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Some patients with epilepsy continue to have seizures despite daily treatment with antiseizure medications. This includes seizure clusters (also known as acute repetitive seizures), which are an increase in seizure frequency that is different from the usual seizure pattern for that patient. In the literature, the term "rescue" is used for pharmacologic treatment for seizure clusters, but clarity regarding timing or whether a caregiver or patient should wait until a moment of life-threatening urgency before administering the medication is lacking. Additionally, the concept of waiting 5 minutes to identify and initiate treatment of status epilepticus has been carried over to the treatment of seizure clusters, as well as the idea of waiting owing to safety concerns, without reevaluation in the context of the reported safety profiles for currently available as-needed therapies when administered as prescribed. Delaying treatment of seizure clusters may have negative outcomes, including injury, emergency room use, hospitalization, and progression to status epilepticus. Additionally, increased time for administration of benzodiazepines, the cornerstone therapies for seizure clusters, may lower the potency and effectiveness once administration takes place, because of physiologic changes. Thus, clarifying the importance of timing in the treatment terminology may be of benefit in the acute context. The term "immediate-use seizure medication" (ISM), meaning treatment that is administered as quickly as possible once a seizure cluster is recognized, may help to clarify the timing of as-needed treatment. This review examines the recognition and definitions of seizure clusters, the physiologic rationale for ISM for seizure clusters, and the effectiveness and safety of early treatment. Remaining knowledge gaps are also discussed. The findings of this review suggest that it may be time to revisit the terminology of "rescue", which implies waiting to administer treatment for seizure clusters, as doing so is not supported by pathophysiologic, effectiveness, or safety data. Plain Language Summary: Some people with epilepsy have seizures even if they take daily medication for their seizures. If they have more seizures than usual in a day, this may be called a seizure cluster. Drugs used to treat clusters are often said to be "rescue" medicines. But the word "rescue" may imply that the medication should only be administered when serious danger is present. Additionally, possibly because of previous instructions, people may think they have to wait to see if the seizure lasts more than 5 minutes to give the medicine, or they may be concerned about how safe the medicine will be if they give it. This older approach needs to be revisited and replaced. Waiting to give medicine could make it more likely that a person could get hurt or require a hospital or emergency room visit or their seizure condition could worsen. Waiting also may allow for changes in the body that may make a medicine less effective once it is given. Because of this, it may be better to say these medicines are for "immediate use" rather than for "rescue". That way, the people giving the medicine know that they should give it as soon as they see the patient needs it. This paper discusses how seizure clusters are described and what can happen if someone waits to give medicine versus giving it right away. The paper shows that waiting may not be needed. [ABSTRACT FROM AUTHOR]

Cholesterol is a critical molecule in the central nervous system, and imbalances in the synthesis and metabolism of brain cholesterol can result in a range of pathologies, including those related to hyperexcitability. The impact of cholesterol on disorders of epilepsy and developmental and epileptic encephalopathies is an area of growing interest. Cholesterol cannot cross the blood–brain barrier, and thus the brain synthesizes and metabolizes its own pool of cholesterol. The primary metabolic enzyme for brain cholesterol is cholesterol 24‐hydroxylase (CH24H), which metabolizes cholesterol into 24S‐hydroxycholesterol (24HC). Dysregulation of CH24H and 24HC can affect neuronal excitability through a range of mechanisms. 24HC is a positive allosteric modulator of N‐methyl‐D‐aspartate (NMDA) receptors and can increase glutamate release via tumor necrosis factor‐α‐dependent pathways. Increasing cholesterol metabolism can lead to dysfunction of excitatory amino acid transporter 2 and impair glutamate reuptake. Finally, overstimulation of NMDA receptors can further activate metabolism of cholesterol, leading to a vicious cycle of overactivation. All of these mechanisms increase extracellular glutamate and can lead to hyperexcitability. For these reasons, the cholesterol pathway represents a new potential mechanistic target for antiseizure medications. CH24H inhibition has been shown to decrease seizure behavior and improve survival in multiple animal models of epilepsy and could be a promising new mechanism of action for the treatment of neuronal hyperexcitability and developmental and epileptic encephalopathies. [ABSTRACT FROM AUTHOR]

Ketogenic dietary therapies (KDTs) are established, effective nonpharmacologic treatments for intractable childhood epilepsy. For many years KDTs were implemented differently throughout the world due to lack of consistent protocols. In 2009, an expert consensus guideline for the management of children on KDT was published, focusing on topics of patient selection, pre-KDT counseling and evaluation, diet choice and attributes, implementation, supplementation, follow-up, side events, and KDT discontinuation. It has been helpful in outlining a state-of-the-art protocol, standardizing KDT for multicenter clinical trials, and identifying areas of controversy and uncertainty for future research. Now one decade later, the organizers and authors of this guideline present a revised version with additional authors, in order to include recent research, especially regarding other dietary treatments, clarifying indications for use, side effects during initiation and ongoing use, value of supplements, and methods of KDT discontinuation. In addition, authors completed a survey of their institution's practices, which was compared to responses from the original consensus survey, to show trends in management over the last 10 years.

