video-electroencephalography (V-EEG). After 30minutes of SE, 2-DG or one of two conventional antiseizure drugs with different mechanisms of action, phenobarbital or levetiracetam, was administrated ip, and V-EEG recording was continued for ~60 additional minutes. The time to seizure cessation after drug injection, EEG scores, and power spectra before and after drug or saline treatment were used to assess drug effects. Once SE became sustained, administration of 2-DG (50, 100, or 500mg/kg, ip) consistently stopped behavioral and electrographic seizures within 10-15minutes; lower doses took longer (25-30minutes) to stop SE, demonstrating a dose-dependent effect. Administration of phenobarbital (30mg/kg, ip) or levetiracetam (100mg/kg, ip) also stopped SE within 10-15minutes in neonatal rats. Our results suggest that the glycolysis inhibitor 2-DG acts quickly to reduce neuronal hyperexcitability and effectively suppress ongoing seizure activity, which may provide translational value in the treatment of neonatal SE.

Ictal Inhibition: Sync Globally, Slack Locally.

Role of Paroxysmal Depolarization in Focal Seizure Activity Tryba AK, Merricks EM, Lee S, et al. J Neuroph. 2019;122(5):1861-1873. doi.org/10.1152/jn.00392.2019We analyze the role of inhibition in sustaining focal epileptic seizure activity. We review ongoing seizure activity at the mesoscopic scale that can be observed with microelectrode arrays as well as at the macroscale of standard clinical electroencephalogram. We provide clinical, experimental, and modeling data to support the hypothesis that paroxysmal depolarization (PD) is a critical component of the ictal machinery. We present dual-patch recordings in cortical cultures showing reduced synaptic transmission associated with presynaptic occurrence of PD, and we find that the PD threshold is cell size related. We further find evidence that optically evoked PD activity in parvalbumin neurons can promote propagation of neuronal excitation in neocortical networks in vitro. Spike sorting results from microelectrode array measurements around ictal wave propagation in human focal seizures demonstrate a strong increase in putative inhibitory firing with an approaching excitatory wave, followed by a sudden reduction of firing at passage. At the macroscopic level, we summarize evidence that this excitatory ictal wave activity is strongly correlated with oscillatory activity across a centimeter-sized cortical network. We summarize Wilson–Cowan-type modeling showing how inhibitory function is crucial for this behavior. Our findings motivated us to develop a network motif of neurons in silico, governed by a reduced version of the Hodgkin–Huxley formalism, to show how feedforward, feedback, PD, and local failure of inhibition contribute to observed dynamics across network scales. The presented multidisciplinary evidence suggests that the PD not only is a cellular marker or epiphenomenon but actively contributes to seizure activity. NEW & NOTEWORTHY: We present mechanisms of ongoing focal seizures across meso- and macroscales of microelectrode array and standard clinical recordings, respectively. We find modeling, experimental, and clinical evidence for a dual role of inhibition across these scales: local failure of inhibition allows propagation of a mesoscopic ictal wave, whereas inhibition elsewhere remains intact and sustains macroscopic oscillatory activity. We present evidence for PD as a mechanism behind this dual role of inhibition in shaping ictal activity.

Acute visual impairment as a main presenting symptom of non-convulsive status epilepticus: a case report

BackgroundNonconvulsive status epilepticus (NCSE) is a state of ongoing seizure activity without convulsions. The heterogeneous and subtle clinical features of NCSE make diagnosis and treatment challenging. Here, we report a patient with NCSE who showed a main presenting symptom of acute visual impairment, which is a rare and atypical clinical symptom of NCSE.Case presentationA 62-year-old man was admitted to the neurology department after complaining of an inability to see in the right eye for 2 days and progressive headache. He had a history of poststroke epilepsy and vascular dementia. Physical examination revealed right visual field hemianopia, visual neglect and cognitive impairment. T2 and diffusion-weighted magnetic resonance imaging showed high signal intensity in the left temporal, parietal and occipital lobes. Electroencephalography monitoring was performed, which found continuous sharp wave discharges, especially in the regions of the left temporal, parietal and occipital lobes. These findings were most consistent with the diagnosis of NCSE. Thus, a treatment of intravenous pumping of diazepam and an oral antiepileptic drug was added immediately. After that, the visual loss in the patient recovered quickly, and electroencephalography did not find epileptiform waves. On day 11, a follow-up MRI was performed, which showed that the abnormal signals of the left temporal, parietal and occipital lobes were markedly attenuated, and the patient returned to his premorbid state with a modified Rankin Scale score of 3.ConclusionsAcute visual impairment can be seen in NCSE, and it can be reversed by administering effective antiepileptic treatment. Meanwhile, transient peri-ictal MRI abnormalities can be observed in NCSE.

