cannabidiol and Lennox-Gastaut-Syndrome

Antiseizure medications (ASMs) are the mainstay for the treatment of seizure disorders. However, about one-third of people with epilepsy remain refractory to current ASMs. Cannabidiol (CBD) has recently been approved as ASM for three refractory epilepsy syndrome indications in children and adults. In this study, we evaluated the overall clinical potential of an oral CBD to treat refractory epilepsy in patients with Dravet syndrome (DS), Lennox-Gastaut syndrome (LGS), and tuberous sclerosis complex (TSC) through a systematic review and meta-analysis. A comprehensive search of databases was conducted, including randomized controlled trials (RCTs) assessing the effect of CBD in epilepsy patients. The review was conducted as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The review focused on RCTs involving patients receiving highly purified oral CBD (Epidiolex, 10 to 50 mg/kg/day) for up to 16 weeks. A subgroup analysis by syndrome and CBD with or without concomitant clobazam was conducted. The key outcomes were reduction in seizure frequency, differences in 50% responder rates, adverse events, and interactions with clobazam as co-therapy. Odds ratio (OR) with 95% confidence interval (CI) were estimated. Of 1183 articles screened, we included 6 RCTs meeting our eligibility criteria. All studies were considered to have a low risk of bias. In the pooled analysis, CBD treatment was found to be more efficacious compared to placebo (OR = 2.45, 95% CI =1.81-3.32, p < 0.01). Subgroup analysis by syndrome demonstrated the odds of ≥50% reduction in seizures with CBD treatment in patients with DS (OR = 2.26, 95% CI:1.38-3.70), LGS (OR = 2.98, 95% CI:1.83-4.85) and TSC (OR = 1.99, 95% CI = 1.06-3.76). Compared with placebo, CBD was associated with increased adverse events (OR = 1.81, 95% CI = 1.33-2.46) such as diarrhea, somnolence, and sedation, and any serious adverse events (OR = 2.86, 95% CI = 1.63-5.05). Other factors, including dosage and clobazam co-therapy, were significantly associated with a greater effect on seizure control and side effects of CBD. In conclusion, the study shows that CBD is highly efficacious both as standalone and adjunct therapy with clobazam for controlling seizures in DS, LGS, and TSC conditions while limiting side effects. Further pharmacodynamic investigation of CBD actions, drug interaction assessments, and therapeutic management guidelines are warranted.

Topics: Adult; Anticonvulsants; Cannabidiol; Child; Clobazam; Drug Resistant Epilepsy; Epilepsies, Myoclonic; Epilepsy; Humans; Lennox Gastaut Syndrome; Seizures; Treatment Outcome

Novel and effective antiseizure medications are needed to treat refractory and rare forms of epilepsy. Cannabinoids, which are obtained from the cannabis plant, have a long history of medical use, including for neurologic conditions. In 2018, the US Food and Drug Administration approved the first phytocannabinoid, cannabidiol (CBD, Epidiolex), which is now indicated for severe seizures associated with three rare forms of developmental and epileptic encephalopathy: Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis complex. Compelling evidence supports the efficacy of CBD in experimental models and patients with epilepsy. In randomized clinical trials, highly-purified CBD has demonstrated efficacy with an acceptable safety profile in children and adults with difficult-to-treat seizures. Although the underlying antiseizure mechanisms of CBD in humans have not yet been elucidated, the identification of novel antiseizure targets of CBD preclinically indicates multimodal mechanisms that include non-cannabinoid pathways. In addition to antiseizure effects, CBD possesses strong anti-inflammatory and neuroprotective activities, which might contribute to protective effects in epilepsy and other conditions. This article provides a succinct overview of therapeutic approaches and clinical foundations of CBD, emphasizing the clinical utility of CBD for the treatment of seizures associated with refractory and rare epilepsies. CBD has shown to be a safe and effective antiseizure medicine, demonstrating a broad spectrum of efficacy across multiple seizure types, including those associated with severe epilepsies with childhood onset. Despite such promise, there are many perils with CBD that hampers its widespread use, including limited understanding of pharmacodynamics, limited exposure-response relationship, limited information for seizure freedom with continued use, complex pharmacokinetics with drug interactions, risk of adverse effects, and lack of expert therapeutic guidelines. These scientific issues need to be resolved by further investigations, which would decide the unique role of CBD in the management of refractory epilepsy.

Topics: Adult; Anticonvulsants; Cannabidiol; Cannabinoids; Child; Drug Resistant Epilepsy; Epilepsies, Myoclonic; Epilepsy; Humans; Lennox Gastaut Syndrome; Seizures

To compare and rank the efficacy and safety of antiseizure medication (ASM) in patients with Lennox-Gastaut syndrome (LGS).. We included randomized controlled trials (RCTs) assessing the efficacy of ASM for LGS compared with placebo or with each other. The efficacy and safety were reported in terms of an at least 50% monthly seizure frequency reduction in drop seizures, dropout, and serious adverse events. Outcomes were ranked according to the surface under the cumulative ranking curve (SUCRA).. A total of eight RCTs with 1171 patients were included, involving six ASMs: lamotrigine, rufinamide, cannabidiol, topiramate, clobazam, and felbamate. The calculated SUCRA showed that rufinamide, cannabidiol, and topiramate had the highest probability of achieving a response; however, no significant differences were found among these treatments. Cannabidiol, topiramate, and rufinamide were more likely to result in dropouts; moreover, a significantly greater percentage of patients receiving cannabidiol experienced premature discontinuation as compared to placebo, clobazam, and lamotrigine.. All ASMs showed a significantly higher response rate than placebo. SUCRA ranking demonstrated that rufinamide and cannabidiol are more efficacious than other treatments in reducing drop seizures. However, there was no significant difference between these treatments.

Topics: Anticonvulsants; Cannabidiol; Child; Humans; Lennox Gastaut Syndrome; Outcome Assessment, Health Care; Randomized Controlled Trials as Topic; Triazoles

To assess the short-term and long-term comparative efficacy and safety of ASMs for Lennox-Gastaut syndrome (LGS).. Following a systematic literature search, randomized controlled trial (RCT) and open-label extension (OLE) studies on LGS comparing ASMs with placebo or other ASMs were included. ≥50% reduction in drop seizure frequency from baseline and occurrence of treatment-emergent adverse events (TEAEs) were the primary efficacy and safety outcomes. For short-term outcomes, a network meta-analysis (NMA) reporting odds ratio (OR) with 95% confidence intervals (CIs) and hierarchy of competing interventions [surface under the cumulative ranking curve(SUCRA)] was done. Long-term outcomes were reported as proportion with 95% CIs using the random-effects model.. Fifteen studies including 1263 participants with LGS (aged 2-54years) receiving any of six ASMs [cannabidiol (CBD), clobazam (CLB), felbamate (FLB), lamotrigine (LTG), rufinamide (RFM), topiramate (TPM)] or placebo were included. High-dose CLB (1.0 mg/kg/day; CLB_H) [OR: 4.9; 95% CI: 2.3-10.8] was significantly associated with ≥50% reduction in drop seizure frequency as compared with placebo, and achieved the highest-ranking probability (0.89) based on SUCRA values (although there was an overlap between confidence intervals of effect sizes of CLB, RFM and CBD), while high-dose CBD (20 mg/kg/day; CBD_H) [OR: 3.8; 95% CI:1.6-9.0] had significantly higher odds for occurrence of any TEAEs and had the highest-ranking probability (0.85). Furthermore, the long-term treatment with CLB [78%; 95% CI: 70-85%] was associated with a significantly higher proportion of patients with reduction in drop-seizures, and long-term use of CBD [96%; 95% CI: 95-98%] was associated with a higher frequency of TEAEs.. The study findings suggest that CLB_H, CBD and RFM are the most efficacious and safest in terms of both short and long-term outcomes with CLB_H probably leading the hierarchy. Future head-to-head trials comparing these ASMs are needed.

