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Objective Methods Results Significance The cannabinoid cannabidiol has established antiseizure effects in drug‐resistant epilepsies such as Dravet syndrome and Lennox–Gastaut syndrome. Amorfrutin 2, honokiol, and magnolol are structurally similar to cannabinoids (cannabis‐like drugs) but derive from non‐cannabis plants. We aimed to study the antiseizure potential of these compounds in various mouse seizure models. In addition, we aimed to characterize their molecular pharmacology at cannabinoid CB1 and CB2 receptors and at T‐type calcium channels, which are known targets of the cannabinoids.Brain and plasma pharmacokinetic profiles were determined. Antiseizure activity was assessed against hyperthermia‐induced seizures in a Scn1a+/− mouse model of Dravet syndrome. We then elaborated on the most promising compounds in the maximal electroshock (MES) test in mice and the Gabrb3+/D120N mouse model of Lennox–Gastaut syndrome. Fluorescence‐based assays were used to examine modulatory activity at cannabinoid CB1 and CB2 receptors and T‐type calcium channel subtypes CaV3.1, CaV3.2, and CaV3.3 overexpressed in mammalian cells. Automated patch‐clamp electrophysiology was then used to confirm inhibitory activity on CaV3.1, CaV3.2, and CaV3.3 channels.Magnolol and honokiol had high brain‐to‐plasma ratios (3.55 and 7.56, respectively), unlike amorfrutin 2 (0.06). Amorfrutin 2 and magnolol but not honokiol significantly increased the body temperature threshold at which Scn1a+/− mice had a generalized tonic–clonic seizure. Both amorfrutin 2 and magnolol significantly decreased the proportion of mice exhibiting hindlimb extension in the MES test. Furthermore, magnolol reduced the number and duration of atypical absence seizures in Gabrb3+/D120N mice. The three compounds inhibited all T‐type calcium channel subtypes but were without specific activity at cannabinoid receptors.We show for the first time that amorfrutin 2 and magnolol display novel antiseizure activity in mouse drug‐resistant epilepsy models. Our results justify future drug discovery campaigns around these structural scaffolds that aim to develop novel antiseizure drugs for intractable epilepsies. [ABSTRACT FROM AUTHOR]

The article delves into the significance of recognizing variations among direct-acting oral anticoagulants (DOACs) when treating patients with epilepsy, particularly in relation to concomitant antiseizure medications (ASMs). It suggests that edoxaban may be the preferred DOAC for patients with epilepsy, especially when paired with mild to moderate CYP3A-inducing ASMs. The study also cautions about potential interactions with CYP3A4/P-gp inhibiting ASMs, advising careful monitoring, especially with cannabidiol. Additionally, the article explores the association between non-vitamin K oral anticoagulants and the risk of major bleeding in patients with nonvalvular atrial fibrillation, emphasizing the importance of assessing drug interactions for effective and safe treatment. [Extracted from the article]

The article discusses a case report of a 36-year-old male with drug-resistant post-traumatic epilepsy who achieved seizure freedom without medication after stereoelectroencephalography (sEEG) implantation. The patient underwent sEEG monitoring, which captured a single event without sEEG correlate, prompting further investigation. Despite discontinuing all seizure medications, the patient remained seizure-free for over 3.5 years. The article highlights the potential benefits and risks of sEEG procedures in drug-resistant epilepsy cases, emphasizing the need for further research into potential tissue injury caused by depth electrode insertion. [Extracted from the article]

Fenfluramine (FFA), an antiseizure medication (ASM) with serotonergic and sigma‐1 receptor activity, is used to manage patients with developmental and epileptic encephalopathies (DEEs). It is approved in the US for treating seizures associated with Dravet syndrome (DS) and Lennox–Gastaut syndrome (LGS) in patients ≥2 years old and as add‐on therapy for seizures associated with DS and LGS in the EU, UK, and Japan in similarly aged patients. Consensus guidelines for treatment of DS have recommended FFA to be an early‐line ASM, and it has also shown efficacy in managing seizures associated with LGS. DS and LGS are DEEs associated with a range of seizure types, developmental impairments, and multiple comorbidities. Here we provide case vignettes describing 4 patients (3 DS and 1 LGS) aged 4–29 years old in whom up to 14 ASMs had previously failed, to illustrate real‐world practice issues encountered by neurologists. This review provides guidance on the use of FFA in the context of ASM polytherapy and drug–drug interactions (DDIs), behavioral issues, dose titration, and adverse events. Along with data from the clinical trial program, these case vignettes emphasize the low risk of DDIs, a generally well‐tolerated safety profile, and other seizure and nonseizure benefits (eg, improved cognition and sleep) associated with the use of FFA in DS or LGS. Plain Language Summary: Fenfluramine is used to treat seizures in individuals with Dravet syndrome and Lennox–Gastaut syndrome, but there are a range of issues that clinicians may face when treating patients. This review highlights four patients from the authors' everyday clinical work and offers guidance and practical considerations by neurologists with expertise in managing these complex conditions related to drug interactions, dosing, and side effects associated with fenfluramine. [ABSTRACT FROM AUTHOR]

Background: Drug-resistant epilepsy (DRE) impacts a significant portion, onethird, of individuals diagnosed with epilepsy. In such cases, exploring nonpharmacological interventions are crucial, with the ketogenic diet (KD) standing out as a valuable option. KD, a high-fat and low-carb dietary approach with roots dating back to the 1920s for managing DRE, triggers the formation of ketone bodies and modifies biochemistry to aid in seizure control. Recent studies have increasingly supported the efficacy of KD in addressing DRE, showcasing positive outcomes. Furthermore, while more research is needed, limited data suggests that KD May also be beneficial for specific genetic epilepsy syndromes (GESs). Objective: This study aimed to assess the short-term efficacy of KD among pediatric patients diagnosed with GESs. Materials and methods: This is a multi-center retrospective analysis of pediatric patients with GESs diagnosed using next-generation sequencing. The enrolled patients followed the keto-clinic protocol, and the KD efficacy was evaluated at 3, 6, and 12-month intervals based on seizure control and compliance. The collection instrument included demographic, baseline, and prognostic data. The collected data was coded and analyzed promptly. Results: We enrolled a cohort of 77 patients with a mean current age of 7.94 ± 3.83 years. The mean age of seizure onset was 15.5 months. Notably, patients experienced seizures at a younger age tended to have less positive response to diet. Overall, 55 patients responded favorably to the diet (71.4%) while 22 patients (28.6%) showed no improvement. Patients with genetic etiology showed a significantly more favorable responses to the dietary intervention. Patients with Lennox-Gastaut syndrome showed the most significant improvement (14/15) followed by patients with Dravet syndrome (6/8), and West syndrome (3/4). The number of used anti-seizure medications also played a significant role in determining their response to the diet. While some patients experienced mild adverse events, the most common being constipation, these occurrences were not serious enough to necessitate discontinuation of the diet. Conclusion: The study revealed a high improvement rate in seizure control, especially among younger patients and those with later seizure onset. The success of dietary treatment hinges greatly on early intervention and the patient's age. Certain genetic mutations responded favorably to the KD, while efficacy varied among various genetic profiles. [ABSTRACT FROM AUTHOR]

Objective: Historically, epilepsy has been the most frequently presenting feature of tuberous sclerosis complex (TSC). Advances in TSC health care have occurred over the past decade; thus, we studied whether TSC epilepsy outcomes have changed. Method: A retrospective chart review was undertaken for all children with TSC in Queensland, Australia. Epilepsy outcome and TSC diagnosis data were extracted, and data were compared between children born before 2012 with those born in or after 2012. Results: In this retrospective cohort, TSC diagnosis in children born in or after 2012 is now predominantly antenatal (51%, p <.05). Most patients with epilepsy are now known to have TSC before they develop epilepsy. Despite earlier TSC diagnosis, the frequency of epilepsy (85%) has not changed (p =.92), but diagnosis trends toward an earlier age (median = 3 months for patients born in or after 2012 vs. 5.5 months for those born before 2012, p =.23). Most (95%) patients had focal seizures as their initial clinical seizure type; it was rare (5%) for epileptic spasms (ES) to be the initial seizure type. The frequency of ES was lower in patients born in or after 2012 (36% vs. 50%, p =.27). Infantile (<24 months) onset ES was not associated with worse epilepsy outcome. Late onset ES was seen in 14%, and these patients had a lower rate of epilepsy remission. Lennox–Gastaut syndrome was seen in 7%. Febrile/illness‐related status epilepticus occurred in 12% of patients, between 1 and 4 years of age. Despite many (78%) patients having multiple daily seizures at maximal seizure frequency, and 74% meeting criteria for treatment‐refractory epilepsy, most patients achieved epilepsy remission (66%), either with epilepsy surgery (47%) or with age (53%). At the time of inclusion in this study, only 21% of patients had uncontrolled frequent (daily to 3 monthly) seizures and 14% had uncontrolled infrequent (3 monthly to <2 yearly) seizures. Significance: This study provides updated information that informs the counseling of parents of newly diagnosed pediatric TSC patients. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to investigate the prevalence of autism spectrum disorder and its possible correlations with clinical characteristics in patients with infantile epileptic spasms syndrome in a single center in Brazil. Methods: This retrospective cross-sectional study examined 53 children with the diagnosis of infantile epileptic spasms syndrome prior to an autism spectrum disorder assessment. Participants were divided into two groups based on the presence or absence of autism spectrum disorder. Available variables (sex, medications, median age at onset of infantile epileptic spasms syndrome, and presence of comorbidities) were compared using Mann-Whitney U or chi-square tests. Results: Among the included patients, 12 (23 %) were diagnosed with autism spectrum disorder, corresponding to a relative risk of 0.29 (95 % confidence interval 0.174-0.492). The age at the first seizure ranged from 3 to 15 months, with a mean of 6.65 months. This age significantly differed between participants with autism spectrum disorder (10.58 months) and those without (5.43 months), p<0.001. [ABSTRACT FROM AUTHOR]