Pharmacotherapy for Pediatric Convulsive Status Epilepticus.

Convulsive status epilepticus (CSE) is one of the most common pediatric neurological emergencies. Ongoing seizure activity is a dynamic process and may be associated with progressive impairment of gamma-aminobutyric acid (GABA)-mediated inhibition due to rapid internalization of GABAA receptors. Further hyperexcitability may be caused by AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and NMDA (N-methyl-d-aspartic acid) receptors moving from subsynaptic sites to the synaptic membrane. Receptor trafficking during prolonged seizures may contribute to difficulties treating seizures of longer duration and may provide some of the pathophysiological underpinnings of established and refractory SE (RSE). Simultaneously, a practice change toward more rapid initiation of first-line benzodiazepine (BZD) treatment and faster escalation to second-line non-BZD treatment for established SE is in progress. Early administration of the recommended BZD dose is suggested. For second-line treatment, non-BZD anti-seizure medications (ASMs) include valproate, fosphenytoin, or levetiracetam, among others, and at this point there is no clear evidence that any one of these options is better than the others. If seizures continue after second-line ASMs, RSE is manifested. RSE treatment consists of bolus doses and titration of continuous infusions under continuous electro-encephalography (EEG) guidance until electrographic seizure cessation or burst-suppression. Ultimately, etiological workup and related treatment of CSE, including broad spectrum immunotherapies as clinically indicated, is crucial. A potential therapeutic approach for future studies may entail consideration of interventions that may accelerate diagnosis and treatment of SE, as well as rational and early polytherapy based on synergism between ASMs by utilizing medications targeting different mechanisms of epileptogenesis and epileptogenicity.

The Neuroprotective Effects of Histamine H3 Receptor Antagonist E177 on Pilocarpine-Induced Status Epilepticus in Rats.

Epilepsy is a multifaceted neurological disorder which severely affects neuronal function. Some patients may experience status epilepticus (SE), a life-threatening state of ongoing seizure activity linked to cognitive dysfunction, necessitating an immediate intervention. The potential of histamine H3 receptors in several neuropsychiatric diseases including epilepsy is well recognized. In the current study, we aimed to explore the effect of H3R antagonist E177 on prevention and termination of pilocarpine (PLC)-induced SE in rats as well as evaluating the effects of E177 on the levels of oxidative stress in hippocampus tissues. The results showed that the survival rate of animals pretreated with E177 (5 and 10 mg/kg, intraperitoneal (i.p.)) was significantly increased during the first hour of observation, and animals were protected from SE incidence and showed a prolonged average of latency to the first seizure when compared with animals pretreated with PLC (400 mg/kg, i.p.). Moreover, the protective effect of E177 (10 mg/kg) on SE was partially reversed when rats were co- administered with H3R agonist R-(α)-methylhistamine (RAM) and with the H2R antagonist zolantidine (ZOL), but not with the H1R antagonist pyrilamine (PYR). Furthermore, pretreatment with E177 (5 and 10 mg/kg) significantly decreased the abnormal levels of malondialdehyde (MDA), and increased levels of glutathione (GSH) in the hippocampal tissues of the treated rats. However, E177 failed to modulate the levels of catalase (CAT), superoxide dismutase (SOD), or acetylcholine esterase activity (AChE). Our findings suggest that the newly developed H3R antagonist E177 provides neuroprotection in a preclinical PLC-induced SE in rats, highlighting the histaminergic system as a potential therapeutic target for the therapeutic management of SE.

Systemic thrombin inhibition ameliorates seizures in a mouse model of pilocarpine-induced status epilepticus.