Topics: Anticonvulsants; Cannabidiol; Clobazam; Humans; Lennox Gastaut Syndrome; Network Meta-Analysis; Randomized Controlled Trials as Topic; Seizures; Treatment Outcome

The aim of this current report was to present a critical review of the use of cannabidiol (CBD) in the treatment of refractory epilepsies in the pediatric population.. Literature review was carried out in the Medline (PubMed), Cochrane, and Scientific Electronic Library Online (SciELO) databases with the descriptors "Cannabidiol" and "Epilepsy." The search was not limited by the date of publication, language, or study design. A total of 69 articles were included in the review.. The efficacy of CBD in treating epileptic seizures has been confirmed by randomized controlled trials for Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex. The incidence of side effects reported in subjects of the studies is high. However, most studies indicate a good safety profile and tolerance to the drug, with most of the adverse effects being mild to moderate and transient.. There is no consensus on the release of CBD as a therapeutic tool by the drug regulatory agencies worldwide. However, the use of CBD is promising since it has presented satisfactory results in crisis control in well-designed studies. In addition, this drug has a good safety and tolerance profile. However, further studies with a long follow-up period are needed to confirm its usefulness and the long-term safety in pediatric patients.

Topics: Anticonvulsants; Cannabidiol; Child; Drug Resistant Epilepsy; Drug-Related Side Effects and Adverse Reactions; Epilepsy; Humans; Lennox Gastaut Syndrome

Epilepsy is a common neurological condition, affecting over 70 million individuals worldwide.. The present paper reviews current and future (under preclinical and clinical development) pharmacotherapy options for the treatment of drug-resistant focal and generalized epilepsies.. Current pharmacotherapy options for drug-resistant epilepsy include perampanel, brivaracetam and the newly approved cenobamate for focal epilepsies; cannabidiol (Epidiolex) for Lennox-Gastaut Syndrome (LGS), Dravet and Tuberous Sclerosis Complex (TSC); fenfluramine for Dravet syndrome and ganaxolone for seizures in Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder. Many compounds are under clinical development and may hold promise for future pharmacotherapies. For adult focal epilepsies, padsevonil and carisbamate are at a more advanced Phase III stage of clinical development followed by compounds at Phase II like selurampanel, XEN1101 and JNJ-40411813. For specific epilepsy syndromes, XEN 496 is under Phase III development for potassium voltage-gated channel subfamily Q member 2 developmental and epileptic encephalopathy (KCNQ2-DEE), carisbamate is under Phase III development for LGS and Ganaxolone under Phase III development for TSC. Finally, in preclinical models several molecular targets including inhibition of glycolysis, neuroinflammation and sodium channel inhibition have been identified in animal models although further data in animal and later human studies are needed.

Topics: Adult; Animals; Anticonvulsants; Cannabidiol; Epilepsies, Partial; Epilepsy; Humans; Lennox Gastaut Syndrome; Spasms, Infantile; Tuberous Sclerosis

The objective of this systematic review with meta-analysis was to evaluate the efficacy, safety, and short- and long-term tolerability of cannabidiol (CBD), as an adjunct treatment, in children and adults with Dravet syndrome (SD), Lennox-Gataut syndrome (LGS), or tuberous sclerosis complex (TSC), with inadequate control of seizures.. This systematic review was conducted through a search for scientific evidence in the Mediline/PubMed, Central Cochrane, and ClinicalTrials.gov databases until April 2022. Selected randomized clinical trials (RCTs) that presented the outcomes: reduction in the frequency of seizures and total seizures (all types), number of patients with a response greater than or equal to 50%, change in caregiver global impression of change (CGIC) (improvement ≥1 category on the initial scale), adverse events (AEs), and tolerability to treatment. This review followed Preferred Reporting Items for Systematic reviews and Meta-Analyses.. Notably, six RCTs were included, with a total of 1,034 patients with SD, LGS, and TSC, of which 3 were open-label extension RCTs. The meta-analysis of the studies showed that the use of CBD as compared with placebo, in patients with convulsive seizures refractory to the use of medications, reduces the frequency of seizures by 33%; increases the number of patients with a reduction ≥50% in the frequency of seizures by 20%; increases the number of patients with absence of seizures by 3%; improves the clinical impression evaluated by the caregiver or patient (S/CGIC) in 21%; increases total AEs by 12%; increases serious AE by 16%; increases the risk of treatment abandonment by 12%; and increases the number of patients with transaminase elevation (≥3 times the referral) by 15%.. This systematic review, with meta-analysis, supports the use of CBD in the treatment of patients with seizures, originated in DS, LGS, and TSC, who are resistant to the common medications, presenting satisfactory benefits in reducing seizures and tolerable toxicity.

Topics: Adult; Anticonvulsants; Cannabidiol; Child; Epilepsies, Myoclonic; Epilepsy; Humans; Lennox Gastaut Syndrome; Seizures; Tuberous Sclerosis

Cannabidiol (CBD) is one of the main components of the cannabis plant that has demonstrated anti-epileptic seizure effect. Following its clinical development, in September 2019 the European Medicines Agency approved its indication for the adjunctive therapy of epileptic seizures associated with Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS), combined with clobazam (CLB), in patients of 2 years of age and older.. To establish recommendations on the use of plant-derived highly purified CBD on which Spanish experts have reached consensus for the treatment of epilepsy in patients with DS and LGS based on their clinical experience and the scientific evidence.. Consensus meeting with the participation of four Spanish neurologists and neuropediatric who are experts in epilepsy secondary to DS and LGS and with clinical experience in the use and management of CBD. They discussed on several topics, including posology (starting dose, dose escalation schema), efficacy (assessment of outcomes and indications for treatment withdrawal), and safety (evaluation, drug-drug interactions, adverse events management).. In order to optimise CBD treatment, a slow dose escalation (= 4 weeks) is recommended until the maximum recommended dose or the desire effect is reached. It is also recommended that the concomitant antiseizure medications (ASMs) be reduced in case of adverse events due to interactions, and that the treatment continues for at least 6 months if it is well tolerated. The efficacy and safety of CBD must be assessed individually, considering the benefits and risks for individual patients.. Cannabidiol para el tratamiento del síndrome de Lennox-Gastaut y del síndrome de Dravet: recomendaciones de expertos sobre su uso en la práctica clínica en España.. Introducción. El cannabidiol (CBD) es uno de los componentes principales de la planta del cannabis que ha demostrado efecto ante las crisis epilépticas. Tras su desarrollo clínico, obtuvo su aprobación por la Agencia Europea del Medicamento en septiembre de 2019 para el tratamiento de las crisis epilépticas asociadas con el síndrome de Lennox-Gastaut (SLG) y el síndrome de Dravet (SD), en combinación con el clobazam (CLB), en pacientes a partir de los dos años. Objetivo. Establecer unas recomendaciones de manejo del CBD derivado de la planta altamente purificado consensuadas por expertos españoles en el tratamiento de la epilepsia para su uso en pacientes con SD y SLG, basándose en su experiencia clínica y en la evidencia científica. Desarrollo. Reunión de consenso de un grupo de cuatro neurólogos y neuropediatras españoles expertos en el manejo de la epilepsia asociada al SD y el SLG y con experiencia clínica en el uso de CBD. Se debatió sobre diferentes áreas, incluyendo la posología (dosis de inicio, pauta de escalada), la eficacia (valoración de resultados e indicaciones para la suspensión del tratamiento) y la seguridad (evaluación, interacciones entre fármacos, manejo de efectos adversos). Conclusiones. Para optimizar el tratamiento con CBD, se recomienda una pauta lenta de escalada de dosis (de cuatro semanas o más) hasta alcanzar la dosis máxima recomendada o el efecto deseado, reducir los fármacos anticrisis epilépticas concomitantes si aparecen efectos adversos por interacciones y mantener el tratamiento al menos seis meses si se tolera. La eficacia y la seguridad del CBD deben evaluarse de forma individual, considerando el beneficio y el riesgo para cada paciente.