Abstract Fenfluramine (FFA), an antiseizure medication (ASM) with serotonergic and sigma‐1 receptor activity, is used to manage patients with developmental and epileptic encephalopathies (DEEs). It is approved in the US for treating seizures associated with Dravet syndrome (DS) and Lennox–Gastaut syndrome (LGS) in patients ≥2 years old and as add‐on therapy for seizures associated with DS and LGS in the EU, UK, and Japan in similarly aged patients. Consensus guidelines for treatment of DS have recommended FFA to be an early‐line ASM, and it has also shown efficacy in managing seizures associated with LGS. DS and LGS are DEEs associated with a range of seizure types, developmental impairments, and multiple comorbidities. Here we provide case vignettes describing 4 patients (3 DS and 1 LGS) aged 4–29 years old in whom up to 14 ASMs had previously failed, to illustrate real‐world practice issues encountered by neurologists. This review provides guidance on the use of FFA in the context of ASM polytherapy and drug–drug interactions (DDIs), behavioral issues, dose titration, and adverse events. Along with data from the clinical trial program, these case vignettes emphasize the low risk of DDIs, a generally well‐tolerated safety profile, and other seizure and nonseizure benefits (eg, improved cognition and sleep) associated with the use of FFA in DS or LGS. Plain Language Summary Fenfluramine is used to treat seizures in individuals with Dravet syndrome and Lennox–Gastaut syndrome, but there are a range of issues that clinicians may face when treating patients. This review highlights four patients from the authors’ everyday clinical work and offers guidance and practical considerations by neurologists with expertise in managing these complex conditions related to drug interactions, dosing, and side effects associated with fenfluramine.

Abstract Objective To evaluate the Refractory Epilepsy Screening Tool for Lennox–Gastaut Syndrome (REST‐LGS) for real‐world identification of LGS in adults and to develop a scoring system for the tool. Methods A retrospective chart review of adults with drug resistant epilepsy (DRE) and intellectual development disorder (IDD) was conducted by 2 primary care providers blinded to diagnosis. The REST‐LGS was designed via the Modified Delphi Consensus and was previously validated. This tool consists of 8 criteria (4 major, 4 minor) considered indicative of LGS. To account for missing data in the earlier validation study and to evaluate applicability in a real‐world setting, the REST‐LGS was refined to include a scoring system in which major criteria were more heavily weighted than minor criteria, producing categories of “likely” (>11 points), “possible” (8–11 points), and “unlikely” (

This article explores the challenges of treating epilepsy and the high prevalence of treatment failure. It suggests that a lack of understanding of why medications fail or why side effects occur is a major obstacle to successful treatment. The article emphasizes the need to identify the basis for treatment failure in order to develop more effective treatments. It also discusses different patterns of treatment failure and highlights the need for new approaches to discovery and a better understanding of treatment failure mechanisms. [Extracted from the article]

Developmental and epileptic encephalopathies (DEEs) are characterized by pharmacoresistant seizures and developmental delay. Patients with DEEs experience multiple seizure types, including tonic–clonic seizures (TCS) that can be generalized tonic–clonic (GTCS) or focal evolving to bilateral tonic–clonic (FBTCS). Fenfluramine (FFA) has demonstrated efficacy in reduction of TCS in patients with Dravet syndrome (DS), Lennox–Gastaut syndrome (LGS), and other DEEs. Using the PRISMA‐ScR (Preferred Reporting Items for Systematic Review and Meta‐Analyses extension for Scoping Review) guidelines, we performed a scoping review to describe changes in TCS in patients treated with FFA. A comprehensive search of five literature databases was conducted up to February 14, 2023. Studies were included if they reported change in GTCS or TCS (but not FBTCS) after treatment with FFA in patients with DEEs. Duplicate patients and studies with unclear efficacy data were excluded. Fourteen of 422 studies met the eligibility criteria. Data extracted and evaluated by expert clinicians identified 421 unique patients with DS (in nine studies), CDKL5 deficiency disorder, SCN8A‐related disorder, LGS, SCN1B‐related disorder, and other DEEs. The median percent reduction in GTCS or TCS from baseline was available in 10 studies (n = 328) and ranged from 47.2% to 100%. Following FFA treatment, 10 studies (n = 144) reported ≥50% reduction in GTCS or TCS from baseline in 72% of patients; in nine of those (n = 112), 54% and 29% of patients achieved ≥75% and 100% reduction in GTCS or TCS from baseline, respectively. Overall, this analysis highlighted improvements in GTCS or TCS frequency when patients were treated with FFA regardless of the DEE evaluated. Future studies may confirm the impact of FFA on TCS reduction and on decreased premature mortality risk (including sudden unexpected death in epilepsy), improvement in comorbidities and everyday executive function, decreased health care costs, and improvement in quality of life. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the Refractory Epilepsy Screening Tool for Lennox–Gastaut Syndrome (REST‐LGS) for real‐world identification of LGS in adults and to develop a scoring system for the tool. Methods: A retrospective chart review of adults with drug resistant epilepsy (DRE) and intellectual development disorder (IDD) was conducted by 2 primary care providers blinded to diagnosis. The REST‐LGS was designed via the Modified Delphi Consensus and was previously validated. This tool consists of 8 criteria (4 major, 4 minor) considered indicative of LGS. To account for missing data in the earlier validation study and to evaluate applicability in a real‐world setting, the REST‐LGS was refined to include a scoring system in which major criteria were more heavily weighted than minor criteria, producing categories of "likely" (>11 points), "possible" (8–11 points), and "unlikely" (<8 points) LGS. Statistical analyses were descriptive. Results: Of the 100 patients included in the analysis, data for slow spike–waves in electroencephalography and seizure onset age – both major REST‐LGS criteria – were missing for 46% and 42% of patients, respectively. The majority of patients met 4 of the 8 REST‐LGS criteria (cognitive impairment since childhood, 71%; persistent seizures despite a trial of ≥2 antiseizure medications, 65%; seizure onset before the age of 12 years, 57%; ≥2 seizure types, 56%). All 4 major criteria were met in 22 patients (22%). The percentages of patients considered "likely," "possible," or "unlikely" to have LGS were 26%, 30%, and 44%, respectively. Of the 74 patients without a previous LGS diagnosis, 42 (57%) were identified as "possible" or "likely" to have LGS using REST‐LGS. Significance: In this analysis, the validated REST‐LGS was evaluated in a real‐world setting. The majority of previously undiagnosed patients were identified via REST‐LGS as "possible" or "likely" to have LGS. Extensive missing data highlights challenges of LGS diagnosis in adults. Plain Language Summary: There is a need to identify adult patients with Lennox–Gastaut syndrome (LGS) so they can receive appropriate treatment. The Refractory Epilepsy Screening Tool for LGS (REST‐LGS) questionnaire was designed by experts to identify whether patients with seizures that are not controlled by medications may have LGS. In this study, 2 physicians completed the REST‐LGS using charts for 100 patients who experience seizures not controlled by medications. Of the patients who were previously diagnosed as not having LGS, the majority were "likely" or "possible" to have LGS based on the REST‐LGS; therefore, the REST‐LGS can identify patients for further evaluation. [ABSTRACT FROM AUTHOR]

Lennox–Gastaut syndrome (LGS) is a severe developmental and epileptic encephalopathy characterized by drug-resistant seizures, cognitive impairments, and abnormal electroencephalographic patterns. Vagus nerve stimulation (VNS) is a widely used neuromodulation therapy for LGS, but its effects on seizure outcomes, different seizure types, non-seizure outcomes, and adverse events in this population have not been comprehensively reviewed. To conduct a scoping review on the use of VNS in LGS, a literature search was performed in PubMed, OVID, Web of Science, and Embase from inception to 9 June 2024, using relevant keywords and without restrictions on study design. The search yielded forty eligible studies (twenty-four retrospective cohorts, fourteen prospective cohorts, and two registry analyses) comprising 1400 LGS patients treated with VNS. No randomized controlled trials were identified. Across studies, the median seizure reduction ranged from 20.6% to 65%, with 0% to 100% of patients achieving a ≥50% seizure reduction. No consistent preoperative biomarker of VNS responsiveness was identified in LGS. Although inconsistent among different studies, tonic, atonic, and tonic–clonic seizures responded best, while focal seizures responded worst. Improvements in seizure severity, alertness, and quality of life were reported in some studies, but cognitive and adaptive functioning generally remained unchanged. Adverse events were mostly mild and transient, including hoarseness, cough, and paresthesia. Device-related complications and infections were uncommon. In conclusion, further research is needed to better understand VNS's position in the evolving LGS treatment landscape and its cost effectiveness. [ABSTRACT FROM AUTHOR]

