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Objective: For an antiseizure medication (ASM) to be effective in status epilepticus (SE), the drug should be administered intravenously (i.v.) to provide quick access to the brain. However, poor aqueous solubility is a major problem in the development of parenteral drug solutions. Given its multiple mechanisms of action, topiramate (TPM) is a promising candidate for the treatment of established or refractory SE, as supported by clinical studies using nasogastric tube TPM administration. However, TPM is not clinically available as a solution for i.v. administration, which hampers its use in the treatment of SE. Here, we describe a novel easy‐to‐use and easy‐to‐prepare i.v. TPM formulation using the U.S. Food and Drug Administration (FDA)–approved excipient meglumine. Methods: During formulation development, we compared the solubility of TPM in bi‐distilled water with vs without a range of meglumine concentrations. Furthermore, the solubility of combinations of TPM and levetiracetam and TPM, levetiracetam, and atorvastatin in aqueous meglumine concentrations was determined. Subsequently, the pharmacokinetics and tolerability of meglumine‐based solutions of TPM and TPM combinations were evaluated in rats, including animals following fluid percussion injury or pilocarpine‐induced SE. Results: The amino sugar meglumine markedly enhances the aqueous solubility of TPM. A comparison with data on dissolving TPM using sulfobutylether‐β‐cyclodextrin (Captisol) demonstrates that meglumine is much more effective for dissolving TPM. Furthermore, meglumine can be used to prepare drug cocktails where TPM is co‐administered with another ASM for SE treatment. The tolerability studies of the meglumine‐based TPM solution and meglumine‐based TPM combinations in normal rats and the rat fluid percussion injury and pilocarpine‐induced SE models demonstrate excellent tolerability of the novel drug solutions. Preclinical studies on antiseizure efficacy in the SE model are underway. Significance: In conclusion, the novel meglumine‐based solution of TPM presented here may be well suited for clinical development. [ABSTRACT FROM AUTHOR]

Objective: Pediatric epilepsy is often associated with diminished health‐related quality of life (HRQOL). Our aim was to establish the validity of the Pediatric Epilepsy Learning Healthcare System Quality of Life (PELHS‐QOL‐2) questions, a novel two‐item HRQOL prompt for children with epilepsy, primarily for use in clinical care. Methods: We performed a multicenter cross‐sectional study to validate the PELHS‐QOL‐2. Construct validity was established through bivariate comparisons with four comparator measures and known drivers of quality of life in children with epilepsy, as well as by creating an a priori multivariable model to predict the Quality of Life in Childhood Epilepsy Questionnaire (QOLCE‐55). Validity generalization was established through bivariate comparisons with demographic and clinical information. Content validity and clinical utility were established by assessing how well the PELHS‐QOL‐2 met eight design criteria for an HRQOL prompt established by a multistakeholder group of experts. Results: The final participant sample included 154 English‐speaking caregivers of children with epilepsy (mean age = 9.7 years, range =.5–18, 49% female, 70% White). The PELHS‐QOL‐2 correlated with the four comparator instruments (ρ =.44–.56), was significantly associated with several known drivers of quality of life in children with epilepsy (p <.05), and predicted QOLCE‐55 scores in the multivariate model (adjusted R2 =.54). The PELHS‐QOL‐2 item was not associated with the age, sex, and ethnicity of the children nor with the setting and location of data collection, although PELHS‐QOL‐Medications was significantly associated with race (worse for White race). Following both quantitative and qualitative analysis, the PELHS‐QOL‐2 met seven of eight design criteria. Significance: The PELHS‐QOL‐2 is a valid HRQOL prompt and is well suited for use in clinical care as a mechanism to routinely initiate conversations with caregivers about quality of life in children with epilepsy. The association of PELHS‐QOL‐Medications with race merits further study. [ABSTRACT FROM AUTHOR]