Topics: Anticonvulsants; Cannabidiol; Clobazam; Clonazepam; Diazepam; Dioxolanes; Drug Administration Schedule; Drug Synergism; Drug Therapy, Combination; Epilepsies, Myoclonic; Humans; Lennox Gastaut Syndrome; Phenobarbital; Practice Guidelines as Topic; Pyrrolidinones; Spain; Triazoles; Valproic Acid

To assess the efficacy and safety profile of add-on cannabidiol (CBD) in patients with Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) on clobazam and in the overall population of four randomized, controlled phase 3 trials.. 396 patients with LGS (49% on clobazam) and 318 patients with DS (64% on clobazam) were included. CBD treatment resulted in a reduction in primary seizure frequency vs placebo in the overall population (treatment ratio [95% confidence interval]: LGS, 0.70 [0.62-0.80]; DS, 0.71 [0.60-0.83]) and in patients receiving clobazam (LGS, 0.56 [0.47-0.67]; DS, 0.63 [0.52-0.77]). The antiseizure efficacy of CBD was also demonstrated across other endpoints vs placebo (≥50% responder rate, total seizure frequency, number of seizure-free days, and Subject/Caregiver Global Impression of Change scores) in the overall populations and in patients receiving clobazam. There were higher incidences of somnolence and sedation in patients on CBD and clobazam. Most incidences of elevated transaminases occurred in patients on concomitant valproate and, to a lesser extent, clobazam.. Add-on CBD was effective in reducing seizures in the overall populations and in conjunction with clobazam. Somnolence and sedation occurred more frequently in patients on CBD and clobazam.

Topics: Adult; Anticonvulsants; Cannabidiol; Clobazam; Epilepsies, Myoclonic; Female; Humans; Lennox Gastaut Syndrome; Male; Randomized Controlled Trials as Topic

Pharmaceutically purified oral cannabidiol (CBD) has been recently approved by the US Food and Drug Administration and European Medicines Agency as treatment of seizures associated with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS), which are severe and difficult-to-treat developmental and epileptic encephalopathies with onset in early childhood.. This review will critically review the pharmacokinetic properties of CBD, the interactions with antiseizure and non-antiseizure medications, and the main tolerability and safety issues to provide guidance for its use in everyday practice.. CBD is metabolized in the liver and can influence the activity of enzymes involved in drug metabolism. The best characterized drug-drug interaction is between CBD and clobazam. The most common adverse events include somnolence, gastrointestinal discomfort, and increase in serum transaminases. High-grade purified CBD oral solution represents an effective therapeutic option in patients with DS and LGS. The findings cannot be extrapolated to other cannabis-based products, synthetic cannabinoids for medicinal use and non-medicinal cannabis and CBD derivatives.

Topics: Anticonvulsants; Cannabidiol; Child, Preschool; Epilepsies, Myoclonic; Humans; Lennox Gastaut Syndrome; Spasms, Infantile

Cannabis-derived cannabinoids have neuroactive properties. Recently, there has been emerging interest in the use of cannabidiol (CBD)-enriched products for treatment of drug-resistant epilepsy. In 2018, the FDA approved the use of CBD-rich Epidiolex for two severe forms of epilepsy in children (Lennox-Gastaut and Dravet syndromes). Experimental research supports the use of CBD in many CNS disorders, though the mechanisms underlying its anticonvulsant and neuroprotective effects remain unclear. CBD has been shown to reduce inflammation, protect against neuronal loss, normalize neurogenesis, and act as an antioxidant. These actions appear to be due to the multimodal mechanism of action of CBD in the brain. This chapter briefly describes the current information on cannabis pharmacology with an emphasis on the clinical utility of CBD in the treatment of refractory epilepsies and other related seizure conditions. Clinical trials are ongoing for other forms of epilepsy and refractory seizures associated with infantile spasms, tuberous sclerosis, and Rett syndrome. Overall, adjunct CBD has been found to be generally safe and effective for treatment-resistant seizures in children with severe early-onset epilepsy. Whether an add-on CBD is efficacious for the long-term treatment of various epilepsy and seizure types in adults being tested in various clinical trials.

Topics: Anticonvulsants; Cannabidiol; Drug Resistant Epilepsy; Epilepsies, Myoclonic; Humans; Lennox Gastaut Syndrome; Seizures

Cannabidiol, a non-intoxicating phytocannabinoid, has potential therapeutic effects over a broad range of disorders. Recently, there has been increased interest in CBD, as several studies showed promising anticonvulsant efficacy with few side effects. In 2018, a CBD-based oral solution, Epidiolex®, was approved by the FDA to treat two severe forms of pediatric epilepsy, Dravet syndrome, and Lennox-Gastaut syndrome. Although only these two syndromes are recognized indications for CBD, it has been consumed in an unregulated fashion for a variety of indications including chronic pain, muscle stiffness, inflammation, anxiety, smoking cessation, and even cancer. While CBD legislation in the USA is confusing due to the differences in state and federal laws, CBD has proliferated in the US market in several forms such as CBD oil or capsules, hemp oil/extract, and also as an ingredient in several dietary supplements, syrups, teas, and creams. With the ever-increasing use of CBD and its widespread availability to the general public, it is important to examine and report on possible drug-drug interactions between CBD and other therapeutic agents as well as addictive substances such as alcohol and tobacco. A detailed literature search for CBD's possible interactions was conducted using online databases. As expected, CBD has been reported to interact with anti-epileptic drugs, antidepressants, opioid analgesics, and THC, but surprisingly, it interacts with several other common medications, e.g. acetaminophen, and substances including alcohol. This review provides a comprehensive list of interacting drugs. The possible mechanisms for these drug-drug interactions are presented in table format. Given the growing popularity of CBD as a medication and the dearth of available information on CBD drug-drug interactions, it is critical to be aware of current drug-drug interactions and it will be important to investigate the impact of CBD upon concomitant medication use in future randomized, controlled trials.

