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Due to extensive connectivity of the parietal lobe, non‐lesional drug‐resistant (DRE) parietal lobe epilepsies (PLEs) are difficult to localize and often imitate other epilepsies. Therefore, patients with PLEs have low rates of seizure freedom following epilepsy surgery. Previous studies have highlighted the need to combine EEG and semiology for more accurate localization of PLEs. As sophisticated tools for localization become more available, the use of multiple different neuroimaging and neurophysiologic diagnostic tests may more readily identify PLE. We hereby report a unique case of a complex localization in a non‐lesional PLE, which was initially falsely localized to frontal lobe. This case underscores the utility of voxel‐based morphometry (VBM) in identifying an epileptogenic lesion on a non‐lesional MRI and the significance of multimodality approach including PET, magnetoencephalopathy (MEG), interictal and ictal EEG, semiology and cortical stimulation for accurate localization of PLEs. Understanding epilepsy through multimodality approach in this fashion can help with accurate localization especially in difficulty to localize and deceptive non‐lesional PLEs. Plain Language Summary: Parietal lobe epilepsies are hard to pinpoint in the brain and can mimic other types of epilepsy, especially when brain MRIs appear normal. As sophisticated tools for locating epilepsies in the brain become more available, using multiple diagnostic tests may help identify parietal lobe epilepsies more easily. We describe a unique case of a parietal lobe epilepsy patient with normal brain MRI whose epilepsy was initially misidentified as being in the frontal lobe. Using various advanced diagnostic tests, we accurately found the epilepsy's true location in the parietal lobe and successfully treated the patient with surgery. [ABSTRACT FROM AUTHOR]

Delayed treatment in status epilepticus (SE) is independently associated with increased treatment resistance, morbidity, and mortality. We describe the prehospital management pathway and Emergency Medical Services (EMS) timeliness in children who developed refractory convulsive status epilepticus (RCSE). Retrospective multicenter study in the United States using prospectively collected observational data from June 2011 to March 2020. We selected pediatric patients (one month–21 years) with RCSE initiated outside the hospital and transported to the hospital by EMS. We included 91 patients with a median (percentile 25 -percentile 75) age of 3.0 (1.5–7.3) years. The median time from seizure onset to hospital arrival was 45 (30–67) minutes, with a median time cared for by EMS of 24 (15–36) minutes. Considering treatment by caregivers and EMS before hospital arrival, 20 (22%) patients did not receive any anti-seizure medications (ASM) and 71 (78%) received one to five doses of benzodiazepines (BZD), without non-BZD ASM. We provided the prehospital treatment flow path of these patients through caregivers and EMS including relevant time points. Patients with a history of SE were more likely to receive the first BZD in the prehospital setting compared to patients without a history of SE (adjusted HR 3.25, 95% CI 1.72–6.12, p <0.001). In this multicenter study of pediatric RCSE, prehospital treatment may be streamlined further. Patients with a history of SE were more likely to receive prehospital rescue medication. [ABSTRACT FROM AUTHOR]

Pediatric convulsive status epilepticus (cSE) is a neurologic emergency with potential for morbidity and mortality. Rapid treatment and escalation of therapies to achieve early seizure control is paramount in preventing complications and providing the best patient outcomes. Although guidelines recommend early treatment, cessation of out-of-hospital SE is undermined by treatment delay and inadequate dosing. Logistical challenges include prompt seizure recognition, first-line benzodiazepine (BZD) availability, comfort and expertise in administration of BZD, and timely arrival of emergency personnel. In-hospital, SE onset is additionally impacted by delays to first- and second-line treatment and availability of resources. This review presents an evidence-based, clinically oriented review of pediatric cSE, including its definitions and treatments. It provides evidence and rationale for timely treatment of first-line BZD treatment followed by prompt escalation to second-line antiseizure medication therapies for established SE. Treatment delays and barriers to care are discussed, with practical considerations for opportunities for areas of improvement in the initial treatment of cSE. [ABSTRACT FROM AUTHOR]

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]