Background: Neither radiological phenotypic characteristics nor reconstruction CT scan has been used to study the early anatomical disruption of the cranial bone in children with the so-called idiopathic type of West syndrome. Material and Methods: The basic diagnostic measures and the classical antiepileptic treatments were applied to these children in accordance with the conventional protocol of investigations and treatment for children with West syndrome. Boys from three unrelated families were given the diagnosis of the idiopathic type of West syndrome, aged 7, 10 and 12 years old. Parents underwent extensive clinical examinations. Three parents (age range of 28–41 year) were included in this study. All children showed a history of intellectual disabilities, cryptogenic epileptic spasms and fragmented hypsarrhythmia. These children and their parents were referred to our orthopedic departments because of variable skeletal deformities. Variable forms of skeletal deformities were the motive for the families to seek orthopedic advice. A constellation of flat foot, torticollis and early-onset osteoarthritis were observed by the family doctor. Apparently, and from the first clinical session in our practice, we felt that all these children are manifesting variable forms of abnormal craniofacial contour. Thereby, we immediately performed detailed cranial radiological phenotypic characterization of every affected child, as well as the siblings and parents, and all were enrolled in this study. All affected children underwent whole-exome sequence analysis. Results: The craniofacial phenotype of all children revealed apparent developmental anatomical disruption of the cranial bones. Palpation of the skull bones showed unusual palpable bony ridges along different sutural locations. A 7-year-old child showed abnormal bulging over the sagittal suture, associated with bilateral bony ridges over the squamosal sutures. AP skull radiograph of a 7-year-old boy with West syndrome showed facial asymmetry with early closure of the metopic suture, and other sutures seemed ill-defined. A 3D reconstruction CT scan of the skull showed early closure of the metopic suture. Another 3D reconstruction CT scan of the skull while the patient was in flexion showed early closure of the squamosal sutures, pressing the brain contents upward, causing the development of a prominent bulge at the top of the mid-sagittal suture. A reformatted 3D reconstruction CT scan confirmed the bilateral closure of the squamosal suture. Examination of the parents revealed a similar skull radiographic abnormality in his mother. A 3D reformatted frontal cranial CT of a 35-year-old mother showed early closure of the metopic and sagittal sutures, causing a mid-sagittal bony bulge. A 10-year-old boy showed an extremely narrow frontal area, facial asymmetry and a well palpable ridge over the lambdoid sutures. A 3D axial reconstruction CT scan of a 10-year-old boy with West syndrome illustrated the asymmetry of the posterior cranial bones along the lambdoid sutures. Interestingly, his 28-year-old mother has been a client at the department of spine surgery since she was 14 years old. A 3D reconstruction CT scan of the mother showed a noticeable bony ridge extending from the metopic suture upwards to involve the sagittal suture (red arrow heads). The black arrow shows a well demarcated bony ridge over the squamosal suture. A 3D reconstruction CT scan of the skull and spine showed the thick bony ridge of the metopic and the anterior sagittal as well as bilateral involvement of the squamosal, causing apparent anterior narrowing of the craniofacial contour. Note the lumbar scoliosis. A 12-year-old boy showed brachycephaly. A lateral skull radiograph of a 12-year-old boy with West syndrome showed premature sutural fusion, begetting an abnormal growth pattern, resulting in cranial deformity. The nature of the deformity depends on which sutures are involved, the time of onset and the sequence in which individual sutures fuse. In this child, brachycephalic secondary to craniosynostosis, which occurred because of bilateral early ossification of the coronal sutures, led to bi-coronal craniosynostosis. Thickened frontal bones and an ossified interclinoid ligament of the sella turcica were encountered. The lateral skull radiograph of a 38-year-old mother with a history of poor schooling achievements showed a very similar cranial contour of brachycephaly, thickening of the frontal bones and massive ossification of the clinoid ligament of the sella turcica. Maternal history revealed a history of multiple spontaneous miscarriages in the first trimester of more than five times. Investigating his parents revealed a brachycephalic mother with borderline intelligence. We affirm that the pattern of inheritance in the three boys was compatible with the X-linked recessive pattern of inheritance. Whole-exome sequencing showed non-definite phenotype/genotype correlation. Conclusions: The aim of this study was sixfold: firstly, to refute the common usage of the term idiopathic; secondly, we feel that it could be possible that West syndrome is a symptom complex rather than a separate diagnostic entity; thirdly, to further detect the genetic carrier, we explored the connection between the cranial bones in children with West syndrome with what has been clinically observed in their parents; fourthly, the early life anatomical disruptions of the cranial bones among these children seem to be heterogeneous; fifthly, it shows that the progressive deceleration in the development of this group of children is highly connected to the progressive closure of the cranial sutures; sixthly, we affirm that our findings are novel. [ABSTRACT FROM AUTHOR]

Introduction: Although the contribution of enhanced glial activity in seizure induction is increasingly recognized, the role of glia-induced neuroinflammation in the physiopathology of epileptic encephalopathy (EE) has been scarcely investigated. Methods: To delineate the contribution of glial activity in EE, we measured levels of glia-derived mediators with previously described biomarker value, including glial fibrillary acidic protein (GFAP), high mobility group box 1 (HMGB1), chitinase-3-like protein 1 (CHI3L1), soluble CD163 (sCD163) and triggering receptor expressed on myeloid cells 2 (TREM2) by ELISA in sera of patients with idiopathic West syndrome (WS, n=18), idiopathic Lennox-Gastaut syndrome (LGS, n=13) and healthy controls (n=31). Results: Patients with EE showed significantly higher CHI3L1 levels compared to healthy controls. Levels of HMGB1, CHI3L1, sCD163 and TREM2 were higher in LGS patients than WS patients and/or healthy controls. One or more of the investigated mediators were associated with treatment responsiveness, disease severity and presence of pathological features on electroencephalography (EEG). Conclusions: To our knowledge, our findings provide the initial patient-based evidence that astrocyte- and microglia-mediated neuroinflammation might be involved in the pathogenesis of LGS and WS. Moreover, glial mediators may serve as prognostic biomarkers in patients with idiopathic EE. [ABSTRACT FROM AUTHOR]

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]

Introduction: The efficacy of stiripentol in Dravet syndrome children was evidenced in two randomized, double-blind, placebo-controlled, phase 3 studies, namely STICLO France (October 1996–August 1998) and STICLO Italy (April 1999–October 2000), but data were not fully exploited at the time. Methods: This post-hoc analysis used additional information, notably collected during the open-label extension (OLE) month, or reported by caregivers in individual diaries, to evaluate new outcomes. Results: Overall, 64 patients were included (31 in the placebo group, 33 in the stiripentol group) of whom 34 (53.1%) were female. Patients' mean and median (25%; 75%) age were 9.2 years (range 3.0–20.7 years) and 8.7 years (6.0; 12.1) respectively. At the end of the double-blind treatment period, 72% of the patients in the stiripentol group had a ≥ 50% decrease in generalized tonic–clonic seizure (GTCS) frequency, versus 7% in the placebo group (P < 0.001), 56% had a profound (≥ 75%) decrease versus 3% in the placebo group (P < 0.001), and 38% were free of GTCS, but none in the placebo group (P < 0.001). The onset of stiripentol efficacy was rapid, significant from the fourth day of treatment onwards. The median longest period of consecutive days with no GTCS was 32 days in the stiripentol group compared to 8.5 days in the placebo group (P < 0.001). Further to the switch to the third month OLE, an 80.2% decrease in seizure frequency from baseline was observed in patients previously receiving placebo, while no change in efficacy was observed in those already on stiripentol. Adverse events were more frequent in the stiripentol group, with significantly more episodes of somnolence, anorexia, and weight decrease than in the placebo group. Conclusion: Altogether these new analyses of the STICLO data reinforce the evidence for a remarkable efficacy of stiripentol in Dravet syndrome, with a demonstrated rapid onset of action and sustained response, as also evidenced in further post-randomized trials. [ABSTRACT FROM AUTHOR]

This article discusses the successful use of cannabidiol (CBD) in the treatment of nonconvulsive status epilepticus (NCSE) in a patient with Angelman syndrome (AS). AS is a rare neurogenetic disorder characterized by developmental delay, seizures, cognitive impairment, and motor dysfunction. NCSE is a common complication in AS, and treatment options are limited. The patient in this case study was treated with Epidyolex® CBD, which resulted in improved responsiveness, seizure freedom, and significant improvement in EEG abnormalities. The use of CBD in refractory status epilepticus has shown favorable outcomes in previous studies. While this case study is anecdotal, it suggests that CBD may be a promising treatment for NCSE in AS and warrants further research and clinical trials. [Extracted from the article]

Lennox-Gastaut syndrome (LGS) is a severe, epileptic encephalopathy.In recent years, a variety of drugs have been approved for the treatment of LGS. The U.S. Food and Drug Administration approved clobazam and cannabidiol as adjunctive therapy for LGS in October 2011 and June 2018, respectively. This article provides an overview of clobazam and cannabidiol, including their chemical structures, pharmacological actions, curative effects, safety profile, drug interactions, to introduce the current state of research and the achievements of both drugs.

Abstract Objective Lennox‐Gastaut syndrome (LGS) is an archetypal developmental and epileptic encephalopathy, for which novel treatments are emerging. Diagnostic criteria for LGS have recently been defined by the International League Against Epilepsy (ILAE). We aimed to apply these criteria in a real‐world setting. Methods We applied ILAE diagnostic criteria to a cohort of patients diagnosed with LGS by epileptologists following inpatient video‐EEG monitoring (VEM) at tertiary comprehensive epilepsy centers between 1995 and 2015. We also assessed mortality in this cohort. Results Sixty patients diagnosed with LGS and had complete records available for review were identified. Among them, 29 (48%) patients met ILAE diagnostic criteria for LGS (ILAE‐DC group). Thirty‐one did not meet criteria (non‐ILAE‐DC) due to the absence of documented tonic seizures (n = 7), EEG features (n = 12), or both tonic seizures and EEG features (n = 10), intellectual disability (n = 1), or drug resistance (n = 1). The ILAE‐DC group had a shorter duration of epilepsy at VEM than the non‐ILAE‐DC group (median = 12.0 years vs. 23.7 years, respectively; p = 0.015). The proportions of patients with multiple seizure types (100% vs. 96.7%), ≤2.5 Hz slow spike‐and‐wave EEG activity (100% vs. 90%), seizure‐related injuries (27.6% vs. 25.8%), and mortality (standardized mortality ratio 4.60 vs. 5.12) were similar between the groups. Significance Up to 52% of patients diagnosed with LGS following VEM may not meet recently accepted ILAE criteria for LGS diagnosis. This may reflect both the limitations of retrospective medical record review and a historical tendency of applying the LGS diagnosis to a broad spectrum of severe, early‐onset drug‐resistant epilepsies with drop attacks. The ILAE criteria allow the delineation of LGS based on distinct electroclinical features, potentiating accurate diagnosis, prognostication, and management formulation. Nonetheless, mortality outcomes between those who did and did not meet ILAE diagnostic criteria for LGS were similarly poor, and both groups suffered high rates of seizure‐related injury. Plain Language Summary More than half of patients diagnosed with Lennox‐Gastaut Syndrome (LGS) at three Australian epilepsy monitoring units between 1995 and 2015 did not meet the recently devised International League Against Epilepsy (ILAE) diagnostic criteria for LGS. Mortality was equally high in those who did and did not meet the ILAE diagnostic criteria, and seizure‐related injury was common. The ILAE diagnostic criteria will guide accurate diagnosis, management, prognostication, and research in patients with LGS, however may be limited in their practical application to patients with a longer duration of epilepsy, or to those for whom detailed assessment is difficult.

