Search Results (10)

Lennox–Gastaut syndrome (LGS) is a severe childhood-onset developmental and epileptic encephalopathy characterized by multiple drug-resistant seizure types, cognitive impairment, and distinctive electroencephalographic patterns. Current treatments primarily focus on symptom management through antiseizure medications (ASMs), dietary therapy, epilepsy surgery, and neuromodulation, but often fail to address the underlying pathophysiology or improve cognitive outcomes. As genetic causes are identified in 30–40% of LGS cases, precision therapeutics targeting specific molecular mechanisms are emerging as promising disease-modifying approaches. This narrative review explores precision therapeutic strategies for LGS based on molecular pathophysiology, including channelopathies (SCN2A, SCN8A, KCNQ2, KCNA2, KCNT1, CACNA1A), receptor and ligand dysfunction (GABA/glutamate systems), cell signaling abnormalities (mTOR pathway), synaptopathies (STXBP1, IQSEC2, DNM1), epigenetic dysregulation (CHD2), and CDKL5 deficiency disorder. Treatment modalities discussed include traditional ASMs, dietary therapy, targeted pharmacotherapy, antisense oligonucleotides, gene therapy, and the repurposing of existing medications with mechanism-specific effects. Early intervention with precision therapeutics may not only improve seizure control but could also potentially prevent progression to LGS in susceptible populations. Future directions include developing computable phenotypes for accurate diagnosis, refining molecular subgrouping, enhancing drug development, advancing gene-based therapies, personalizing neuromodulation, implementing adaptive clinical trial designs, and ensuring equitable access to precision therapeutic approaches. While significant challenges remain, integrating biological insights with innovative clinical strategies offers new hope for transforming LGS treatment from symptomatic management to targeted disease modification. Full article

The FDA approved rufinamide, chemically 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide, a triazole-based scaffold, as an anticonvulsant drug in 2008. It is mainly used to treat seizures associated with Lennox–Gastaut Syndrome (LGS). The exact mechanism of rufinamide is unknown, but some literature reported that rufinamide works by regulating the brain’s sodium channel activity, which aids in maintaining the stability of neuronal membranes and averting the overabundance of electrical activity. In the view of computational chemistry, the amide group, fluorine atom, and triazole ring are the specific parts of this skeleton and play an important role in action with the receptor. This study explored computerized simulations of quantum chemistry techniques to investigate the chemical structure and electrical properties of rufinamide. An optimizing structure started the quantum calculation through the B3LYP 6311-G (++, d, p) basis set, explored along with investigating the maximal quantity of electronic charge transfer (N_max), chemical hardness (η), electrostatic potential, chemical potential (µ), and electrophilicity (ω). The Natural Bond Orbital (NBO) analysis-based observation reveals that the molecule’s chemically active regions have hyperconjugated electron interactions within the molecule, which contributes to the molecule’s stability. This study explores the role of the amide group and difluoro-substituted phenyl group in chemical structure and in binding property with the receptor of the Ca²⁺–and voltage-activated K⁺ channel. Full article

Pediatric genetic epilepsies, such as CDKL5 Deficiency Disorder (CDD), are severely debilitating, with early-onset seizures occurring more than ten times daily in extreme cases. Existing antiseizure drugs frequently prove ineffective, which significantly impacts child development and diminishes the quality of life for patients and caregivers. The relaxation of cannabis legislation has increased research into potential therapeutic properties of phytocannabinoids such as cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC). CBD’s antiseizure properties have shown promise, particularly in treating drug-resistant genetic epilepsies associated with Lennox–Gastaut syndrome (LGS), Dravet syndrome (DS), and Tuberous Sclerosis Complex (TSC). However, specific research on CDD remains limited. Much of the current evidence relies on anecdotal reports of artisanal products lacking accurate data on cannabinoid composition. Utilizing model systems like patient-derived iPSC neurons and brain organoids allows precise dosing and comprehensive exploration of cannabinoids’ pharmacodynamics. This review explores the potential of CBD, THC, and other trace cannabinoids in treating CDD and focusing on clinical trials and preclinical models to elucidate the cannabinoid’s potential mechanisms of action in disrupted CDD pathways and strengthen the case for further research into their potential as anti-epileptic drugs for CDD. This review offers an updated perspective on cannabinoid’s therapeutic potential for CDD. Full article

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. Full article

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. Full article

Lennox–Gastaut Syndrome (LGS) is a developmental and epileptic encephalopathy (DEE) characterized by multiple seizure types, electroencephalogram (EEG) patterns, and cognitive decline. Its etiology has a prominent genetic component, including variants in GABRB3 that encodes the GABA_A receptor (GABA_AR) β₃ subunit. LGS has an unknown pathophysiology, and few animal models are available for studying LGS. The objective of this study was to evaluate Gabrb3^+/N328D knock-in mice as a model for LGS. We generated a heterozygous knock-in mouse expressing Gabrb3 (c.A982G, p.N238D), a de novo mutation identified in a patient with LGS. We investigated Gabrb3^+/N328D mice for features of LGS. In 2–4-month-old male and female C57BL/J6 wild-type and Gabrb3^+/N328D mice, we investigated seizure severity using video-monitored EEG, cognitive impairment using a suite of behavioral tests, and profiled GABA_AR subunit expression by Western blot. Gabrb3^+/N328D mice showed spontaneous seizures and signs of cognitive impairment, including deficits in spatial learning, memory, and locomotion. Moreover, Gabrb3^+/N328D mice showed reduced β₃ subunit expression in the cerebellum, hippocampus, and thalamus. This phenotype of epilepsy and neurological impairment resembles the LGS patient phenotype. We conclude that Gabrb3^+/N328D mice provide a good model for investigating the pathophysiology and therapeutic intervention of LGS and DEEs. Full article