Topics: Anticonvulsants; Cannabidiol; Child; Epilepsies, Myoclonic; Humans; Lennox Gastaut Syndrome; Spasms, Infantile

Cannabidiol is efficacious as an adjunctive treatment in children with epilepsy associated with Dravet and Lennox-Gastaut syndromes. As its role is currently adjunctive, we reviewed the interactions of cannabidiol with other antiseizure medications (ASMs).. A search of Cochrane, Pubmed and Embase databases from January 2015 to April 2020 was performed. All original research papers discussing interactions between cannabidiol and ASMs were included. Bibliographies of review articles were searched to identify further papers. Adverse events and side effects were excluded.. Cannabidiol interacts with ASMs through both pharmacokinetic and pharmacodynamic mechanisms. Thirty studies were identified (eighteen observational cohort studies, two randomised-control trials, three case reports/series, three animal studies, two briefing reports, an analysis of cohort data and a clinical trial simulation). There is potential for pharmacokinetic interactions between CBD and brivaracetam, clobazam, eslicarbazepine, lacosamide, gabapentin, oxcarbazepine, phenobarbital, potassium bromide, pregabalin, rufinamide, sirolimus/everolimus, stiripentol, tiagabine, topiramate and zonisamide. Pharmacodynamic interactions were identified for clobazam, valproate and levetiracetam. An animal study identified that the brain concentration of ASMs may be altered while the serum concentration remains the same.. Pharmacokinetic and pharmacodynamic interactions exist between cannabidiol and ASMs. The cytochrome p450 system in particular has been implicated in pharmacokinetic interactions, although not exclusively. The existing literature is limited for some ASMs by studies having relatively small cohorts. As increasing numbers of patients use cannabidiol, specialists need to monitor closely for interactions clinically and with blood levels when required.

Topics: Animals; Anticonvulsants; Cannabidiol; Clobazam; Drug Interactions; Humans; Lennox Gastaut Syndrome; Randomized Controlled Trials as Topic

Anecdotal reports addressing the successful seizure treatment of severe epilepsies with cannabidiol (CBD) have increased both public interest and academic research. Placebo-controlled, randomized, controlled trials proved the efficacy of pharmaceutical-grade CBD in epilepsy treatment, thus leading to pharmaceutical-grade CBD approval by the US Food and Drug Administration and the European Medicines Agency for the treatment of seizures in Dravet syndrome and Lennox-Gastaut syndrome as well as for tuberous complex syndrome by the Food and Drug Administration only. However, the CBD market is confusing because an array of products of different origins, purity, and concentration is available. Additionally, the results from the pivotal studies with plant-derived, pharmaceutical-grade CBD cannot simply be transferred to other epilepsy types or CBD of any origin. Because of the high demands and expectations that patients with epilepsy and their caregivers have regarding CBD, information outlining the proven facts and potential risks is essential. The aim of this article is to thoroughly review available research data and practical recommendations to provide the treating physician with the necessary information for counseling patients with epilepsy.

Topics: Anticonvulsants; Cannabidiol; Epilepsies, Myoclonic; Epilepsy; Humans; Lennox Gastaut Syndrome; Randomized Controlled Trials as Topic; Seizures; United States; United States Food and Drug Administration

Developmental and epileptic encephalopathies (DEEs) are among the most challenging of all epilepsies to manage, given the exceedingly frequent and often severe seizure types, pharmacoresistance to conventional antiseizure medications, and numerous comorbidities. During the past decade, efforts have focused on development of new treatment options for DEEs, with several recently approved in the United States or Europe, including cannabidiol as an orphan drug in Dravet and Lennox-Gastaut syndromes and everolimus as a possible antiepileptogenic and precision drug for tuberous sclerosis complex, with its impact on the mammalian target of rapamycin pathway. Furthermore, fenfluramine, an old drug, was repurposed as a novel therapy in the treatment of Dravet syndrome. The evolution of new insights into pathophysiological processes of various DEEs provides possibilities to investigate novel and repurposed drugs and to place them into the context of their role in future management of these patients. The purpose of this review is to provide an overview of these new medical treatment options for the DEEs and to discuss the clinical implications of these results for improved treatment.

Topics: Anticonvulsants; Cannabidiol; Disease Management; Drug Repositioning; Epilepsies, Myoclonic; Everolimus; Fenfluramine; Humans; Lennox Gastaut Syndrome; Precision Medicine; Treatment Outcome

Cannabidiol (CBD), which is one major constituent of the Cannabis sativa plant, has anti-seizure properties and does not produce euphoric or intrusive side effects. A plant-derived, highly purified CBD formulation with a known and constant composition has been approved by the US Food and Drug Administration for the treatment of seizures associated with Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis complex. In the European Union, the drug has been authorized by the European Medicines Agency for the treatment of seizures associated with Dravet syndrome and Lennox-Gastaut syndrome, in conjunction with clobazam, and is under regulatory review for the treatment of seizures in patients with tuberous sclerosis complex.. This systematic review aimed to summarize the currently available body of knowledge about the use of this US Food and Drug Administration/European Medicines Agency-approved oral formulation of pharmaceutical-grade CBD in patients with epileptic conditions, especially developmental and epileptic encephalopathies other than Dravet syndrome and Lennox-Gastaut syndrome.. The relevant studies were identified through MEDLINE and the US National Institutes of Health Clinical Trials Registry in October 2020. There were no date limitations or language restrictions. The following types of studies were included: clinical trials, cohorts, case-control, cross-sectional, clinical series, and case reports. Participants had to meet the following criteria: any sex, any ethnicity, any age, diagnosis of epilepsy, receiving plant-derived, highly purified (> 98% w/w) CBD in a sesame oil-based oral solution for the treatment of seizures. Data extracted from selected records included efficacy, tolerability, and safety outcomes.. Five hundred and seventy records were identified by database and trial register searching. Fifty-seven studies were retrieved for detailed assessment, of which 42 were eventually included for the review. The participants of the studies included patients of both pediatric and adult age. Across the trials, purified CBD was administered at dosages up to 50 mg/kg/day. In a randomized double-blind controlled trial in patients with tuberous sclerosis complex, CBD was associated with a significantly greater percent reduction in seizure frequency than placebo over the treatment period. Open-label studies suggested the effectiveness of CBD in the treatment of children and adults presenting with other epilepsy syndromes than those addressed by regulatory trials, including CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes, SYNGAP1 encephalopathy, and epilepsy with myoclonic absences. The most common adverse events observed during treatment with CBD included somnolence, decreased appetite, diarrhea, and increased serum aminotransferases.. The currently available data suggest that response to treatment with a highly purified, plant-derived CBD oil-based solution can be seen in patients across a broad range of epilepsy disorders and etiologies. The existing evidence can provide preliminary support for additional research.