Status epilepticus (SE) is a life-threatening condition characterized by ongoing seizure activity which can lead to severe brain damage and death if not treated properly. Recent work suggests that alterations in blood-brain barrier (BBB) function and subsequent cortical exposure to coagulation factors may initiate, promote, and/or sustain SE. This suggestion is based on the observation that the serine protease thrombin, which plays a fundamental role in the blood coagulation cascade, increases neural excitability through the activation of protease-activated receptor 1 (PAR1). However, it remains unclear whether systemic inhibition of thrombin asserts "anti-epileptic" effects in vivo. We here used the pilocarpine model of SE in adult 3-month-old male mice to address the question whether intraperitoneal injection of the thrombin inhibitor α-NAPAP (0.75 mg/kg) counters SE. Indeed, pharmacological inhibition of thrombin ameliorates the behavioral outcome of pilocarpine-induced SE. Similar results are obtained when the thrombin receptor PAR1 is pharmacologically blocked using intraperitoneal injection of SCH79797 (25 μg/kg) prior to SE induction. Consistent with these results, an increase in thrombin immunofluorescence is detected in the hippocampus of pilocarpine-treated animals. Moreover, increased hippocampal serine protease activity is detected 90 min after SE induction, which is not observed in animals treated with α-NAPAP prior to SE induction. Together, these results corroborate and extend recent studies suggesting that novel oral anticoagulants which target thrombin (and PAR1) may assert anti-epileptic effects in vivo. KEY MESSAGES: Systemic thrombin/PAR1-inhibition ameliorates anticoagulants behavioral seizures. Status epilepticus increases thrombin levels in the hippocampus. Increased serine protease activity in the hippocampus after status epileptic. Anti-epileptic potential of clinically used anticoagulants must be evaluated.

Innate Immunity in the Central Nervous System: A Missing Piece of the Autoimmune Encephalitis Puzzle?

The autoimmune encephalitides are a group of autoimmune conditions targeting the central nervous system and causing severe clinical symptoms including drug-resistant seizures, cognitive dysfunction and psychiatric disturbance. Although these disorders appear to be antibody mediated, the role of innate immune responses needs further clarification. Infiltrating monocytes and microglial proliferation at the site of pathology could contribute to the pathogenesis of the disease with resultant blood brain barrier dysfunction, and subsequent activation of adaptive immune response. Both innate and adaptive immune cells can produce pro-inflammatory molecules which can perpetuate ongoing neuroinflammation and drive ongoing seizure activity. Ultimately neurodegenerative changes can ensue with resultant long-term neurological sequelae that can impact on ongoing patient morbidity and quality of life, providing a potential target for future translational research.

Role of paroxysmal depolarization in focal seizure activity.

We analyze the role of inhibition in sustaining focal epileptic seizure activity. We review ongoing seizure activity at the mesoscopic scale that can be observed with microelectrode arrays as well as at the macroscale of standard clinical EEG. We provide clinical, experimental, and modeling data to support the hypothesis that paroxysmal depolarization (PD) is a critical component of the ictal machinery. We present dual-patch recordings in cortical cultures showing reduced synaptic transmission associated with presynaptic occurrence of PD, and we find that the PD threshold is cell size related. We further find evidence that optically evoked PD activity in parvalbumin neurons can promote propagation of neuronal excitation in neocortical networks in vitro. Spike sorting results from microelectrode array measurements around ictal wave propagation in human focal seizures demonstrate a strong increase in putative inhibitory firing with an approaching excitatory wave, followed by a sudden reduction of firing at passage. At the macroscopic level, we summarize evidence that this excitatory ictal wave activity is strongly correlated with oscillatory activity across a centimeter-sized cortical network. We summarize Wilson-Cowan-type modeling showing how inhibitory function is crucial for this behavior. Our findings motivated us to develop a network motif of neurons in silico, governed by a reduced version of the Hodgkin-Huxley formalism, to show how feedforward, feedback, PD, and local failure of inhibition contribute to observed dynamics across network scales. The presented multidisciplinary evidence suggests that the PD not only is a cellular marker or epiphenomenon but actively contributes to seizure activity.NEW & NOTEWORTHY We present mechanisms of ongoing focal seizures across meso- and macroscales of microelectrode array and standard clinical recordings, respectively. We find modeling, experimental, and clinical evidence for a dual role of inhibition across these scales: local failure of inhibition allows propagation of a mesoscopic ictal wave, whereas inhibition elsewhere remains intact and sustains macroscopic oscillatory activity. We present evidence for paroxysmal depolarization as a mechanism behind this dual role of inhibition in shaping ictal activity.