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ObjectiveTo compare the effectiveness of initial treatment for infantile spasms.MethodsThe National Infantile Spasms Consortium prospectively followed up children with new-onset infantile spasms that began at age 2 to 24 months at 23 US centers (2012-2018). Freedom from treatment failure at 60 days required no second treatment for infantile spasms and no clinical spasms after 30 days of treatment initiation. We managed treatment selection bias with propensity score weighting and within-center correlation with generalized estimating equations.ResultsFreedom from treatment failure rates were as follows: adrenocorticotropic hormone (ACTH) 88 of 190 (46%), oral steroids 42 of 95 (44%), vigabatrin 32 of 87 (37%), and nonstandard therapy 4 of 51 (8%). Changing from oral steroids to ACTH was not estimated to affect response (observed 44% estimated to change to 44% [95% confidence interval 34%-54%]). Changing from nonstandard therapy to ACTH would improve response from 8% to 39% (17%-67%), and changing to oral steroids would improve response from 8% to 38% (15%-68%). There were large but not statistically significant estimated effects of changing from vigabatrin to ACTH (29% to 42% [15%-75%]), from vigabatrin to oral steroids (29% to 42% [28%-57%]), and from nonstandard therapy to vigabatrin (8% to 20% [6%-50%]). Among children treated with vigabatrin, those with tuberous sclerosis complex (TSC) responded more often than others (62% vs 29%; p < 0.05).DiscussionCompared to nonstandard therapy, ACTH and oral steroids are superior for initial treatment of infantile spasms. The estimated effectiveness of vigabatrin is between that of ACTH/oral steroids and nonstandard therapy, although the sample was underpowered for statistical confidence. When used, vigabatrin worked best for TSC.Classification of evidenceThis study provides Class III evidence that for children with new-onset infantile spasms, ACTH or oral steroids were superior to nonstandard therapies.

Objective: Infantile epileptic spasms syndrome (IESS) is a common and urgent diagnosis with seizure and nonseizure mimics. Evaluation with prolonged video–electroencephalography (EEG) can be time‐consuming and costly. This study investigated the use of EEG review of a single sleep–wake cycle to exclude IESS. Methods: We retrospectively reviewed video‐EEG studies to rule out IESS in children between the ages of 2 months and 2 years in the period from January 2019 through June 2020. EEG studies were reviewed from the start of the recording through the first sleep–wake cycle and scored as "normal," "consistent with IESS," or "abnormal but not diagnostic of IESS." Scores were compared to the clinical report created by analysis of the entire video‐EEG. Results: Inclusion criteria were met in 238 EEG studies. The mean patient age was 7.6 months. The median duration of the full study was 908 min, compared to 107.5 min for the first sleep–wake cycle only. The median difference in recording time was 801 min, p‐value <.01. Scored outcomes were similar. Sixty‐eight percent of EEG studies were scored as "normal" on first sleep–wake cycle review as compared to 63% on full study review, 13% scored as "consistent with IESS" compared to 16% and 19% scored as "abnormal but not diagnostic of IESS" compared to 21%. Sensitivity and specificity of the first sleep–wake cycle review for studies "consistent with IESS" was 84% and 100%, respectively. No cases of IESS were scored as normal on first sleep–wake cycle review. Significance: A single sleep–wake cycle captured on EEG can triage studies when IESS is suspected. A normal first sleep–wake cycle did not miss cases of IESS and could result in reduced EEG recording time. Because most of these cases presented to an emergency department, a normal first sleep–wake cycle may help providers determine the acuity, or necessity, of further testing. [ABSTRACT FROM AUTHOR]

ObjectiveInfantile spasms (IS) represent a severe epileptic encephalopathy presenting in the first 2 years of life. Recommended first-line therapies (hormonal therapy or vigabatrin) often fail. We evaluated response to second treatment for IS in children in whom the initial therapy failed to produce both clinical remission and electrographic resolution of hypsarhythmia and whether time to treatment was related to outcome.MethodsThe National Infantile Spasms Consortium established a multicenter, prospective database enrolling infants with new diagnosis of IS. Children were considered nonresponders to first treatment if there was no clinical remission or persistence of hypsarhythmia. Treatment was evaluated as hormonal therapy (adrenocorticotropic hormone [ACTH] or oral corticosteroids), vigabatrin, or "other." Standard treatments (hormonal and vigabatrin) were compared to all other nonstandard treatments. We compared response rates using chi-square tests and multivariable logistic regression models.ResultsOne hundred eighteen infants were included from 19 centers. Overall response rate to a second treatment was 37% (n = 44). Children who received standard medications with differing mechanisms for first and second treatment had higher response rates than other sequences (27/49 [55%] vs. 17/69 [25%], p < 0.001). Children receiving first treatment within 4 weeks of IS onset had a higher response rate to second treatment than those initially treated later (36/82 [44%] vs. 8/34 [24%], p = 0.040).SignificanceGreater than one third of children with IS will respond to a second medication. Choosing a standard medication (ACTH, oral corticosteroids, or vigabatrin) that has a different mechanism of action appears to be more effective. Rapid initial treatment increases the likelihood of response to the second treatment.