Topics: Anticonvulsants; Cannabidiol; Case-Control Studies; Cross-Sectional Studies; Double-Blind Method; Epilepsies, Myoclonic; Epilepsy; Epileptic Syndromes; Humans; Lennox Gastaut Syndrome; Seizures

Lennox-Gastaut syndrome (LGS) is an age-specific epilepsy syndrome characterised by multiple seizure types, including drop seizures. LGS has a characteristic electroencephalogram, an onset before age eight years and an association with drug resistance. This is an updated version of the Cochrane Review published in 2013.. To assess the efficacy and tolerability of anti-seizure medications (ASMs) for LGS.. We searched the Cochrane Register of Studies (CRS Web) and MEDLINE (Ovid, 1946 to 28 February 2020) on 2 March 2020. CRS Web includes randomised controlled trials (RCTs) or quasi-RCTs from the Cochrane Central Register of Controlled Trials (CENTRAL); the Specialised Registers of Cochrane Review Groups, including Cochrane Epilepsy; PubMed; Embase; ClinicalTrials.gov; and the World Health Organization's International Clinical Trials Registry Platform (ICTRP). We imposed no language restrictions. We contacted pharmaceutical companies and colleagues in the field to seek any unpublished or ongoing studies.. We considered RCTs, including cross-over trials, of ASMs for LGS in children and adults. We included studies of ASMs used as either monotherapy or as an add-on (adjunctive) therapy. We excluded studies comparing different doses of the same ASM.. We used standard Cochrane methodological procedures, including independent, dual assessment for risk of bias and application of the GRADE approach to rate the evidence certainty for outcomes.. We found no trials of ASM monotherapy. The review included 11 trials (1277 participants; approximately 11 weeks to 112 weeks follow-up after randomisation) using add-on ASMs for LGS in children, adolescents and adults. Two studies compared add-on cannabidiol (two doses) with add-on placebo in children and adolescents only. Neither study reported overall seizure cessation or reduction. We found high-certainty evidence that 72 more people per 1000 (confidence interval (CI) 4 more to 351 more) had adverse events (AE) leading to study discontinuation with add-on cannabidiol, compared to add-on placebo (two studies; 396 participants; risk ratio (RR) 4.90, 95% CI 1.21 to 19.87). One study compared add-on cinromide with add-on placebo in children and adolescents only. We found very low-certainty evidence that 35 more people per 1000 (CI 123 fewer to 434 more) had 50% or greater average reduction of overall seizures with add-on cinromide compared to add-on placebo (one study; 56 participants; RR 1.15, 95% CI 0.47 to 2.86). This study did not report participants with AE leading to study discontinuation. One study compared add-on clobazam (three doses) with add-on placebo. This study did not report overall seizure cessation or reduction. We found high-certainty evidence that 106 more people per 1000 (CI 0 more to 538 more) had AE leading to study discontinuation with add-on clobazam compared to add-on placebo (one study; 238 participants; RR 4.12, 95% CI 1.01 to 16.87). One study compared add-on felbamate with add-on placebo. No cases of seizure cessation occurred in either regimen during the treatment phase (one study; 73 participants; low-certainty evidence). There was low-certainty evidence that 53 more people per 1000 (CI 19 fewer to 716 more) with add-on felbamate were seizure-free during an EEG recording at the end of the treatment phase, compared to add-on placebo (RR 2.92, 95% CI 0.32 to 26.77). The study did not report overall seizure reduction. We found low-certainty evidence that one fewer person per 1000 (CI 26 fewer to 388 more) with add-on felbamate had AE leading to study discontinuation compared to add-on placebo (one study, 73 participants; RR 0.97, 95% CI 0.06 to 14.97). Two studies compared add-on lamotrigine with add-on placebo. Neither study reported overall seizure cessation. We found high-certainty evidence that 176 more people per 1000 (CI 30 more to 434 more) had ≥ 50% average seizure reduction with add-on lamotrigine compared to add-on pla. RCTs of monotherapy and head-to-head comparison of add-on ASMs are currently lacking. However, we found high-certainty evidence for overall seizure reduction with add-on lamotrigine and rufinamide, with low-certainty evidence for AE leading to study discontinuation compared with add-on placebo or another add-on ASM. The evidence for other add-on ASMs for overall seizure cessation or reduction was low to very low with high- to low-certainty evidence for AE leading to study discontinuation. Future research should consider outcome reporting of overall seizure reduction (applying automated seizure detection devices), impact on development, cognition and behaviour; future research should also investigate age-specific efficacy of ASMs and target underlying aetiologies.

Topics: Adolescent; Adult; Age of Onset; Anticonvulsants; Cannabidiol; Child; Child, Preschool; Cinnamates; Clobazam; Electroencephalography; Felbamate; Humans; Lamotrigine; Lennox Gastaut Syndrome; Middle Aged; Placebos; Randomized Controlled Trials as Topic; Topiramate; Triazoles; Wakefulness; Young Adult

Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) are two serious epileptic syndromes with paediatric onset which are refractory to therapy and are associated with an important increase in mortality rates and comorbidities compared to the general population. These pathologies have a strong impact on the lives of patients and their families, because they undergo multiple pharmacological therapies (many of them without specific indication), with frequent changes due to poor efficacy and associated adverse effects. The specialists who care for these patients highlight unmet needs and the lack of specific, safe and effective treatments for better management of the syndrome.. A group of four neurologists specializing in epilepsy has met to review the scientific literature and evaluate the efficacy and safety of oral solution cannabidiol in the treatment of these syndromes, both in randomized clinical trials (CT) and in some observational studies.. Cannabidiol is positioned as an innovative therapy that allows better control of epileptic seizures and comorbidities of DS and LGS, furthermore its efficacy and safety have been evaluated in more than 700 patients. In CTs, cannabidiol significantly reduced the percentage of convulsive seizures and drop seizures compared to placebo in patients with DS and LGS respectively, which could improve their quality of life and that of their family members. The most frequent adverse effects reported were somnolence and decreased appetite. Elevated liver aminotransferase levels were also reported, especially in patients given concomitant sodium valproate. This therapy may allow better control of the epileptic seizures associated with these syndromes.. Cannabidiol en los síndromes de Dravet y Lennox-Gastaut: un nuevo abordaje terapéutico.. Introducción. Los síndromes de Dravet (SD) y Lennox-Gastaut (SLG) son dos síndromes epilépticos graves y de inicio en la edad pediátrica, refractarios al tratamiento, asociados a un notable incremento en las tasas de mortalidad y comorbilidades respecto a la población general. Suponen un fuerte impacto en la vida de los pacientes y sus familiares, ya que los pacientes están sometidos a múltiples terapias farmacológicas (muchas sin indicación específica), con cambios frecuentes debido a la escasa eficacia y a los efectos adversos. Los especialistas que les atienden destacan las necesidades no cubiertas y la falta de tratamientos específicos, seguros y eficaces para un mejor manejo de la enfermedad. Desarrollo. Se ha reunido un grupo formado por cuatro neurólogos especialistas en epilepsia para hacer una revisión de la literatura científica y evaluar los resultados de eficacia y seguridad de la solución oral de cannabidiol en el tratamiento de estos síndromes, tanto en ensayos clínicos aleatorizados como en diversos estudios observacionales. Conclusiones. El cannabidiol se sitúa como una terapia innovadora que permite un mejor control de las crisis epilépticas y comorbilidades del SD y el SLG; además, su eficacia y seguridad han sido evaluadas en más de 700 pacientes. En los ensayos clínicos redujo significativamente el porcentaje de crisis convulsivas y de caída en comparación con placebo en los pacientes con SD y SLG, respectivamente, y puede mejorar su calidad de vida y la de sus familiares. Los efectos adversos más frecuentes fueron la somnolencia y la disminución del apetito. También se notificaron niveles elevados de aminotransferasas hepáticas, especialmente en pacientes tratados concomitantemente con ácido valproico. Esta terapia podría permitir un mejor control de las crisis epilépticas asociadas a estas patologías.