Background. Lennox–Gastaut syndrome (LGS) is a developmental and epileptic encephalopathy (DEE) in which drug resistance to antiepileptic drugs (AEDs) is common. Focal-onset seizures (FOS) are among the seizure types characterizing LGS. Cenobamate (CNB) is a new AED indicated for the treatment of FOS and it has shown promising results in terms of seizure frequency reduction in both clinical trials and real-world experience. To date, the use of CNB in patients with DEEs is limited to Dravet syndrome. Methods: This was a retrospective study aimed to determine the 12-month effectiveness and tolerability of CNB in patients with LGS following real-world practice. Results: Four patients with LGS receiving CNB treatment were identified. At 12 months from starting CNB, the reduction in baseline seizure frequency ranged from 25 to 74%, with two patients achieving ≥50% seizure reduction. CNB was generally well tolerated and adjustments in doses of concomitant AEDs were required. Conclusions: CNB may represent a promising therapeutic option in patients with drug-resistant epilepsy associated with LGS. Further research is needed to confirm this preliminary evidence. Full article

Recently, the potential use of phytocannabinoids (pCBs) to treat different pathological conditions has attracted great attention in the scientific community. Among the different pCBs, cannabidiol (CBD) has showed interesting biological properties, making it a promising molecule with a high security profile that has been approved for treatment as an add-on therapy in patients afflicted by severe pharmaco-resistant epilepsy, including Dravet syndrome (DS), Lennox–Gastaut syndrome (LGS) and tuberous sclerosis complex (TSC). CBD is pharmacologically considered a “dirty drug”, since it has the capacity to bind different targets and to activate several cellular pathways. GABAergic impairment is one of the key processes during the epileptogenesis period able to induce a generalized hyperexcitability of the central nervous system (CNS), leading to epileptic seizures. Here, by using the microtransplantation of human brain membranes approach in Xenopus oocytes and electrophysiological recordings, we confirm the ability of CBD to modulate GABAergic neurotransmission in human cerebral tissues obtained from patients afflicted by different forms of pharmaco-resistant epilepsies, such as DS, TSC, focal cortical dysplasia (FCD) type IIb and temporal lobe epilepsy (TLE). Furthermore, using cDNAs encoding for human GABA_A receptor subunits, we found that α1β2 receptors are still affected by CBD, while classical benzodiazepine lost its efficacy as expected. Full article

Epilepsy is an important medical problem with approximately 50 million patients globally. No more than 70% of epileptic patients will achieve seizure control after antiepileptic drugs, and several epileptic syndromes, including Lennox-Gastaut syndrome (LGS), are predisposed to more frequent pharmacoresistance. Ketogenic dietary therapies (KDTs) are a form of non-pharmacological treatments used in attempts to provide seizure control for LGS patients who experience pharmacoresistance. Our review aimed to evaluate the efficacy and practicalities concerning the use of KDTs in LGS. In general, KDTs are diets rich in fat and low in carbohydrates that put the organism into the state of ketosis. A classic ketogenic diet (cKD) is the best-evaluated KDT, while alternative KDTs, such as the medium-chain triglyceride diet (MCT), modified Atkins diet (MAD), and low glycemic index treatment (LGIT) present several advantages due to their better tolerability and easier administration. The literature reports regarding LGS suggest that KDTs can provide ≥50% seizure reduction and seizure-free status in a considerable percentage of the patients. The most commonly reported adverse effects are constipation, diarrhea, and vomiting, while severe adverse effects such as nephrolithiasis or osteopenia are rarely reported. The literature review suggests that KDTs can be applied safely and are effective in LGS treatment. Full article

Background: Lennox-Gastaut syndrome (LGS) is a severe form of childhood-onset epilepsy associated with serious injuries due to frequent and severe seizures. Of the antiepileptic drugs (AEDs) approved for LGS, clobazam is a more recent market entrant, having been approved in October 2011. Recent AED budget impact and cost-effectiveness analyses for LGS suggest that adding clobazam to a health plan formulary may result in decreased medical costs; however, research on clinical and economic outcomes and treatment patterns with these AED treatments in LGS is limited. Objectives: To compare the baseline characteristics and treatment patterns of new initiators of clobazam and other AEDs among LGS patients and compare healthcare utilization and costs before and after clobazam initiation among LGS patients. Methods: A retrospective study of probable LGS patients was conducted using the MarketScan® Commercial, Medicare Supplemental, and Medicaid databases (10/1/2010-3/31/2014). Results: In the Commercial/Medicare Supplemental population, clobazam users were younger, had fewer comorbidities, and more prior AED use than non-clobazam users. In the 12 months pre-treatment initiation, clobazam users had significantly more seizure-related inpatient stays and outpatient visits and higher total seizure-related (p < 0.001) and all-cause (p < 0.001) costs than non-clobazam users. Among clobazam users, when compared to the 12 months pre-clobazam initiation, seizure-related medical utilization and costs were lower in the 12 months post-clobazam initiation (p = 0.004). Total all-cause (p < 0.001) and seizure-related (p = 0.029) costs increased post-clobazam initiation mainly due to the increase in outpatient pharmacy costs. Similar results were observed in the Medicaid population. Conclusions: Baseline results suggest a prescribing preference for clobazam in severe LGS patients. Clobazam users had a reduction in seizure-related medical utilization and costs after clobazam initiation. The improvement in medical costs mostly offset the higher prescription costs following clobazam initiation. Full article