The International League Against Epilepsy (ILAE) introduced a classification for seizure types in 2017 and updated the classification for epilepsy syndromes in 2022. These classifications aim to improve communication among healthcare professionals and help patients better describe their condition. So far, regulatory agencies have used different terminology. This paper stresses the crucial need for consistently adopting ILAE terminology in both regulatory processes and clinical practice. It highlights how language plays a significant role in healthcare communication and how standardized terminology can enhance patient comprehension. The ongoing review of guidelines by regulatory bodies offers a timely opportunity. Aligning regulatory terminologies holds the potential to facilitate discussions on future drug development and harmonize practices across diverse regions, ultimately fostering improved care and research outcomes in epilepsy treatment. [ABSTRACT FROM AUTHOR]

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]

Objective: This study was undertaken to assess the safety and efficacy of fenfluramine in the treatment of convulsive seizures in patients with Dravet syndrome. Methods: This multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group, phase 3 clinical trial enrolled patients with Dravet syndrome, aged 2–18 years with poorly controlled convulsive seizures, provided they were not also receiving stiripentol. Eligible patients who had ≥6 convulsive seizures during the 6‐week baseline period were randomized to placebo, fenfluramine.2 mg/kg/day, or fenfluramine.7 mg/kg/day (1:1:1 ratio) administered orally (maximum dose = 26 mg/day). Doses were titrated over 2 weeks and maintained for an additional 12 weeks. The primary endpoint was a comparison of the monthly convulsive seizure frequency (MCSF) during baseline and during the combined titration–maintenance period in patients given fenfluramine.7 mg/kg/day versus patients given placebo. Results: A total of 169 patients were screened, and 143 were randomized to treatment. Mean age was 9.3 ± 4.7 years (±SD), 51% were male, and median baseline MCSF in the three groups ranged 12.7–18.0 per 28 days. Patients treated with fenfluramine.7 mg/kg/day demonstrated a 64.8% (95% confidence interval = 51.8%–74.2%) greater reduction in MCSF compared with placebo (p <.0001). Following fenfluramine.7 mg/kg/day, 72.9% of patients had a ≥50% reduction in MCSF compared with 6.3% in the placebo group (p <.0001). The median longest seizure‐free interval was 30 days in the fenfluramine.7 mg/kg/day group compared with 10 days in the placebo group (p <.0001). The most common adverse events (>15% in any group) were decreased appetite, somnolence, pyrexia, and decreased blood glucose. All occurred in higher frequency in fenfluramine groups than placebo. No evidence of valvular heart disease or pulmonary artery hypertension was detected. Significance: The results of this third phase 3 clinical trial provide further evidence of the magnitude and durability of the antiseizure response of fenfluramine in children with Dravet syndrome. [ABSTRACT FROM AUTHOR]

The article discusses the use of a modified Delphi process to develop consensus guidelines for the management of rare genetic epilepsies, specifically focusing on SCN8A. SCN8A is a rare condition with limited available literature and treatment options. The modified Delphi process involves incorporating the perspectives of various stakeholders, including parents/caregivers, community partners, and physicians, to establish consensus guidelines. This approach has been successfully used in other rare diseases, such as Dravet syndrome and Ring 14, to develop diagnostic and treatment recommendations. While the modified Delphi process has its limitations, it provides valuable guidance for physicians and families navigating rare diseases. [Extracted from the article]

Objective: This study was undertaken to evaluate the long‐term safety and effectiveness of fenfluramine in patients with Lennox–Gastaut syndrome (LGS). Methods: Eligible patients with LGS who completed a 14‐week phase 3 randomized clinical trial enrolled in an open‐label extension (OLE; NCT03355209). All patients were initially started on.2 mg/kg/day fenfluramine and after 1 month were titrated by effectiveness and tolerability, which were assessed at 3‐month intervals. The protocol‐specified treatment duration was 12 months, but COVID‐19‐related delays resulted in 142 patients completing their final visit after 12 months. Results: As of October 19, 2020, 247 patients were enrolled in the OLE. Mean age was 14.3 ± 7.6 years (79 [32%] adults) and median fenfluramine treatment duration was 364 days; 88.3% of patients received 2–4 concomitant antiseizure medications. Median percentage change in monthly drop seizure frequency was −28.6% over the entire OLE (n = 241) and −50.5% at Month 15 (n = 142, p <.0001); 75 of 241 patients (31.1%) experienced ≥50% reduction in drop seizure frequency. Median percentage change in nondrop seizure frequency was −45.9% (n = 192, p =.0038). Generalized tonic–clonic seizures (GTCS) and tonic seizures were most responsive to treatment, with median reductions over the entire OLE of 48.8% (p <.0001, n = 106) and 35.8% (p <.0001, n = 186), respectively. A total of 37.6% (95% confidence interval [CI] = 31.4%–44.1%, n = 237) of investigators and 35.2% of caregivers (95% CI = 29.1%–41.8%, n = 230) rated patients as Much Improved/Very Much Improved on the Clinical Global Impression of Improvement scale. The most frequent treatment‐emergent adverse events were decreased appetite (16.2%) and fatigue (13.4%). No cases of valvular heart disease (VHD) or pulmonary arterial hypertension (PAH) were observed. Significance: Patients with LGS experienced sustained reductions in drop seizure frequency on fenfluramine treatment, with a particularly robust reduction in frequency of GTCS, the key risk factor for sudden unexpected death in epilepsy. Fenfluramine was generally well tolerated; VHD or PAH was not observed long‐term. Fenfluramine may provide an important long‐term treatment option for LGS. [ABSTRACT FROM AUTHOR]