Topics: Administration, Oral; Adolescent; Algorithms; Anticonvulsants; Cannabidiol; Child; Child, Preschool; Clinical Trials, Phase III as Topic; Clobazam; Compassionate Use Trials; Double-Blind Method; Drug Resistant Epilepsy; Drug Synergism; Epilepsies, Myoclonic; Humans; Infant; Lennox Gastaut Syndrome; Treatment Outcome

Drug-resistant seizures are life-threatening and contribute to sustained hospitalization. We present the case of a critically ill 28-year-old male with Lennox-Gastaut syndrome who had approximately 30 seizures/day in the intensive care unit.. Patient required mechanical ventilation and pharmacologically induced thiopentone coma. He was commenced on cannabidiol and subsequently extubated. He remained seizure-free thereafter on a combination of cannabidiol and anti-epileptic medication that predated his critical illness.. Our case report provides a unique perspective on the role of cannabidiol in achieving remission from drug-resistant seizures in critically ill patients.

Topics: Adult; Anticonvulsants; Cannabidiol; Critical Illness; Humans; Lennox Gastaut Syndrome; Male; Seizures

With the licensing of cannabidiol for drug resistant seizures in Dravet and Lennox Gastaut syndromes in the United states in 2018, interest in the potential for cannabis-based-medicinal products to meet currently unmet needs for people with epilepsy continues to grow. This review summarizes current knowledge and discusses the implications for future research and practice. Both cannabidiol and tetrahydrocannabinol, the main components, have been extensively studied in animal models, with multimodal mechanisms of action proposed. Only pure cannabidiol formulations have been rigorously evaluated in controlled trials thus far, with modest but significant improvements in motor seizures. Adverse effects include diarrhoea, somnolence and reduced appetite, with mostly acceptable tolerability, but a not insignificant (up to 1 in 23) risk of serious adverse events. Recognized drug interactions include with valproate (increased risk of hepatotoxicity) and clobazam (contributing to somnolence, increased secretions, probably chest infections, and potentially efficacy). Whilst there is public (and producer) interest in products also containing tetrahydrocannabinol, clinicians have justifiable concerns about exposing a group already vulnerable to mental health and neurobehavioural comorbidities to the associated additional risks in these domains. Artisanal preparations, with often inconsistent/unknown constituents are frequently used but not recommended. A gulf exists between the actual evidence, including a lack of comparative studies and public beliefs, fuelled by media and anecdote. Continued education of the public, policymakers, researchers and healthcare providers about what is and isn't yet known, together with on-going good quality research is essential to mitigate against future potential risks, particularly in relation to vulnerable populations. This article is part of the special issue entitled 'New Epilepsy Therapies for the 21st Century - From Antiseizure Drugs to Prevention, Modification and Cure of Epilepsy'.

Topics: Animals; Anticonvulsants; Cannabidiol; Cannabinoids; Clinical Trials as Topic; Culture; Dronabinol; Drug Resistant Epilepsy; Evidence-Based Medicine; Humans; Lennox Gastaut Syndrome

The growing interest in cannabidiol (CBD), specifically a pure form of CBD, as a treatment for epilepsy, among other conditions, is reflected in recent changes in legislation in some countries. Although there has been much speculation about the therapeutic value of cannabis-based products as an anti-seizure treatment for some time, it is only within the last two years that Class I evidence has been available for a pure form of CBD, based on placebo-controlled RCTs for patients with Lennox-Gastaut syndrome and Dravet syndrome. However, just as we are beginning to understand the significance of CBD as a treatment for epilepsy, in recent years, a broad spectrum of products advertised to contain CBD has emerged on the market. The effects of these products are fundamentally dependent on the purity, preparation, and concentration of CBD and other components, and consensus and standardisation are severely lacking regarding their preparation, composition, usage and effectiveness. This review aims to provide information to neurologists and epileptologists on the therapeutic value of CBD products, principally a purified form, in routine practice for patients with intractable epilepsy.

Topics: Cannabidiol; Cannabinoid Receptor Modulators; Drug Resistant Epilepsy; Epilepsies, Myoclonic; Humans; Lennox Gastaut Syndrome; Practice Guidelines as Topic

There are currently five compounds (clobazam, felbamate, lamotrigine, topiramate, rufinamide) available for prescription with a demonstrated efficacy on drop seizures for Lennox-Gastaut syndrome (LGS). There are also currently new and under-investigation compounds. This paper gives an overview on these novel developments for LGS based on the lecture given at the French Chapter meeting of the International League Against Epilepsy (ILAE) held in Paris in October 2019. Five compounds were discussed. Epidiolex (cannabidiol) has been approved recently based on positive randomized control trials in LGS patients. Four drugs are under investigation according to a search on the 'clinicaltrials.gov' database. Perampanel and fenfluramine are both being studied in ongoing phase 3 studies. Two compounds are in an earlier stage of development with ongoing phase 1 and 2 studies: carisbamate and OV953. We summarized the publicly available data. Based on these drug development programs, we can expect that new compounds will become available for LGS in the next years, possibly resulting in new treatment paradigms.

Topics: Anticonvulsants; Cannabidiol; Drug Development; Drugs, Investigational; Fenfluramine; Humans; Lennox Gastaut Syndrome; Nitriles; Pyridones; Therapies, Investigational; Triazoles

To evaluate the potential impact of concomitant clobazam (CLB) use on the efficacy of cannabidiol (CBD) treatment in patients with Dravet syndrome and Lennox-Gastaut syndrome using meta-analytical techniques.. We searched for randomized, placebo-controlled, single- or double-blinded trials. The proportion of patients who achieved ≥50% reduction from baseline in seizure frequency during the treatment period was assessed according to CLB status. Risk ratios (RRs) with 95% confidence intervals (CIs) were estimated.. Four trials were included and enrolled 714 participants, 429 for the add-on CBD group and 285 for the add-on placebo group. Among CBD-treated patients, 240 (55.9%) were taking concomitant CLB (CLB-On) and 189 (44.1%) were not taking concomitant CLB (CLB-Off); in placebo-treated patients, 158 (55.4%) were CLB-On and 127 (44.6%) CLB-Off. The percentages of patients who had at least 50% reduction in seizure frequency during the treatment period were 29.1% in the CBD arm and 15.7% in the placebo group among CLB-Off patients (RR = 1.80, 95% CI = 1.12-2.90, P = .015). Among CBL-On patients, the ≥50% reduction in seizure frequency was found in 52.9% and 27.8% in the CBD and placebo groups, respectively (RR = 1.85, 95% CI = 1.40-2.44, P < .001).. CBD was associated with a higher rate of seizure response in comparison to placebo when added to the existing antiepileptic regimen both in patients taking and in those not taking concomitant CLB. The lack of randomization for CLB status and the limited sample size need to be considered in the interpretation of the findings.