Abstract Objective Evaluate the long‐term efficacy of vagus nerve stimulation (VNS) in patients with developmental and epileptic encephalopathies (DEE) compared with epilepsy patients without intellectual disability (ID). Methods Long‐term outcomes from a Norwegian VNS quality registry are reported in 105 patients with DEEs (Lennox–Gastaut syndrome [LGS] n = 62; Dravet n = 16; Rett n = 9; other syndromes n = 18) were compared with 212 epilepsy patients without ID, with median follow‐up of 88 and 72 months, respectively. Total seizure reduction was evaluated at 6, 12, 24, 36, and 60 months. Effect on different seizure types was evaluated at baseline and last observation carried forward (LOCF). Results Median monthly seizure frequency at LOCF was reduced by 42.2% (p

Abstract Background RARS2-related mitochondrial disorder is an autosomal recessive mitochondrial encephalopathy caused by biallelic pathogenic variants in the gene encoding the mitochondrial arginyl-transfer RNA synthetase 2 (RARS2, MIM *611524, NM_020320.5). RARS2 catalyzes the transfer of L-arginine to its cognate tRNA during the translation of mitochondrially-encoded proteins. The classical presentation of RARS2-related mitochondrial disorder includes pontocerebellar hypoplasia (PCH), progressive microcephaly, profound developmental delay, feeding difficulties, and hypotonia. Most patients also develop severe epilepsy by three months of age, which consists of focal or generalized seizures that frequently become pharmacoresistant and lead to developmental and epileptic encephalopathy (DEE). Case presentation Here, we describe a six-year-old boy with developmental delay, hypotonia, and failure to thrive who developed an early-onset DEE consistent with Lennox-Gastaut Syndrome (LGS), which has not previously been observed in this disorder. He had dysmorphic features including bilateral macrotia, overriding second toes, a depressed nasal bridge, retrognathia, and downslanting palpebral fissures, and he did not demonstrate progressive microcephaly. Whole genome sequencing identified two variants in RARS2, c.36 + 1G > T, a previously unpublished variant that is predicted to affect splicing and is, therefore, likely pathogenic and c.419 T > G (p.Phe140Cys), a known pathogenic variant. He exhibited significant, progressive generalized brain atrophy and ex vacuo dilation of the supratentorial ventricular system on brain MRI and did not demonstrate PCH. Treatment with a ketogenic diet (KD) reduced seizure frequency and enabled him to make developmental progress. Plasma untargeted metabolomics analysis showed increased levels of lysophospholipid and sphingomyelin-related metabolites. Conclusions Our work expands the clinical spectrum of RARS2-related mitochondrial disorder, demonstrating that patients can present with dysmorphic features and an absence of progressive microcephaly, which can help guide the diagnosis of this condition. Our case highlights the importance of appropriate seizure phenotyping in this condition and indicates that patients can develop LGS, for which a KD may be a viable therapeutic option. Our work further suggests that analytes of phospholipid metabolism may serve as biomarkers of mitochondrial dysfunction.

The mediator complex subunit 23 (MED23) gene encodes a protein that acts as a tail module mediator complex, a multi-subunit co-activator involved in several cellular activities. MED23 has been shown to have substantial roles in myogenesis and other molecular mechanisms. The functions of MED23 in the neurological system remain unclear and the clinical phenotype is not thoroughly described. Whole exome sequencing was used to identify a novel mutation in the MED23 gene. DNA capture probes using next-generation sequencing-based copy number variation analysis with Illumina array were performed. The clinical, demographic, neuroimaging, and electrophysiological data of the patients were collected, and similarly, the data of all reported cases in the literature were extracted to compare findings. Screening a total of 9,662 articles, we identified 22 main regulatory processes for the MED23 gene, including suppressive activity for carcinogenic processes. MED23 is also involved in the brain’s neurogenesis and functions. The identified cases mainly presented with intellectual disability (87.5%) and developmental delay (50%). Seizures were present in only 18.75% of the patients. Slow backgrounds and spike and sharp-wave complexes were reported on the electroencephalogram (EEG) of a few patients and delayed myelination, thin corpus callosum, and pontine hypoplasia on magnetic resonance imaging (MRI). The MED23 gene regulates several processes in which its understanding promotes considerable therapeutic potential for patients. It is crucial to consider genetic and laboratory testing, particularly when encountering potential carriers. Intellectual disability and developmental delay are the most notable clinical signs with heterogeneous features on EEG and MRI. [ABSTRACT FROM AUTHOR]

Interest in using cannabis products for a medical purpose in children under the age of 18 years is increasing. There are many medical cannabis products available that can include cannabidiol (CBD) or delta-9-tetrahydrocannabinol (THC), or both. Despite many therapeutic claims, there are few rigorous studies to inform the dosing, safety, and efficacy of medical cannabis in paediatric clinical practice. This statement reviews the current evidence and provides recommendations for using medical cannabis in children. Longer-term (2-year) reports support the sustained tolerability and efficacy of cannabidiol therapy for patients with Lennox-Gastaut and Dravet syndromes. CBD-enriched cannabis extracts containing small amounts of THC have been evaluated in a small number of paediatric patients, and further research is needed to inform clinical practice guidelines. Given the widespread use of medical cannabis in Canada, paediatricians should be prepared to engage in open, ongoing discussions with families about its potential benefits and risks, and develop individualized plans that monitor efficacy, reduce harms, and mitigate drug–drug interactions. [ABSTRACT FROM AUTHOR]

It has been several years since highly purified cannabidiol (CBD) was registered as a medication that can be used in children of at least 2 years of age to treat different types of seizures related to Lennox–Gastaut syndrome (LGS), Dravet syndrome (DS), and more recently tuberous sclerosis complex (TSC). During this time, 39 randomized clinical trials (RCTs) and 13 meta-analyses on the efficacy and safety of CBD treatment have been published. Each of the meta-analyses had its own criteria for the RCTs' inclusion and, therefore, slightly different interpretations of the analyzed data. Each of them contributed in its own way to the understanding of CBD pharmacology, mechanisms of therapeutic action, development of adverse reactions, and drug–drug interactions. Hence, it seemed reasonable to gather the most relevant data in one article and present all the current knowledge on the use of CBD in epilepsy. The results of the 13 meta-analyses presented herein confirmed the effectiveness and safety of CBD in children and adolescents with DREs. In adults, reliable conclusions cannot be drawn due to insufficient data. [ABSTRACT FROM AUTHOR]

Fully elucidating the burden that Lennox–Gastaut syndrome (LGS) places on individuals with the disease and their caregivers is critical to improving outcomes and quality of life (QoL). This systematic literature review evaluated the global burden of illness of LGS, including clinical symptom burden, care requirements, QoL, comorbidities, caregiver burden, economic burden, and treatment burden (PROSPERO ID: CRD42022317413). MEDLINE, Embase, and the Cochrane Library were searched for articles that met predetermined criteria. After screening 1442 deduplicated articles and supplementary manual searches, 113 articles were included for review. A high clinical symptom burden of LGS was identified, with high seizure frequency and nonseizure symptoms (including developmental delay and intellectual disability) leading to low QoL and substantial care requirements for individuals with LGS, with the latter including daily function assistance for mobility, eating, and toileting. Multiple comorbidities were identified, with intellectual disorders having the highest prevalence. Although based on few studies, a high caregiver burden was also identified, which was associated with physical problems (including fatigue and sleep disturbances), social isolation, poor mental health, and financial difficulties. Most economic analyses focused on the high direct costs of LGS, which arose predominantly from medically treated seizure events, inpatient costs, and medication requirements. Pharmacoresistance was common, and many individuals required polytherapy and treatment changes over time. Few studies focused on the humanistic burden. Quality concerns were noted for sample representativeness, disease and outcome measures, and reporting clarity. In summary, a high burden of LGS on individuals, caregivers, and health care systems was identified, which may be alleviated by reducing the clinical symptom burden. These findings highlight the need for a greater understanding of and better definitions for the broad spectrum of LGS symptoms and development of treatments to alleviate nonseizure symptoms. [ABSTRACT FROM AUTHOR]

Dravet syndrome (DS) and Lennox–Gastaut syndrome (LGS) are rare developmental and epileptic encephalopathies associated with seizure and nonseizure symptoms. A comprehensive understanding of how many individuals are affected globally, the diagnostic journey they face, and the extent of mortality associated with these conditions is lacking. Here, we summarize and evaluate published data on the epidemiology of DS and LGS in terms of prevalence, incidence, diagnosis, genetic mutations, and mortality and sudden unexpected death in epilepsy (SUDEP) rates. The full study protocol is registered on PROSPERO (CRD42022316930). After screening 2172 deduplicated records, 91 unique records were included; 67 provided data on DS only, 17 provided data on LGS only, and seven provided data on both. Case definitions varied considerably across studies, particularly for LGS. Incidence and prevalence estimates per 100 000 individuals were generally higher for LGS than for DS (LGS: incidence proportion = 14.5–28, prevalence = 5.8–60.8; DS: incidence proportion = 2.2–6.5, prevalence = 1.2–6.5). Diagnostic delay was frequently reported for LGS, with a wider age range at diagnosis reported than for DS (DS, 1.6–9.2 years; LGS, 2–15 years). Genetic screening data were reported by 63 studies; all screened for SCN1A variants, and only one study specifically focused on individuals with LGS. Individuals with DS had a higher mortality estimate per 1000 person‐years than individuals with LGS (DS, 15.84; LGS, 6.12) and a lower median age at death. SUDEP was the most frequently reported cause of death for individuals with DS. Only four studies reported mortality information for LGS, none of which included SUDEP. This systematic review highlights the paucity of epidemiological data available for DS and especially LGS, demonstrating the need for further research and adoption of standardized diagnostic criteria. [ABSTRACT FROM AUTHOR]