Objective: This study was undertaken to evaluate benzodiazepine (BZD) administration patterns before transitioning to non‐BZD antiseizure medication (ASM) in pediatric patients with refractory convulsive status epilepticus (rSE). Methods: This retrospective multicenter study in the United States and Canada used prospectively collected observational data from children admitted with rSE between 2011 and 2020. Outcome variables were the number of BZDs given before the first non‐BZD ASM, and the number of BZDs administered after 30 and 45 min from seizure onset and before escalating to non‐BZD ASM. Results: We included 293 patients with a median (interquartile range) age of 3.8 (1.3–9.3) years. Thirty‐six percent received more than two BZDs before escalating, and the later the treatment initiation was after seizure onset, the less likely patients were to receive multiple BZD doses before transitioning (incidence rate ratio [IRR] =.998, 95% confidence interval [CI] =.997–.999 per minute, p =.01). Patients received BZDs beyond 30 and 45 min in 57.3% and 44.0% of cases, respectively. Patients with out‐of‐hospital seizure onset were more likely to receive more doses of BZDs beyond 30 min (IRR = 2.43, 95% CI = 1.73–3.46, p <.0001) and beyond 45 min (IRR = 3.75, 95% CI = 2.40–6.03, p <.0001) compared to patients with in‐hospital seizure onset. Intermittent SE was a risk factor for more BZDs administered beyond 45 min compared to continuous SE (IRR = 1.44, 95% CI = 1.01–2.06, p =.04). Forty‐seven percent of patients (n = 94) with out‐of‐hospital onset did not receive treatment before hospital arrival. Among patients with out‐of‐hospital onset who received at least two BZDs before hospital arrival (n = 54), 48.1% received additional BZDs at hospital arrival. Significance: Failure to escalate from BZDs to non‐BZD ASMs occurs mainly in out‐of‐hospital rSE onset. Delays in the implementation of medical guidelines may be reduced by initiating treatment before hospital arrival and facilitating a transition to non‐BZD ASMs after two BZD doses during handoffs between prehospital and in‐hospital settings. [ABSTRACT FROM AUTHOR]

Objective: This study was undertaken to describe long‐term clinical and developmental outcomes in pediatric refractory status epilepticus (RSE) and identify factors associated with new neurological deficits after RSE. Methods: We performed retrospective analyses of prospectively collected observational data from June 2011 to March 2020 on pediatric patients with RSE. We analyzed clinical outcomes from at least 30 days after RSE and, in a subanalysis, we assessed developmental outcomes and evaluated risk factors in previously normally developed patients. Results: Follow‐up data on outcomes were available in 276 patients (56.5% males). The median (interquartile range [IQR]) follow‐up duration was 1.6 (.9–2.7) years. The in‐hospital mortality rate was 4% (16/403 patients), and 15 (5.4%) patients had died after hospital discharge. One hundred sixty‐six (62.9%) patients had subsequent unprovoked seizures, and 44 (16.9%) patients had a repeated RSE episode. Among 116 patients with normal development before RSE, 42 of 107 (39.3%) patients with available data had new neurological deficits (cognitive, behavioral, or motor). Patients with new deficits had longer median (IQR) electroclinical RSE duration than patients without new deficits (10.3 [2.1–134.5] h vs. 4 [1.6–16] h, p =.011, adjusted odds ratio = 1.003, 95% confidence interval = 1.0008–1.0069, p =.027). The proportion of patients with an unfavorable functional outcome (Glasgow Outcome Scale‐Extended score ≥ 4) was 22 of 90 (24.4%), and they were more likely to have received a continuous infusion. Significance: About one third of patients without prior epilepsy developed recurrent unprovoked seizures after the RSE episode. In previously normally developing patients, 39% presented with new deficits during follow‐up, with longer electroclinical RSE duration as a predictor. [ABSTRACT FROM AUTHOR]

Objective: We aimed to characterize the clinical profile and outcomes of new onset refractory status epilepticus (NORSE) in children, and investigated the relationship between fever onset and status epilepticus (SE). Methods: Patients with refractory SE (RSE) between June 1, 2011 and October 1, 2016 were prospectively enrolled in the pSERG (Pediatric Status Epilepticus Research Group) cohort. Cases meeting the definition of NORSE were classified as "NORSE of known etiology" or "NORSE of unknown etiology." Subgroup analysis of NORSE of unknown etiology was completed based on the presence and time of fever occurrence relative to RSE onset: fever at onset (≤24 h), previous fever (2 weeks–24 h), and without fever. Results: Of 279 patients with RSE, 46 patients met the criteria for NORSE. The median age was 2.4 years, and 25 (54%) were female. Forty (87%) patients had NORSE of unknown etiology. Nineteen (48%) presented with fever at SE onset, 16 (40%) had a previous fever, and five (12%) had no fever. The patients with preceding fever had more prolonged SE and worse outcomes, and 25% recovered baseline neurological function. The patients with fever at onset were younger and had shorter SE episodes, and 89% recovered baseline function. Significance: Among pediatric patients with RSE, 16% met diagnostic criteria for NORSE, including the subcategory of febrile infection‐related epilepsy syndrome (FIRES). Pediatric NORSE cases may also overlap with refractory febrile SE (FSE). FIRES occurs more frequently in older children, the course is usually prolonged, and outcomes are worse, as compared to refractory FSE. Fever occurring more than 24 h before the onset of seizures differentiates a subgroup of NORSE patients with distinctive clinical characteristics and worse outcomes. [ABSTRACT FROM AUTHOR]