Topics: Anticonvulsants; Cannabidiol; Clobazam; Drug Therapy, Combination; Epilepsies, Myoclonic; Humans; Lennox Gastaut Syndrome; Randomized Controlled Trials as Topic; Seizures; Treatment Outcome

Four pivotal randomized placebo-controlled trials have demonstrated that adjunctive therapy with cannabidiol (CBD) improves seizure control in patients with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS). Between 47% and 68% of patients allocated to CBD treatment in these trials were receiving clobazam (CLB), which shows complex interactions with CBD resulting, in particular, in a 3.4- to 5-fold increase in plasma concentration of the active metabolite norclobazam. This raises concern as to the role played by these interactions in determining the reduction in seizure frequency in CBD-treated patients, and the question of whether CBD per se has clinically evident antiseizure effects. We appraised available evidence on the clinical consequences of the CBD-CLB interaction, focusing on subgroup analyses of seizure outcomes in patients on and off CLB comedication in the pivotal CBD trials, as provided by the European Medicines Agency Public Assessment Report. Evaluation of the results of individual trials clearly showed that improvement in seizure control over placebo was greater when CBD was added on to CLB than when it was added on to other medications. However, seizure control was also improved in patients off CLB, and despite the small sample size the difference vs placebo was statistically significant for the 10 mg/kg/d dose in one of the two LGS trials. Stronger evidence for an antiseizure effect of CBD independent of an interaction with CLB emerges from meta-analyses of seizure outcomes in the pooled population of LGS and DS patients not receiving CLB comedication. Although these results need to be interpreted taking into account methodological limitations, they provide the best clinical evidence to date that CBD exerts therapeutic effects in patients with epilepsy that are independent of its interaction with CLB. Greater antiseizure effects, and a greater burden of adverse effects, are observed when CBD is combined with CLB.

Topics: Anticonvulsants; Cannabidiol; Clobazam; Drug Interactions; Drug Therapy, Combination; Epilepsies, Myoclonic; Evidence-Based Medicine; Humans; Lennox Gastaut Syndrome; Randomized Controlled Trials as Topic; Seizures

Topics: Cannabidiol; Cost-Benefit Analysis; Epilepsies, Myoclonic; Humans; Lennox Gastaut Syndrome; Quality-Adjusted Life Years; Seizures; Technology; Technology Assessment, Biomedical

Cannabidiol (CBD), which is nonintoxicating pharmacologically relevant constituents of Cannabis, demonstrates several beneficial effects. It has been found to have antioxidative, anti-inflammatory, and neuroprotective effects. As the medicinal use of CBD is gaining popularity for treatment of various disorders, the recent flare-up of largely unproven and unregulated cannabis-based preparations on medical therapeutics may have its greatest impact in the field of neurology. Currently, as lot of clinical trials are underway, CBD demonstrates remarkable potential to become a supplemental therapy in various neurological conditions. It has shown promise in the treatment of neurological disorders such as anxiety, chronic pain, trigeminal neuralgia, epilepsy, and essential tremors as well as psychiatric disorders. While recent FDA-approved prescription drugs have demonstrated safety, efficacy, and consistency enough for regulatory approval in spasticity in multiple sclerosis (MS) and in Dravet and Lennox-Gastaut Syndromes (LGS), many therapeutic challenges still remain. In the current review, the authors have shed light on the application of CBD in the management and treatment of various neurological disorders.

Topics: Anticonvulsants; Cannabidiol; Cannabis; Epilepsy; Humans; Lennox Gastaut Syndrome

The efficacy of cannabidiol (CBD) with and without concomitant clobazam (CLB) was evaluated in stratified analyses of four large randomized controlled trials, two in Lennox-Gastaut syndrome, and two in Dravet syndrome.. The meta-analysis favored CBD vs. placebo regardless of CLB use. The treatment ratio (95% CI) of CBD over placebo for the average reduction in seizure frequency was 0.59 (0.52, 0.68; P < .0001) with CLB and 0.85 (0.73, 0.98; P = .0226) without CLB, and the 50% responder rate odds ratio (95% CI) was 2.51 (1.69, 3.71; P < .0001) with CLB and 2.40 (1.38, 4.16; P = .0020) without CLB. Adverse events (AEs) related to somnolence, rash, pneumonia, or aggression were more common in patients with concomitant CLB. There was a significant exposure/response relationship for CBD and its active metabolite.. These results indicate CBD is efficacious with and without CLB, but do not exclude the possibility of a synergistic effect associated with the combination of agents. The safety and tolerability profile of CBD without CLB show a lower rate of certain AEs than with CLB.

Topics: Anticonvulsants; Cannabidiol; Clobazam; Drug Therapy, Combination; Epilepsies, Myoclonic; Humans; Lennox Gastaut Syndrome; Randomized Controlled Trials as Topic; Seizures

Highly purified cannabidiol (CBD) has demonstrated efficacy with an acceptable safety profile in patients with Lennox-Gastaut syndrome or Dravet syndrome in randomized, double-blind, add-on, controlled phase 3 trials. It is important to consider the possibility of drug-drug interactions (DDIs). Here, we review six trials of CBD (Epidiolex/Epidyolex; 100 mg/mL oral solution) in healthy volunteers or patients with epilepsy, which investigated potential interactions between CBD and enzymes involved in drug metabolism of common antiseizure drugs (ASDs). CBD did not affect CYP3A4 activity. Induction of CYP3A4 and CYP2C19 led to small reductions in exposure to CBD and its major metabolites. Inhibition of CYP3A4 activity did not affect CBD exposure and caused small increases in exposure to CBD metabolites. Inhibition of CYP2C19 activity led to a small increase in exposure to CBD and small decreases in exposure to CBD metabolites. One potentially clinically important DDI was identified: combination of CBD and clobazam (CLB) did not affect CBD or CLB exposure, but increased exposure to major metabolites of both compounds. Reduction of CLB dose may be considered if adverse reactions known to occur with CLB are experienced when it is coadministered with CBD. There was a small increase of exposure to stiripentol (STP) when coadministered with CBD. STP had no effect on CBD exposure but led to minor decreases in exposure to CBD metabolites. Combination of CBD and valproate (VPA) did not cause clinically important changes in the pharmacokinetics of either drug, or 2-propyl-4-pentenoic acid. Concomitant VPA caused small increases in exposure to CBD metabolites. Dose adjustments are not likely to be necessary when CBD is combined with STP or VPA. The safety results from these trials were consistent with the known safety profile of CBD. These trials indicate an overall low potential for DDIs between CBD and other ASDs, except for CLB.