Introduction. Drug-resistant epilepsy (DRE) remains poorly-controlled in c.33% of patients, and up to 50% of patients suffering from DRE are deemed not to be suitable candidates for resective surgery. For these patients, deep brain stimulation (DBS) may constitute the last resort in the treatment of DRE. State of the art. We undertook a systematic review of the current literature on DBS efficacy and the safety of two thalamic nuclei--anterior nucleus of the thalamus (ANT) and the centromedian nucleus of the thalamus in the management of patients with DRE. A search using two electronic databases, the Medical Literature, Analysis, and Retrieval System on-line (MEDLINE) and the Cochrane Central Register of Controlled Trials (CEN-TRAL) was conducted. Clinical implications. We found 30 articles related to ANT DBS and 13 articles related to CMN DBS which were further analysed. Based on the clinical research articles, we found a mean seizure frequency reduction for both thalamic nuclei. For ANT DBS, the mean seizure frequency reduction ranged from 48% to 75%, and for CMN DBS from 46.7% to 91%. The responder rate (defined as at least 50% reduction in seizure frequency) was reported to be 53.2-75% for patients after ANT DBS and 50--90% for patients after CMN DBS. Future directions. ANT and CMN DBS appear to be safe and efficacious treatments, particularly in patients with refractory partial seizures and primary generalised seizures. ANT DBS reduces most effectively seizures originating in the temporal and frontal lobes. CMN DBS reduces mostly primary generalised tonic-clonic and atypical absences and atonic seizures. Seizures related to Lennox-Gastaut syndrome respond very favourably to CMN DBS. [ABSTRACT FROM AUTHOR]

Aim: To differentiate phenotypic features of individuals with CDKL5 deficiency disorder (CDD) from those of individuals with other infantile‐onset epilepsies. Method: We performed a retrospective cohort study and ascertained individuals with CDD and comparison individuals with infantile‐onset epilepsy who had epilepsy gene panel testing. We reviewed records, updated variant classifications, and compared phenotypic features. Wilcoxon rank‐sum tests and χ2 or Fisher's exact tests were performed for between‐cohort comparisons. Results: We identified 137 individuals with CDD (110 females, 80.3%; median age at last follow‐up 3 year 11 months) and 313 individuals with infantile‐onset epilepsies (156 females, 49.8%; median age at last follow‐up 5 years 2 months; 35% with genetic diagnosis). Features reported significantly more frequently in the CDD group than in the comparison cohort included developmental and epileptic encephalopathy (81% vs 66%), treatment‐resistant epilepsy (95% vs 71%), sequential seizures (46% vs 6%), epileptic spasms (66% vs 42%, with hypsarrhythmia in 30% vs 48%), regression (52% vs 29%), evolution to Lennox–Gastaut syndrome (23% vs 5%), diffuse hypotonia (72% vs 36%), stereotypies (69% vs 11%), paroxysmal movement disorders (29% vs 17%), cerebral visual impairment (94% vs 28%), and failure to thrive (38% vs 22%). Interpretation: CDD, compared with other suspected or confirmed genetic epilepsies presenting in the first year of life, is more often characterized by a combination of treatment‐resistant epilepsy, developmental and epileptic encephalopathy, sequential seizures, spasms without hypsarrhythmia, diffuse hypotonia, paroxysmal movement disorders, cerebral visual impairment, and failure to thrive. Defining core phenotypic characteristics will improve precision diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Objective: Lead time to treatment (clinical onset of epileptic spasms [ES] to initiation of appropriate treatment) is known to predict outcomes in infantile epileptic spasms syndrome (IESS). Timing the clinical onset of ES is crucial to establish lead time. We investigated how often ES onset could be established to the nearest week. We aimed to (1) ascertain the exact date or estimate the nearest week of ES onset and (2) compare clinical/demographic factors between patients where date of ES onset was determined or estimated to the nearest week and patients whose date of ES onset could not be estimated to the nearest week. Reasons for difficulties in estimating date of ES onset were explored. Methods: Retrospective chart review of new onset IESS patients (January 2019–May 2022) extracted the date or week of the clinical onset of ES. Predictors of difficulty in date of ES onset estimation to the nearest week were examined by regression analysis. Sources contributing to difficulties determining date of ES onset were assessed after grouping into categories (provider‐, caregiver‐, disease‐related). Results: Among 100 patients, date of ES onset was estimated to the nearest week in 47%. On univariable analysis, age at diagnosis (p =.021), development delay (p =.007), developmental regression/stagnation (p =.021), ES intermixed with other seizures (p =.011), and nonclustered ES at onset (p =.005) were associated with difficulties estimating date of ES onset. On multivariable analysis, failure to establish date of ES onset was related to ES intermixed with other seizures (p =.004) and nonclustered ES at onset (p =.003). Sources contributing to difficulties determining date of ES onset included disease‐related factors (ES characteristics, challenges interpreting electroencephalograms) and provider/caregiver‐related factors (delayed diagnosis). Significance: Difficulties with estimation of lead time (due to difficulties timing ES onset) can impact clinical care (prognostication), as even small increments in lead time duration can have adverse developmental consequences. [ABSTRACT FROM AUTHOR]

Objective: Evaluate the long‐term efficacy of vagus nerve stimulation (VNS) in patients with developmental and epileptic encephalopathies (DEE) compared with epilepsy patients without intellectual disability (ID). Methods: Long‐term outcomes from a Norwegian VNS quality registry are reported in 105 patients with DEEs (Lennox–Gastaut syndrome [LGS] n = 62; Dravet n = 16; Rett n = 9; other syndromes n = 18) were compared with 212 epilepsy patients without ID, with median follow‐up of 88 and 72 months, respectively. Total seizure reduction was evaluated at 6, 12, 24, 36, and 60 months. Effect on different seizure types was evaluated at baseline and last observation carried forward (LOCF). Results: Median monthly seizure frequency at LOCF was reduced by 42.2% (p < 0.001) in patients with DEE and by 55.8% (p < 0.001) in patients without ID. In DEE patients, ≥50% seizure reduction at 6 and 24 months were 17.1% and 37.1%, respectively, and 33.5% and 48.6% for patients without ID. Seizure reduction ≥75% at 60 months occurred in 14.3% of DEE patients and 23.1% of patients without ID. Highest median reduction was for atonic seizures, most notably 64.6% for LGS patients. A better effect was seen at 2 years among DEE patients with unchanged medication compared with those with changed medication (54.5% vs. 35.6% responders, p = 0.078). More DEE patients were reported to have greater improvement in ictal or postictal severity (43.8% vs. 28.3%, p = 0.006) and alertness (62.9% vs. 31.6%, p < 0.001) than patients without ID. For both groups, use of the magnet reduced seizure severity. Hoarseness was the most common adverse effect in both groups. In addition, DEE patients were frequently reported to have sleep disturbance, general discomfort, or abdominal problems. Significance: Our data indicate that VNS is very effective for atonic seizures. Patients without ID had best overall seizure reduction, however, patients with DEE had higher retention rates probably due to other positive effects. Plain Language Summary: DEE refers to a group of patients with severe epilepsy and intellectual disability. Many of these patients have restricted lifestyles with frequent seizures. VNS is a treatment option for patients who do not respond well to medicines, either because of insufficient effect or serious adverse effects. Our study shows that VNS is well tolerated in this patient group and leads to a reduction in all seizure types, most notably for seizures leading to fall. Many patients experience other positive effects like shorter and milder seizures, as well as improvement in alertness. [ABSTRACT FROM AUTHOR]

Objective: Lennox‐Gastaut syndrome (LGS) is an archetypal developmental and epileptic encephalopathy, for which novel treatments are emerging. Diagnostic criteria for LGS have recently been defined by the International League Against Epilepsy (ILAE). We aimed to apply these criteria in a real‐world setting. Methods: We applied ILAE diagnostic criteria to a cohort of patients diagnosed with LGS by epileptologists following inpatient video‐EEG monitoring (VEM) at tertiary comprehensive epilepsy centers between 1995 and 2015. We also assessed mortality in this cohort. Results: Sixty patients diagnosed with LGS and had complete records available for review were identified. Among them, 29 (48%) patients met ILAE diagnostic criteria for LGS (ILAE‐DC group). Thirty‐one did not meet criteria (non‐ILAE‐DC) due to the absence of documented tonic seizures (n = 7), EEG features (n = 12), or both tonic seizures and EEG features (n = 10), intellectual disability (n = 1), or drug resistance (n = 1). The ILAE‐DC group had a shorter duration of epilepsy at VEM than the non‐ILAE‐DC group (median = 12.0 years vs. 23.7 years, respectively; p = 0.015). The proportions of patients with multiple seizure types (100% vs. 96.7%), ≤2.5 Hz slow spike‐and‐wave EEG activity (100% vs. 90%), seizure‐related injuries (27.6% vs. 25.8%), and mortality (standardized mortality ratio 4.60 vs. 5.12) were similar between the groups. Significance: Up to 52% of patients diagnosed with LGS following VEM may not meet recently accepted ILAE criteria for LGS diagnosis. This may reflect both the limitations of retrospective medical record review and a historical tendency of applying the LGS diagnosis to a broad spectrum of severe, early‐onset drug‐resistant epilepsies with drop attacks. The ILAE criteria allow the delineation of LGS based on distinct electroclinical features, potentiating accurate diagnosis, prognostication, and management formulation. Nonetheless, mortality outcomes between those who did and did not meet ILAE diagnostic criteria for LGS were similarly poor, and both groups suffered high rates of seizure‐related injury. Plain Language Summary: More than half of patients diagnosed with Lennox‐Gastaut Syndrome (LGS) at three Australian epilepsy monitoring units between 1995 and 2015 did not meet the recently devised International League Against Epilepsy (ILAE) diagnostic criteria for LGS. Mortality was equally high in those who did and did not meet the ILAE diagnostic criteria, and seizure‐related injury was common. The ILAE diagnostic criteria will guide accurate diagnosis, management, prognostication, and research in patients with LGS, however may be limited in their practical application to patients with a longer duration of epilepsy, or to those for whom detailed assessment is difficult. [ABSTRACT FROM AUTHOR]