Objective: Common data elements (CDEs) are standardized questions and answer choices that allow aggregation, analysis, and comparison of observations from multiple sources. Clinical CDEs are foundational for learning health care systems, a data‐driven approach to health care focused on continuous improvement of outcomes. We aimed to create clinical CDEs for pediatric epilepsy. Methods: A multiple stakeholder group (clinicians, researchers, parents, caregivers, advocates, and electronic health record [EHR] vendors) developed clinical CDEs for routine care of children with epilepsy. Initial drafts drew from clinical epilepsy note templates, CDEs created for clinical research, items in existing registries, consensus documents and guidelines, quality metrics, and outcomes needed for demonstration projects. The CDEs were refined through discussion and field testing. We describe the development process, rationale for CDE selection, findings from piloting, and the CDEs themselves. We also describe early implementation, including experience with EHR systems and compatibility with the International League Against Epilepsy classification of seizure types. Results: Common data elements were drafted in August 2017 and finalized in January 2020. Prioritized outcomes included seizure control, seizure freedom, American Academy of Neurology quality measures, presence of common comorbidities, and quality of life. The CDEs were piloted at 224 visits at 10 centers. The final CDEs included 36 questions in nine sections (number of questions): diagnosis (1), seizure frequency (9), quality of life (2), epilepsy history (6), etiology (8), comorbidities (2), treatment (2), process measures (5), and longitudinal history notes (1). Seizures are categorized as generalized tonic‐clonic (regardless of onset), motor, nonmotor, and epileptic spasms. Focality is collected as epilepsy type rather than seizure type. Seizure frequency is measured in nine levels (all used during piloting). The CDEs were implemented in three vendor systems. Early clinical adoption included 1294 encounters at one center. Significance: We created, piloted, refined, finalized, and implemented a novel set of clinical CDEs for pediatric epilepsy. [ABSTRACT FROM AUTHOR]

In vitro preparations are a powerful tool to explore the mechanisms and processes underlying epileptogenesis and ictogenesis. In this review, we critically review the numerous in vitro methodologies utilized in epilepsy research. We provide support for the inclusion of detailed descriptions of techniques, including often ignored parameters with unpredictable yet significant effects on study reproducibility and outcomes. In addition, we explore how recent developments in brain slice preparation relate to their use as models of epileptic activity. [ABSTRACT FROM AUTHOR]

Objectives To determine if the activity-dependent trafficking of γ2 subunit-containing γ-aminobutyric acid type A receptors (GABAARs) that has been observed in older animals and posited to contribute to benzodiazepine pharmacoresistance during status epilepticus (SE) is age-dependent, and to evaluate whether blockade of protein phosphatases can inhibit or reverse the activity-dependent plasticity of these receptors. Methods The efficacy and potency of diazepam 0.2-10 mg/kg administered 3 or 60 min after the onset of a lithium/pilocarpine-induced seizure in postnatal day 15-16 rats was evaluated using video-electroencephalography (EEG) recordings. The surface expression of γ2 subunit-containing GABAARs was assessed using a biotinylation assay, and GABAAR-mediated miniature inhibitory postsynaptic currents (mIPSCs) were recorded using whole-cell patch-clamp recording techniques from dentate granule cells in hippocampal slices acutely obtained 60 min after seizure onset (SE-treated). The effect of the protein phosphatase inhibitors FK506 and okadaic acid (OA) on the surface expression of these receptors was determined in organotypic slice cultures exposed to high potassium and N-methyl- d-aspartate (NMDA) or in SE-treated slices. Results Diazepam terminated seizures of 3 min but not 60 min duration, even at the highest dose. In the SE-treated slices, the surface expression of γ2 subunit-containing GABAARs was reduced and the amplitude of the mIPSCs was diminished. Inhibition of protein phosphatases prevented the activity-induced reduction of the γ2 subunit-containing GABAARs in organotypic slice cultures. Furthermore, treatment of SE-treated slices with FK506 or OA restored the surface expression of the γ2 subunit-containing GABAARs and the mIPSC amplitude. Significance This study demonstrates that the plasticity of γ2 subunit-containing GABAARs associated with the development of benzodiazepine resistance in young and adult animals is similar. The findings of this study suggest that the mechanisms regulating the activity-dependent trafficking of GABAARs during SE can be targeted to develop novel adjunctive therapy for the treatment of benzodiazepine-refractory SE. [ABSTRACT FROM AUTHOR]