OBJECTIVE To evaluate age, adjunctive antiseizure medication (ASM), and specific ASMs on lacosamide (LCM) weight normalized dose-to-concentration ratio (DCR) and US Food and Drug Administration (FDA) dosing guidelines in pediatric patients. METHODS Patients 1 mo to ≤18 years with a LCM serum concentration between October 2009 and June 2017 were considered. Demographics, LCM DCR, and adjunctive ASM were recorded. LCM DCR/hr was used as a surrogate for clearance. Data were stratified by age (1 mo-< 2 yr; ≥ 2–6 yr; ≥ 6–12 yr; and ≥12–≤18 yr), FDA dosing weights, and ASM potential to interaction with LCM. RESULTS There were 646 sera (380 patients) with median dose 8.36 mg/kg/day (IQR, 5.92–11.16). 50.2% of doses were within FDA-weight guidelines; however, 40.4% exceeded recommendations. Most (81.3%) LCM concentrations were between 2 and 12 mg/L. A difference existed in DCR between ages, with those <2 years having the highest DCR (p < 0.001). Moving across age groups, the DCR decreases by 30.7%, 50.5%, and 63.4%. There was a weak (r2 = 0.073) but significant (p < 0.001) negative correlation between DCR and age. 84.8% received adjunctive ASM consisting of at least one of 31 different ASMs. DCR was higher with adjunctive ASMs compared with monotherapy [0.061 (0.039–0.095) vs 0.043 (0.030–0.062)], respectively (p < 0.001) and was greatest with inducers. Phenobarbital increased DCR by 2.6-fold, topiramate by 72.1%, and clobazam by 32.6%. Inhibitors had no effect. CONCLUSIONS The correlation between age and DCR was weak, accounting for 6% of variability. Strong inducers significantly increased DCR. Synergy may exist when multiple inducers are given. Weak inhibitors did not affect DCR. Those ≥6 to 11 kg, ≥30 to 50 kg, and those given strong inducers may require larger initial LCM doses. Serum concentrations should be used to individualize dosing, especially in those receiving strong inducers. [ABSTRACT FROM AUTHOR]

The diagnosis, evaluation, and management of infantile spasms (IS) continue to pose significant challenges to the treating physician. Although an evidence-based practice guideline with full literature review was published in 2004, diversity in IS evaluation and treatment remains and highlights the need for further consensus to optimize outcomes in IS. For this purpose, a working group committed to the diagnosis, treatment, and establishment of a continuum of care for patients with IS and their families—the Infantile Spasms Working Group (ISWG)—was convened. The ISWG participated in a workshop for which the key objectives were to review the state of our understanding of IS, assess the scientific evidence regarding efficacy of currently available therapeutic options, and arrive at a consensus on protocols for diagnostic workup and management of IS that can serve as a guide to help specialists and general pediatricians optimally manage infants with IS. The overall goal of the workshop was to improve IS outcomes by assisting treating physicians with early recognition and diagnosis of IS, initiation of short duration therapy with a first-line treatment, timely electroencephalography (EEG) evaluation of treatment to evaluate effectiveness, and, if indicated, prompt treatment modification. Differences of opinion among ISWG members occurred in areas where data were lacking; however, this article represents a consensus of the U.S. approach to the diagnostic evaluation and treatment of IS.

Objective: Dravet syndrome (DS) is a developmental and epileptic encephalopathy characterized by high seizure burden, treatment‐resistant epilepsy, and developmental stagnation. Family members rate communication deficits among the most impactful disease manifestations. We evaluated seizure burden and language/communication development in children with DS. Methods: ENVISION was a prospective, observational study evaluating children with DS associated with SCN1A pathogenic variants (SCN1A+ DS) enrolled at age ≤5 years. Seizure burden and antiseizure medications were assessed every 3 months and communication and language every 6 months with the Bayley Scales of Infant and Toddler Development 3rd edition and the parent‐reported Vineland Adaptive Behavior Scales 3rd edition. We report data from the first year of observation, including analyses stratified by age at Baseline: 0:6–2:0 years:months (Y:M; youngest), 2:1–3:6 Y:M (middle), and 3:7–5:0 Y:M (oldest). Results: Between December 2020 and March 2023, 58 children with DS enrolled at 16 sites internationally. Median follow‐up was 17.5 months (range =.0–24.0), with 54 of 58 (93.1%) followed for at least 6 months and 51 of 58 (87.9%) for 12 months. Monthly countable seizure frequency (MCSF) increased with age (median [minimum–maximum] = 1.0 in the youngest [1.0–70.0] and middle [1.0–242.0] age groups and 4.5 [.0–2647.0] in the oldest age group), and remained high, despite use of currently approved antiseizure medications. Language/communication delays were observed early, and developmental stagnation occurred after age 2 years with both instruments. In predictive modeling, chronologic age was the only significant covariate of seizure frequency (effect size =.52, p =.024). MCSF, number of antiseizure medications, age at first seizure, and convulsive status epilepticus were not predictors of language/communication raw scores. Significance: In infants and young children with SCN1A+ DS, language/communication delay and stagnation were independent of seizure burden. Our findings emphasize that the optimal therapeutic window to prevent language/communication delay is before 3 years of age. [ABSTRACT FROM AUTHOR]