Background: Lennox–Gastaut syndrome (LGS), a severe developmental epileptic encephalopathy, has various underlying causes. Mitochondrial respiratory chain complex I (MRC I) deficiency is an important cause of metabolic disorders such as mitochondrial dysfunction that can compromise brain function, thereby causing intractable epilepsy, including LGS. Thus, it can be expected that the presence or absence of MRC I deficiency may affect the treatment outcome of patients with LGS. Objectives: In this retrospective study, we aimed to investigate differences in the epilepsy characteristics and treatment outcomes between patients with LGS with and without MRC I deficiency. Methods: We retrospectively reviewed the medical records of 92 patients with LGS. We divided 68 patients with LGS according to the presence (n = 30) or absence (n = 38) of MRC I deficiency and compared their epilepsy characteristics. Results: Generalized tonic and drop seizures were significantly worse in patients with LGS and MRC I deficiency than in those without MRC I deficiency group at the 1-year follow-up (p < 0.001) and final follow-up 1 (p < 0.001). Patients with LGS and MRC I deficiency had significantly fewer electroencephalogram (EEG) improvements compared to those without MRC I deficiency at the 1-year follow-up (p = 0.031). Additionally, in the final follow-up period, patients with LGS and MRC I deficiency had significantly less improvement in EEG findings compared to patients without MRC I deficiency (p < 0.001). Conclusion: The overall treatment prognosis—in terms of improvement in traumatic generalized tonic seizure, drop seizure, and EEG findings—is worse in patients with LGS and MRC I deficiency than that in patients with LGS but without MRC I deficiency. Additional and targeted treatment is required to treat LGS with MRC I deficiency. [ABSTRACT FROM AUTHOR]

Lennox Gastaut Syndrome (LGS) is characterized by drug-resistant epilepsy that typically leads to decreased quality of life and deleterious neurodevelopmental comorbidities from medically refractory seizures. In recent years there has been a dramatic increase in the development and availability of novel treatment strategies for Lennox Gastaut Syndrome patient to improve seizure. Recent advances in neuromodulation and minimally invasive magnetic resonance guided laser interstitial thermal therapy (MRgLITT) have paved the way for new treatments strategies including deep brain stimulation (DBS), responsive neurostimulation (RNS), and MRgLITT corpus callosum ablation. These new strategies offer hope for children with drug-resistant generalized epilepsies, but important questions remain about the safety and effectiveness of these new approaches. In this review, we describe the opportunities presented by these new strategies and how each treatment strategy is currently being employed. Next, we will critically assess available evidence for these new approaches compared to traditional palliative epilepsy surgery approaches, such as vagus nerve stimulation (VNS) and open microsurgical corpus callosotomy (CC). Finally, we will describe future directions that would help define which of the available strategies should be employed and when. [ABSTRACT FROM AUTHOR]

Background RARS2-related mitochondrial disorder is an autosomal recessive mitochondrial encephalopathy caused by biallelic pathogenic variants in the gene encoding the mitochondrial arginyl-transfer RNA synthetase 2 (RARS2, MIM *611524, NM_020320.5). RARS2 catalyzes the transfer of L-arginine to its cognate tRNA during the translation of mitochondrially-encoded proteins. The classical presentation of RARS2-related mitochondrial disorder includes pontocerebellar hypoplasia (PCH), progressive microcephaly, profound developmental delay, feeding difculties, and hypotonia. Most patients also develop severe epilepsy by three months of age, which consists of focal or generalized seizures that frequently become pharmacoresistant and lead to developmental and epileptic encephalopathy (DEE). Case presentation Here, we describe a six-year-old boy with developmental delay, hypotonia, and failure to thrive who developed an early-onset DEE consistent with Lennox-Gastaut Syndrome (LGS), which has not previously been observed in this disorder. He had dysmorphic features including bilateral macrotia, overriding second toes, a depressed nasal bridge, retrognathia, and downslanting palpebral fssures, and he did not demonstrate progressive microcephaly. Whole genome sequencing identifed two variants in RARS2, c.36+1G>T, a previously unpublished variant that is predicted to afect splicing and is, therefore, likely pathogenic and c.419 T>G (p.Phe140Cys), a known pathogenic variant. He exhibited signifcant, progressive generalized brain atrophy and ex vacuo dilation of the supratentorial ventricular system on brain MRI and did not demonstrate PCH. Treatment with a ketogenic diet (KD) reduced seizure frequency and enabled him to make developmental progress. Plasma untargeted metabolomics analysis showed increased levels of lysophospholipid and sphingomyelin-related metabolites. Conclusions Our work expands the clinical spectrum of RARS2-related mitochondrial disorder, demonstrating that patients can present with dysmorphic features and an absence of progressive microcephaly, which can help guide the diagnosis of this condition. Our case highlights the importance of appropriate seizure phenotyping in this condition and indicates that patients can develop LGS, for which a KD may be a viable therapeutic option. Our work further suggests that analytes of phospholipid metabolism may serve as biomarkers of mitochondrial dysfunction. [ABSTRACT FROM AUTHOR]

CDKL5 deficiency disorder (CDD) is a clinical condition caused by non-functional or absent CDKL5 protein, resulting in early epileptic encephalopathy and severe developmental delay. Other symptoms include hypotonia, sleep disturbances, movement disorders, visual impairment, dysphagia, and gastrointestinal problems. CDD is more common in females due to its X-linked inheritance. Treatment options for CDD are limited, but recent studies have shown promising results with drugs like ganaxolone and fenfluramine, as well as the use of cannabidiol and palliative surgeries like vagus nerve stimulation and corpus callosotomy. However, further research is needed to fully assess the efficacy of these treatments. [Extracted from the article]

Objective: We aimed to identify common genes and recurrent causative variants in a large group of Asian patients with different epilepsy syndromes and subgroups. Methods: Patients with unexplained pediatric‐onset epilepsy were identified from the in‐house Severance Neurodevelopmental Disorders and Epilepsy Database. All patients underwent either exome sequencing or multigene panels from January 2017 to December 2019, at Severance Children's Hospital in Korea. Clinical data were extracted from the medical records. Results: Of the 957 patients studied, 947 (99.0%) were Korean and 570 were male (59.6%). The median age at testing was 4.91 years (interquartile range, 1.53–9.39). The overall diagnostic yield was 32.4% (310/957). Clinical exome sequencing yielded a diagnostic rate of 36.9% (134/363), whereas the epilepsy panel yielded a diagnostic rate of 29.9% (170/569). Diagnostic yield differed across epilepsy syndromes. It was high in Dravet syndrome (87.2%, 41/47) and early infantile developmental epileptic encephalopathy (60.7%, 17/28), but low in West syndrome (21.8%, 34/156) and myoclonic‐atonic epilepsy (4.8%, 1/21). The most frequently implicated genes were SCN1A (n = 49), STXBP1 (n = 15), SCN2A (n = 14), KCNQ2 (n = 13), CDKL5 (n = 11), CHD2 (n = 9), SLC2A1 (n = 9), PCDH19 (n = 8), MECP2 (n = 6), SCN8A (n = 6), and PRRT2 (n = 5). The recurrent genetic abnormalities included 15q11.2 deletion/duplication (n = 9), Xq28 duplication (n = 5), PRRT2 deletion (n = 4), MECP2 duplication (n = 3), SCN1A, c.2556+3A>T (n = 3), and 2q24.3 deletion (n = 3). Significance: Here we present the results of a large‐scale study conducted in East Asia, where we identified several common genes and recurrent variants that varied depending on specific epilepsy syndromes. The overall genetic landscape of the Asian population aligns with findings from other populations of varying ethnicities. [ABSTRACT FROM AUTHOR]

Soticlestat (TAK‐935) is a first‐in‐class, selective inhibitor of cholesterol 24‐hydroxylase (CH24H) under phase III development for the treatment of the developmental and epileptic encephalopathies (DEEs), Dravet syndrome (DS), and Lennox–Gastaut syndrome (LGS). A previous model characterized the pharmacokinetics (PKs), CH24H enzyme occupancy (EO), and pharmacodynamics (PDs) of soticlestat in healthy volunteers. The present study extended this original model for patients with DEEs and investigated sources of variability. Model‐based simulations were carried out to optimize dosing strategies for use in clinical trials. Data from eight phase I and II trials of healthy volunteers or patients with DEEs receiving oral soticlestat 15–1350 mg were included, encompassing 218 individuals for population PK (PopPK) analyses and 306 individuals for PK/PD analyses. Dosing strategies were identified through model‐based simulations. The final mixed‐effect PopPK/EO/PD model consisted of a two‐compartment PK model and an effect‐site compartment in the PK/EO model; soticlestat concentrations at the effect site were linked to 24S‐hydroxycholesterol plasma concentrations using a semimechanistic inhibitory indirect response model. Covariates were included to account for sources of variability. Pediatric dosing strategies were developed for four body weight bands (10 to <15, 15 to <30, 30 to <45, and 45–100 kg) to account for covariate effects by body weight. The final PopPK and PK/EO/PD models accurately described PK, EO, and PD profiles of soticlestat in healthy volunteers and patients with DEEs. Covariate analyses and model‐based simulations facilitated optimization of phase III trial dosing strategies for patients with DS or LGS. [ABSTRACT FROM AUTHOR]