Purpose To examine patterns of use, efficacy, and safety of intravenous ketamine for the treatment of refractory status epilepticus ( RSE). Methods Multicenter retrospective review of medical records and electroencephalography ( EEG) reports in 10 academic medical centers in North America and Europe, including 58 subjects, representing 60 episodes of RSE that were identified between 1999 and 2012. Seven episodes occurred after anoxic brain injury. Key Findings Permanent control of RSE was achieved in 57% (34 of 60) of episodes. Ketamine was felt to have contributed to permanent control ('possible' or 'likely' responses) in 32% (19 of 60) including seven (12%) in which ketamine was the last drug added (likely responses). Four of the seven likely responses, but none of the 12 possible ones, occurred in patients with postanoxic brain injury. No likely responses were observed when infusion rates were lower than 0.9 mg/kg/h, when ketamine was introduced at least 8 days after SE onset, or after failure of seven or more drugs. Ketamine was discontinued due to possible adverse events in five patients. Complications were mostly attributed to concurrent drugs, especially other anesthetics. Mortality rate was 43% (26 of 60), but was lower when SE was controlled within 24 h of ketamine initiation (16% vs. 56%, p = 0.0047). Significance Ketamine appears to be a relatively effective and safe drug for the treatment of RSE. This retrospective series provides preliminary data on effective dose and appropriate time of intervention to aid in the design of a prospective trial to further define the role of ketamine in the treatment of RSE. [ABSTRACT FROM AUTHOR]

The fortuitous discovery of the benzodiazepines and the subsequent application of these agents to the treatment of status epilepticus (SE) heralds in the modern age of treating this neurologic emergency. More than 50 years after their discovery, the benzodiazepines remain the drugs of first choice in the treatment of SE. However, the benzodiazepines can be ineffective, especially in those patients whose seizures are the most prolonged. The benzodiazepines act by increasing the affinity of γ-aminobutyric acid (GABA) for GABAA receptors. A receptor’s subunit composition affects its functional and pharmacologic properties, trafficking, and cellular localization. The GABAA receptors that mediate synaptic inhibition typically contain a γ2 subunit and are diazepam-sensitive. Among the GABAA receptors that mediate tonic inhibition are the benzodiazepine-insensitive δ subunit–containing receptors. The initial studies investigating the pathogenesis of SE demonstrated that a reduction in GABA-mediated inhibition within the hippocampus was important in maintenance of SE, and this reduction correlated with a rapid modification in the postsynaptic GABAA receptor population expressed on the surface of the hippocampal principal neurons. Subsequent studies found that this rapid modification is, in part, mediated by an activity-dependent, subunit-specific trafficking of the receptors that resulted in the reduction in the surface expression of the benzodiazepine-sensitive γ2 subunit–containing receptors and the preserved surface expression of the benzodiazepine-insensitive δ subunit-containing receptors. This improved understanding of the changes in the trafficking of GABAA receptors during SE partially accounts for the development of benzodiazepine-pharmacoresistance and has implications for the current and future treatment of benzodiazepine-refractory SE. [ABSTRACT FROM AUTHOR]

Following its collapse as a result of World War I, the International League Against Epilepsy (ILAE) was reorganized in 1935; and William G. Lennox was appointed its president. Among his initial efforts was developing a professional organization that would be dedicated to the study and care of people with epilepsy and would serve as the International League’s American chapter. His efforts resulted in the founding of the American Epilepsy Society (AES) in Kansas City, MO, on May 12, 1936. This article presents previously lost details of Lennox’s role in establishing the AES and in defining its mission. [ABSTRACT FROM AUTHOR]

The recent discovery of archival material has shed interesting light on the origins of Epilepsia and also the International League Against Epilepsy (ILAE). The idea of an international journal devoted to epilepsy seems first to have arisen from talks between Dr. L. J. J. Muskens and Dr. W. Aldren Turner in 1905. A protracted series of subsequent letters between Muskens and a Haarlem publisher show how the idea slowly took shape. The committee of patronage, editorial board, and editorial assistants was probably first approached at the First International Congress of Psychiatry, Neurology, Psychology, and Nursing of the Insane, held in Amsterdam in 1907. At this meeting, the concept of an international organization to fight epilepsy (to become the ILAE) was also first proposed in public, again by Muskens. The concept of the ILAE was clearly modeled on another international organization—the International Commission for the Study of the Causes of Mental Diseases and Their Prophylaxis. This Commission had been first publicly proposed in 1906 by Ludwig Frank, at the Second International Congress for the Care and Treatment of the Insane. The proposed Commission and ILAE shared many features, aims, and personnel. Despite an auspicious start, the International Commission was prevented by personal and political differences from ever actually coming into being. However, the first issue of Epilepsia appeared in March 1909 and the ILAE was inaugurated in August 1909; and both have flourished and celebrate their centenaries this year. [ABSTRACT FROM AUTHOR]