Kv4.2 subunits, encoded by KCND2, serve as the pore‐forming components of voltage‐gated, inactivating ISA K+ channels expressed in the brain. ISA channels inactivate without opening in response to subthreshold excitatory input, temporarily increasing neuronal excitability, the back propagation of action potentials, and Ca2+ influx into dendrites, thereby regulating mechanisms of spike timing‐dependent synaptic plasticity. As previously described, a de novo variant in Kv4.2, p.Val404Met, is associated with an infant‐onset developmental and epileptic encephalopathy in monozygotic twin boys. The p.Val404Met variant enhances inactivation directly from closed states, but dramatically impairs inactivation after channel opening. We now report the identification of a closely related, novel, de novo variant in Kv4.2, p.Val402Leu, in a boy with an early‐onset pharmacoresistant epilepsy that evolved to an epileptic aphasia syndrome (Continuous Spike Wave during Sleep Syndrome). Like p.Val404Met, the p.Val402Leu variant increases the rate of inactivation from closed states, but significantly slows inactivation after the pore opens. Although quantitatively the p.Val402Leu mutation alters channel kinetics less dramatically than p.Val404Met, our results strongly support the conclusion that p.Val402Leu and p.Val404Met cause the clinical features seen in the affected individuals and underscore the importance of closed state inactivation in ISA channels in normal brain development and function. [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: Sudden unexpected death in epilepsy (SUDEP) is an unpredictable and devastating comorbidity of epilepsy that is believed to be due to cardiorespiratory failure immediately after generalized convulsive seizures.Methods: We performed cardiorespiratory monitoring of seizure-induced death in mice carrying either a p.Arg1872Trp or p.Asn1768Asp mutation in a single Scn8a allele-mutations identified from patients who died from SUDEP-and of seizure-induced death in pentylenetetrazole-treated wild-type mice.Results: The primary cause of seizure-induced death for all mice was apnea, as (1) apnea began during a seizure and continued for tens of minutes until terminal asystole, and (2) death was prevented by mechanical ventilation. Fatal seizures always included a tonic phase that was coincident with apnea. This tonic phase apnea was not sufficient to produce death, as it also occurred during many nonfatal seizures; however, all seizures that were fatal had tonic phase apnea. We also made the novel observation that continuous tonic diaphragm contraction occurred during tonic phase apnea, which likely contributes to apnea by preventing exhalation, and this was only fatal when breathing did not resume after the tonic phase ended. Finally, recorded seizures from a patient with developmental epileptic encephalopathy with a previously undocumented SCN8A likely pathogenic variant (p.Leu257Val) revealed similarities to those of the mice, namely, an extended tonic phase that was accompanied by apnea.Interpretation: We conclude that apnea coincident with the tonic phase of a seizure, and subsequent failure to resume breathing, are the determining events that cause seizure-induced death in Scn8a mutant mice. ANN NEUROL 2021;89:1023-1035. [ABSTRACT FROM AUTHOR]

Infantile spasms (IS) is a devastating epilepsy syndrome that typically begins in the first year of life. Symptoms consist of stereotypical spasms, developmental delay, and electroencephalogram (EEG) that may demonstrate Hypsarhythmia. Current therapeutic approaches are not always effective, and there is no reliable way to predict which patient will respond to therapy. Given this disorder's complexity and the potential impact of a disease‐modifying approach, Citizens United for Research in Epilepsy (CURE) employed a "team science" approach to advance the understanding of IS pathology and explore therapeutic modalities that might lead to the development of new ways to potentially prevent spasms and Hypsarhythmia. This approach was a first‐of‐its‐kind collaborative initiative in epilepsy. The IS initiative funded 8 investigative teams over the course of 1‐3 years. Projects included the following: discovery on the basic biology of IS, discovery of novel therapeutic targets, cross‐validation of targets, discovery of biomarkers, and prognosis and treatment of IS. The combined efforts of a strong investigative team led to numerous advances in understanding the neural pathways underlying IS, testing of small molecules in preclinical models of IS and generated preliminary data on potential biomarkers. Thus far, the initiative has resulted in over 19 publications and subsequent funding for several investigators. Investigators reported that the IS initiative generally affected their research positively due to its collaborative and iterative nature. It also provided a unique opportunity to mentor junior investigators with an interest in translational research. Learnings included the need for a dedicated project manager and more transparent and real‐time communication with investigators. The CURE IS initiative represents a unique approach to fund scientific discoveries on epilepsy. It brought together an interdisciplinary group of investigators—who otherwise would not have collaborated—to find transformative therapies for IS. Learnings from this initiative are being utilized for subsequent initiatives at CURE. [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]