Lennox-Gastaut syndrome (LGS) is a severe childhood-onset developmental and epileptic encephalopathy characterized by treatment-refractory seizures, including tonic/atonic 'drop' seizures, and intellectual impairment and slow spike-wave discharges on the electroencephalogram. Fenfluramine, previously prescribed as a weight-loss drug but then withdrawn, has recently been approved in the US, EU, and UK for the adjunct treatment of seizures associated with LGS. The authors review the efficacy and safety findings from clinical trials of fenfluramine in LGS. The authors then discuss the evidence for adverse effects that may be of particular concern to fenfluramine, namely cardiac abnormalities, and weight loss, in the context of the use of fenfluramine for the treatment of the refractory seizures in LGS. Fenfluramine has demonstrated efficacy in reducing the frequency of seizures in LGS, notably drop seizures, in short-term and long-term clinical trials. Valvular heart disease and pulmonary hypertension have not been reported at the low doses (≤26 mg/day) used in these studies, however, data are limited. Due to its novel mechanism of action, fenfluramine may be of benefit in LGS which has not responded adequately to other antiseizure medications. However, none of these medications, including fenfluramine, achieves the ultimate goal of seizure freedom in most cases. [ABSTRACT FROM AUTHOR]

Background. Lennox–Gastaut syndrome (LGS) is a classic developmental and epileptic encephalopathy with a debut in childhood, characterized by resistance to therapy, a severe course, and an unfavorable prognosis. Due to the existing difficulties in treatment of LGS, hopes are pinned on development of new antiepileptic drugs with fundamentally different mechanisms of action, aimed specifically at the treatment of this severe form of epilepsy.Rufinamide (Inovelon®) is a new antiepileptic drug registered in the Russian Federation for use in the adjunctive therapy of LGS in patients older than 1 year. The main mechanism of action of rufinamide is the restriction of neuronal discharges associated with the blocking effect on sodium channels (regulation of sodium channels activity by increasing duration of their inactive state), and stabilization of neuronal membranes. The drug has a number of advantages concernung pharmacokinetic parameters and efficacy (including a wide spectrum of antiepileptic activity, good oral absorption, absence of active metabolites, urinary excretion, low affinity for plasma proteins, biotransformation without cytochrome P450 isoenzymes, low risk of drug interactions) and fairly good tolerability. The daily dose of rufinamide varies from 600 mg (with simultaneous administration of valproate) to 1000 mg (if the patient does not take valproate) in children over 4 years of age with a body weight of less than 30 kg and up to 2200–3200 mg in children over 4 years of age with a body weight of more than 30 kg and in adults; in children under 4 years of age, the maximum daily dose in combination with valproate is 30 mg/kg, and without valproic acid – 45 mg/kg.Aim. To analyze the efficacy and tolerability of rufinamide in the treatment of epilepsy based on the long-term experience of using the drug in the Svt. Luka’s Association of Medical Institutions.Materials and methods. We observed 64 patients aged from 1.5 to 26 years (44 men, 20 women) treated with rufinamide (Inovelon®). Among them, the structural etiology LGS was diagnosed in 36 patients, the genetic and presumably genetic etiology LGS – in 28. In all cases, rufinamide was used in accordance with approved indications as an additional antiepileptic drug, more often in combination with valproate, topiramate, levetiracetam or lamotrigine. Titration of the drug was carried out according to the recommendations in the instructions for use, up to a therapeutic dose that ranged from 200 to 1600 mg/day (in most cases from 400 to 1200 mg/day), depending on age and concomitant therapy.Results and conclusion. Remission of all types of seizures was registered in 17 (26.6 %) patients, and a decrease in the incidence of seizures by more than 50 % was recorded in 28 (43.8 %) patients. Of them, 13 patients demonstrated reduction in seizures frequency by more than 75–90 % and remission of one of several types of seizures. In general, the therapeutic effect (reduction of seizures frequency by at least 50 %) was achieved in 45 (70.3 %) of 64 patients. A decrease in seizures frequency of by at least 50 % was observed in 8 (12.5 %) patients; in 10 (15.6 %) patients, rufinamide therapy was not effective; in 1 (1.56 %) case an aggravation of bilateral convulsive seizures was noted when rufinamide was administered.In most cases, rufinamide is well tolerated. Our patients had side effects in 10 (15.6 %) cases. Only in 2 (3.1 %) cases, rufinamide was withdrawn directly due to side effects (the reason for withdrawal in these cases was an allergic reaction and psychosis).The retention rate for therapy lasting 1 year or more is 65.6 % (42 of 64 patients).Thus, our data have demonstrated efficacy and good tolerability of rufinamide in treating epileptic seizures associated with LGS, confirming numerous literature data. However, in our analysis, a higher rate of seizure remission was obtained, although we have included patients with mainly resistant forms of epilepsy in the analysis.

Despite significant advances made in epileptology, treatment-resistant epilepsy accounts for approximately 30 % of all forms of this disease. Such diseases include, among others, Lennox–Gastaut syndrome – a classic developmental and epileptic encephalopathy with onset in childhood, characterized by resistance to therapy, severe course and poor prognosis. For patients in this category, the search for new effective antiepileptic drugs remains highly relevant, especially in cases where numerous combinations of antiepileptic drugs do not produce an effect, surgical treatment is impossible, and alternative methods (vagus nerve stimulation and ketogenic diet) are ineffective. The authors present a review of the literature on the modern definition and diagnostic criteria of Lennox–Gastaut syndrome, diagnostic methods and treatment of this form of epilepsy, which has a severe course and a generally unfavorable prognosis.

Vagus nerve stimulation (VNS) is a palliative treatment for drug-resistant epilepsy (DRE) that has been in use for over two decades. VNS suppresses epileptic seizures, prevents emotional disorders, and improves cognitive function and sleep quality, a parallel effect associated with the control of epileptic seizures. The seizure suppression rate with VNS increases monthly to annually, and the incidence of side effects reduces over time. This method is effective in treating DRE in children as well as adults, such as epilepsy associated with tuberous sclerosis, Dravet syndrome, and Lennox–Gastaut syndrome. In children, it has been reported that seizures decreased by >70% approximately 8 years after initiating VNS, and the 50% responder rate was reported to be approximately 70%. VNS regulates stimulation and has multiple useful systems, including self-seizure suppression using magnets, additional stimulation using an automatic seizure detection system, different stimulation settings for day and night, and an automatic stimulation adjustment system that reduces hospital visits. VNS suppresses seizures and has beneficial behavioral effects in children with DRE. This review describes the VNS system, the mechanism of the therapeutic effect, the specific stimulation adjustment method, antiepileptic effects, and other clinical effects in patients with childhood DRE. [ABSTRACT FROM AUTHOR]

Introduction: The prevalence of neurological disorders is high among the Mexican population. Clonazepam is primarily indicated to treat panic disorders, certain kinds of epilepsy such as status epilepticus, childhood motor seizures (petit mal absence, Lennox–Gastaut syndrome, and infantile spasms), anxiety, and muscle spasm. This study was performed to compare bioequivalence between two oral tablet formulations of clonazepam 2 mg in healthy Mexican volunteers under fasting conditions. Methods: This phase I, randomized, open-label, two-treatment, crossover study included 30 healthy volunteers. Subjects were randomly assigned to either test or reference formulation of clonazepam 2 mg. Each study period was separated by 21-day washout period. Blood samples were collected at pre-dose and up to 72 h after drug administration. Clonazepam concentrations were determined using a validated ultra-flow liquid chromatography–tandem mass spectrometric method. Pharmacokinetic parameters were determined using a non-compartmental method. Two formulations were considered bioequivalent if geometric mean ratios (test/reference) were between 80% and 125%. Safety was evaluated by recording adverse events. Results: Pharmacokinetic parameters were comparable between test and reference formulations. The mean maximum plasma concentration (Cmax) was ≈ 13 ng/mL, area under the plasma concentration–time curve from time 0 to last measurable concentration (AUC0–t) was ≈ 360 ng h/mL, time to reach maximum plasma concentration (Tmax) was ≈ 3 h, and elimination half-life (t1/2) was ≈ 43 h. Geometric mean ratios (90% confidence interval) of Cmax (99.2–115.3%), AUC0–t (100.6–110.6%), and AUC0–∞ (98.5–111.6%) were within the bioequivalence range. Seven non-serious adverse events (mostly asymptomatic hypotension) were recorded. Conclusion: The test and reference formulations of clonazepam 2 mg were bioequivalent and well tolerated in healthy Mexican volunteers under fasting conditions. Protocol Authorization Number: 213301410B0051 (Approved on April 13, 2021). [ABSTRACT FROM AUTHOR]

Objective: Identification of EEG waveforms is critical for diagnosing Lennox–Gastaut Syndrome (LGS) but is complicated by the progressive nature of the disease. Here, we assess the interrater reliability (IRR) among pediatric epileptologists for classifying EEG waveforms associated with LGS. Methods: A novel automated algorithm was used to objectively identify epochs of EEG with transient high power, which were termed events of interest (EOIs). The algorithm was applied to EEG from 20 LGS subjects and 20 healthy controls during NREM sleep, and 1350 EOIs were identified. Three raters independently reviewed the EOIs within isolated 15‐second EEG segments in a randomized, blinded fashion. For each EOI, the raters assigned a waveform label (spike and slow wave, generalized paroxysmal fast activity, seizure, spindle, vertex, muscle, artifact, nothing, or other) and indicated the perceived subject type (LGS or control). Results: Labeling of subject type had 85% accuracy across all EOIs and an IRR of κ =0.790, suggesting that brief segments of EEG containing high‐power waveforms can be reliably classified as pathological or normal. Waveform labels were less consistent, with κ =0.558, and the results were highly variable for different categories of waveforms. Label mismatches typically occurred when one reviewer selected "nothing," suggesting that reviewers had different thresholds for applying named labels. Significance: Classification of EEG waveforms associated with LGS has weak IRR, due in part to varying thresholds applied during visual review. Computational methods to objectively define EEG biomarkers of LGS may improve IRR and aid clinical decision‐making. [ABSTRACT FROM AUTHOR]