Investigate whether patients on vigabatrin demonstrated new-onset and reversible T2-weighted magnetic resonance imaging (MRI) abnormalities. MRI of patients treated during vigabatrin therapy was reviewed, following detection of new basal ganglia, thalamus, and corpus callosum hyperintensities in an infant treated for infantile spasms. Patients were assessed for age at time of MRI, diagnosis, duration, and dose, MRI findings pre-, on, and postvigabatrin, concomitant medications, and clinical correlation. These findings were compared to MRI in patients with infantile spasms who did not receive vigabatrin. Twenty-three patients were identified as having MRI during the course of vigabatrin therapy. After excluding the index case, we detected new and reversible basal ganglia, thalamic, brainstem, or dentate nucleus abnormalities in 7 of  22  (32%) patients treated with vigabatrin. All findings were reversible following discontinuation of therapy. Diffusion-weighted imaging (DWI) was positive with apparent diffusion coefficient (ADC) maps demonstrating restricted diffusion. Affected versus unaffected patients, respectively, had a median age of 11 months versus 5 years, therapy duration 3 months versus 12 months, and dosage  170  mg/kg/day versus 87 mg/kg/day. All affected patients were treated for infantile spasms; none of 56 patients with infantile spasms who were not treated with vigabatrin showed the same abnormalities. MRI abnormalities attributable to vigabatrin, characterized by new-onset and reversible T2-weighted hyperintensities and restricted diffusion in thalami, globus pallidus, dentate nuclei, brainstem, or corpus callosum were identified in 8 of 23 patients. Young age and relatively high dose appear to be risk factors. [ABSTRACT FROM AUTHOR]

A rapid modification in the postsynaptic γ-aminobutyric acid (GABAA) receptor population occurs during the prolonged seizures of status epilepticus (SE). This rapid modification contributes to a reduction in GABA-mediated inhibition and the development of benzodiazepine pharmacoresistance. Previous hypotheses to explain the modification have included an alteration in the structural composition or posttranslational modification of the receptors. In a cultured hippocampal neuron model, we found that there was differential subcellular distribution of GABAA receptor subunits and that the constitutive internalization of GABAA receptors containing a β2/3 subunit was rapid and activity-dependent. Based on this finding, we posit that an activity-dependent increase in the rate of internalization of synaptic GABAA receptors during SE contributes to the reduction in inhibitory transmission and the development of benzodiazepine pharmacoresistance. [ABSTRACT FROM AUTHOR]

In December 1946, a joint meeting devoted to epilepsy research and care was held by the Association for the Research in Nervous and Mental Disease and the American Chapter of the International League Against Epilepsy. The American Epilepsy Society (AES) has chosen this date and this meeting to mark its founding and recognizes Dr. Charles D. Aring as the organization's first president. However, the founding process of the AES actually began a decade earlier with a dinner meeting held during the American Medical Association's annual meeting. Based on this historical review, it is recommended that the AES recognize 1936 as the year of its founding and Dr. William G. Lennox as its founder and first president. [ABSTRACT FROM AUTHOR]

Summary: Purpose: Ample evidence exists from both clinical and animal studies that the success of benzodiazepine intervention during status epilepticus (SE) in the mature nervous system is inversely related to seizure duration. This relationship has not been well studied in the developing nervous system. Methods: The objective of this study was to investigate the relation of age and success of diazepam (DZP) treatment in the lithium-pilocarpine model of secondarily generalized seizure in the rat by using naïve rats of three age groups, roughly corresponding to the human ages of infancy (P15), adolescence (P20), and adult (P60). Results: In all age groups, the dosage of DZP that stopped the seizures at 5 min was not effective in terminating seizures at 60 min. This decline in efficacy was present as early as 15 min after seizure onset. Conclusions: These findings demonstrate that the inverse relation between the success of benzodiazepine intervention and seizure duration is observed in young as well as in adult rats and provide further evidence that intervention for SE should commence early. [ABSTRACT FROM AUTHOR]

The article focuses on a study that examined the role of neurotransmitter receptors in the pathogenesis and treatment of status epilepticus (SE). The study analyzed hippocampal slices, that were removed from male Sprague-Dawley rats that had undergone SE induced by a combination of lithium and pilocarpine and age-matched controls. It was found that cholinergic stimulation can initiate SE by enhancing glutamate release from presynaptic terminals.