Subarachnoid haemorrhage (SAH) can trigger a range of poorly understood cerebrovascular responses that may play a role in delayed cerebral ischemia. The brain pulse monitor is a novel non-invasive device that detects a brain photoplethysmography signal that provides information on intracranial pressure (ICP), compliance, blood flow and tissue oxygen saturation. We monitored the cerebrovascular responses in a patient with Lundberg B waves following a SAH. The patient presented with a Fischer grade 4 SAH that required urgent left posterior communicating artery aneurysm coiling and ventricular drain insertion. On hospital day 4 oscillations or spikes on the invasive ICP were noted, consistent with Lundberg B waves. Brain pulse monitoring demonstrated concurrent pulse waveform features consistent with reduced brain compliance and raised ICP over both brain hemispheres. Oxygen levels also demonstrated slow oscillations correlated with the ICP spikes. Brief infrequent episodes of reduced and absent brain pulses were also noted over the right hemisphere. Our findings suggest that the brain pulse monitor holds promise for early detection of delayed cerebral ischemia and could offer insights into the vascular mechanisms at play. Plain Language Summary: In this study, we examined a patient with a serious brain bleed, known as subarachnoid hemorrhage (SAH). Patients with SAH can suffer from vasospasm and consequent delayed cerebral ischemia (DCI), which can happen from 4 to 14 days after the initial bleeding. Detecting and treating DCI early is difficult because methods are imperfect, discontinuous and technically difficult. We used a new, non-invasive device that can monitor various features of brain health. This device helps us understand the pressure inside the skull, blood flow, and the oxygen saturation on the surface of the brain. In this patient, we found evidence of:Brain pulse signals that were directly related to acute changes in the invasive intracranial pressure.Specific brain pulse patterns that may indicate a local reduction in brain blood flow.Signs of a breakdown in the brain's ability to regulate blood flow in the injured hemisphere.The oxygen saturation levels in the brain that related to pressure changes. These results are promising because they suggest the new device could help us identify when someone's brain condition is getting worse. This ability could guide the development of improved care protocols, and aid clinical decision-making. Further research is needed in this patient population with additional forms of monitoring to understand the generalizability of our findings. [ABSTRACT FROM AUTHOR]

Epilepsy is among the most common neurological chronic disorders, with a prevalence of 0.5--1%. Despite the introduction of new antiepileptic drugs during recent years, about one third of the epileptic population remain drug-resistant. Hence, especially in the pediatric population limited by different pharmacokinetics and pharmacodynamics and by ethical and regulatory issues it is needed to identify new therapeutic resources. New molecules initially used with other therapeutic indications, such as fenfluramine, are being considered for the treatment of pharmacoresistant epilepsies, including Dravet Syndrome (DS) and Lennox-Gastaut Syndrome (LGS). Drug-refractory seizures are a hallmark of both these conditions and their treatment remains a major challenge. Fenfluramine is an amphetamine derivative that was previously approved as a weight loss drug and later withdrawn when major cardiac adverse events were reported. However, a new role of fenfluramine has emerged in recent years. Indeed, fenfluramine has proved to be a promising antiepileptic drug with a favorable risk--benefit profile for the treatment of DS, LGS and possibly other drug-resistant epileptic syndromes. The mechanism by which fenfluramine provide an antiepileptic action is not fully understood but it seems to go beyond its pro-serotoninergic activity. This review aims to provide a comprehensive analysis of the literature, including ongoing trials, regarding the efficacy and safety of fenfluramine as adjunctive treatment of pharmacoresistant epilepsies. [ABSTRACT FROM AUTHOR]

Background: Epilepsy contributes to high morbidity among children and adolescents in developing countries. A quarter of all children with epilepsy will be resistant to anti-seizure medications (ASMs), with associated neurocognitive impairments and risk of higher mortality. This study aimed to estimate and characterize drug-resistant epilepsy (DRE) (defined as failure to achieve sustained remission after adequate trials of two tolerated and appropriately chosen ASMs) and its associated factors among children and adolescents with epilepsies attending the pediatric neurology clinic at Muhimbili National Hospital (MNH), Dar es Salaam Tanzania. Methods: This cross-sectional study was conducted from June 2020 to June 2021. Children with epilepsies and who had been treated with ASMs for at least 3 months were eligible for inclusion. Exclusion criteria included children whose caregivers denied consent and those who exhibited acute medical conditions necessitating admission on the scheduled visit day. Data on demographic characteristics, perinatal history, detailed history of the seizures semiology, drug history, magnetic resonance imaging (MRI), and electroencephalography (EEG) results were obtained from caregivers and medical records available during recruitment. Seizures and epilepsies were classified using the 2017 International League Against Epilepsy (ILAE) classification. Logistic regression was used to determine factors associated with DRE. Results: A total of 236 children and adolescents aged between 4 months and 15 years (Median age 72 months (IQR = 42–78)) were enrolled in this study. We found the proportion of DRE to be 14.8% in this cohort. Of the thirty-five patients with DRE, 60% had generalized epilepsy and almost 25% had a diagnosis of an epilepsy syndrome, the most common being Lennox-Gastaut syndrome (LGS). Structural abnormalities on brain MRI were seen in almost 80% of all patients with DRE, the most prevalent being cystic encephalomalacia, which was observed in 34% of patients. Patients using both ASMs and alternative therapies accounted for 9% of this cohort. The onset of seizures during the first month of life (aOR = 1.99; 95%CI 1.7–4.6; p = 0.031) and high initial seizure frequency (aOR = 3.6; 95%CI 1.6-8;p = 0.002) were found to be independently associated with DRE. Conclusion: The proportion of DRE in Tanzania is high. Patients with neonatal onset seizures and high initial seizure frequency should be followed up closely to ensure early diagnosis of DRE. [ABSTRACT FROM AUTHOR]

Objective: Acute Necrotizing Encephalopathy of Childhood (ANEC) is a rare, fulminant neurological disease in children with unknown mechanisms and etiology. This study summarized the clinical characteristics, treatment, and prognosis of ANEC through a retrospective analysis, providing insights into the ANEC early diagnosis and prognosis assessment. Methods: Clinical data of children diagnosed with ANEC at the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University from July 1, 2020, to June 30, 2023, were retrospectively analyzed. Results: There were 25 cases, 14 males and 11 females, with a median age of 3 years. Hospital admissions were mainly in the winter (14/25, 56%) and spring (9/25, 36%). All patients presented with varying degrees of fever and altered consciousness, with 92% (23/25) experiencing high body temperatures (>39.1°C) and 88% (22/25) having a Glasgow coma scale (GCS) score of =8. Seizures were observed in 88% (22/25) of patients. Laboratory findings indicated 100% B lymphocyte activation (14/14), and 78% (14/18) of patients showed cytokine storm (interleukin (IL)-6, IL-8, IL-10, interferon (IFN)-a). Neuroimaging showed symmetrical thalamus involvement, commonly involving basal ganglia and brainstem regions. Viral infection (23/24, 96%) was the predominant etiological finding, with 42% (10/24) of cases due to SARS-CoV-2 infection and 42% (10/24) to influenza A virus infection. Multiorgan dysfunction occurred in 68% (17/25) of patients, and 52% (13/25) died. Correlation analysis revealed the death group exhibited higher proportion of male, lower GCS scores, higher IL-6 level and a greater likelihood of associated brainstem impairment (p < 0.05). Conclusion: ANEC is more prevalent in the winter and spring, and its etiology may be associated with B lymphocyte activation and cytokine storm following viral infections. Clinical manifestations lack specific features, with fever, consciousness disturbances, and seizures being the main presentations, particularly in cases of high fever and hyperpyrexia. ANEC progresses rapidly and has a high mortality rate. The child's gender, GCS score, IL-6 levels, and the presence of brainstem involvement can serve as important risk factors for assessing the risk of mortality. [ABSTRACT FROM AUTHOR]

Purpose: This study examined the characteristics and outcomes of resective epilepsy surgery following corpus callosotomy (CC) in children with Lennox-Gastaut syndrome (LGS). Methods: We retrospectively analyzed 17 children with LGS who underwent resective surgery (RS) after CC over a span of 10 years, with a minimum of 2 years of follow-up, at a single tertiary epilepsy center in Korea. Results: Of the 17 patients, 13 (73.5%) demonstrated favorable surgical outcomes (Engel class I or II) at 1 year after RS, and eight (47.1%) were ultimately free of seizures 2 years after surgery. A significantly larger decrease in the number of anti-seizure medications taken from before to 2 years after the final surgical procedure was observed in the group that became seizure-free than in the group with persistent seizures (P=0.062). Furthermore, a significantly greater decline in daily adaptive function was found in the persistent seizure group (P=0.059). The baseline characteristics, results of presurgical evaluation, and treatment-related factors assessed prior to surgery showed no significant differences between the seizure-free group and the group with persistent seizures. Conclusion: In conclusion, RS may be a viable option for patients with LGS who exhibit lateralization and/or localization on presurgical evaluation after CC, as the procedure may reveal a concealed primary focus. The proactive implementation of two-stage epilepsy surgery could provide significant seizure reduction and preservation of cognitive function in carefully selected patients with LGS. [ABSTRACT FROM AUTHOR]