Topics: Anticonvulsants; Cannabidiol; Clinical Trials as Topic; Clobazam; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP2C19 Inducers; Cytochrome P-450 CYP2C19 Inhibitors; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inducers; Cytochrome P-450 CYP3A Inhibitors; Dioxolanes; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Epilepsies, Myoclonic; Fatty Acids, Monounsaturated; Humans; Lennox Gastaut Syndrome; Valproic Acid

In the United States, access to marijuana and its related products has been outlawed since passing the Controlled Substance Act (CSA) in 1970. Under this act, marijuana is classified as Schedule I substance and is considered to have a high potential for dependency and abuse as well as unaccepted medical use. From that time, multiple states have taken measures to legalize and decriminalize the use of marijuana. In June 2018, Epidiolex® (cannabidiol, CBD) was the first cannabis-derived drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of severe forms of epilepsy, Lennox-Gastaut syndrome, or Dravet syndrome. In December 2018, Farm Bill was significant progress in cannabis-related law by which hemp was removed from the definition of marijuana in the CSA. This paper provides an up-to-date overview of the legal status of cannabis-related aspects, including medical marijuana, home cultivation, patient registration, and hemp-derived CBD from the medical perspective in the United States.

Topics: Cannabidiol; Cannabis; Epilepsy; Humans; Lennox Gastaut Syndrome; Medical Marijuana; United States

In recent years, there has been a growing appreciation by regulatory authorities that cannabis-based medicines can play a useful role in disease therapy. Although often conflagrated by proponents of recreational use, the legislative rescheduling of cannabis-derived compounds, such as cannabidiol (CBD), has been associated with the steady increase in the pursuit of use of medicinal cannabis. One key driver in this interest has been the scientific demonstration of efficacy and safety of CBD in randomised, placebo-controlled clinical trials in children and young adults with difficult-to-treat epilepsies, which has encouraged increasing numbers of human trials of CBD for other indications and in other populations. The introduction of CBD as the medicine Epidiolex in the United States (in 2018) and as Epidyolex in the European Union (in 2019) as the first cannabis-derived therapeutic for the treatment of seizures was underpinned by preclinical research performed at the University of Reading. This work was awarded the British Pharmacological Society Sir James Black Award for Contributions to Drug Discovery 2019 and is discussed in the following review article.

Topics: Anticonvulsants; Cannabidiol; Child; Epilepsies, Myoclonic; Epilepsy; Humans; Lennox Gastaut Syndrome; Young Adult

To review the efficacy, safety, pharmacology and pharmacokinetics of pure, plant-derived cannabidiol (CBD; Epidiolex) in the treatment of Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS).. Relevant information was identified through EMBASE and Ovid MEDLINE (1946 to October 2018). Product labeling and https://www.clinicaltrials.gov were also reviewed.. English language articles evaluating efficacy and safety in humans with treatment-resistant epilepsies were reviewed; additional pharmacology and pharmacokinetic studies in humans, animals, and in vitro were also included.. Pure, plant-based CBD is a pharmaceutical grade extract that exhibits clinically significant antiseizure properties, with a hypothesized multimodal mechanism of action. In the GWPCARE trial series, CBD displayed superior efficacy in reducing key seizure frequencies (convulsive seizures in DS; drop seizures in LGS) by 17% to 23% compared with placebo as adjunctive therapy to standard antiepileptic drugs in patients 2 years of age and older. Common adverse effects were somnolence, diarrhea, and elevated hepatic transaminases. Noteworthy drug-drug interactions included clobazam, valproates, and significant inducers/inhibitors of CYP2C19 and 3A4 enzymes. Relevance to Patient Care and Clinical Practice: A discussion regarding CBD dosing, administration, adverse effects, monitoring parameters, and interactions is provided to guide clinicians. CBD offers patients with DS and LGS a new treatment option for refractory seizures.. This is the first cannabis-derived medication with approval from the US Food and Drug Administration. This CBD formulation significantly reduces seizures as an adjunct to standard antiepileptic therapies in patients ≥2 years old with DS and LGS and is well tolerated.

Topics: Adolescent; Adult; Cannabidiol; Child; Child, Preschool; Female; Humans; Lennox Gastaut Syndrome; Male; Young Adult

Epilepsy is one of the most common chronic disorders of the brain affecting around 70 million people worldwide. Treatment is mainly symptomatic, and most patients achieve long-term seizure control. Up to one-third of the affected subjects, however, are resistant to anticonvulsant therapy. Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) are severe, refractory epilepsy syndromes with onset in early childhood. Currently available interventions fail to control seizures in most cases, and there remains the need to identify new treatments. Cannabidiol (CBD) is the first in a new class of antiepileptic drugs. It is a major chemical of the cannabis plant, which has antiseizure properties in absence of psychoactive effects. This article provides a critical review of the pharmacology of CBD and the most recent clinical studies that evaluated its efficacy and safety as adjunctive treatment of seizures associated with LGS and DS.

Topics: Anticonvulsants; Cannabidiol; Child; Epilepsies, Myoclonic; Humans; Lennox Gastaut Syndrome; Seizures

Several new antiepileptic medicines became available for clinical use in the last two decades. However, the prognosis of epilepsy remains unchanged, with approximately one-third of patients continuing to have drug-resistant seizures. Because many of these patients are not candidates for curative epilepsy surgery, there is a need for new seizure medicines with better efficacy and safety profile. Recently, social media and public pressure sparked a renewed interest in cannabinoids, which had been used for epilepsy since ancient times. However, physicians have significant difficulty prescribing cannabinoids freely because of the paucity of sound scientific studies. Among the two most common cannabinoids, cannabidiol has better antiepileptic potential than tetrahydrocannabinol. The exact antiepileptic mechanism of cannabidiol is currently not known, but it modulates a number of endogenous systems and may have a novel anticonvulsant effect. However, it has broad drug-drug interactions with several agents, including inducer and inhibitor of CYP3A4 or CYP2C19. Cannabidiol can cause liver enzyme elevation, especially when co-administered with valproate. The US Food and Drug Administration (FDA) has approved pharmaceutical-grade cannabidiol oil for two childhood-onset catastrophic epilepsies: Dravet syndrome and Lennox-Gastaut syndrome. The Drug Enforcement Agency also reclassified this product as a schedule V agent. However, other cannabidiol products remain as a schedule I substance and are primarily used without regulation. Additionally, the FDA-approved pharmaceutical-grade cannabidiol oil is expensive, and insurance companies might approve this only for the designated indications. In despair, many individuals may resort to unregulated medical cannabis products in an attempt to control seizures. Rather than spontaneous treatment without medical supervision, adequate medical oversight is indicated to monitor and manage the proper dose, side effects, validity of the product, and drug-drug interactions.

Topics: Cannabidiol; Cannabinoid Receptor Agonists; Epilepsies, Myoclonic; Humans; Lennox Gastaut Syndrome; Treatment Outcome

Topics: Age Factors; Attention Deficit Disorder with Hyperactivity; Autism Spectrum Disorder; Brain; Cannabidiol; Cognition; Dronabinol; Endocannabinoids; Epilepsies, Myoclonic; Humans; Infant; Lennox Gastaut Syndrome; Medical Marijuana; Organ Size; Spasms, Infantile

Cannabidiol (CBD) is a major active component of the Cannabis plant, which, unlike tetrahydrocannabinol (THC), is devoid of euphoria-inducing properties. During the last 10 years, there has been increasing interest in the use of CBD-enriched products for the treatment of epilepsy. In 2018, an oil-based highly purified liquid formulation of CBD (Epidiolex) derived from Cannabis sativa was approved by the US Food and Drug Administration for the treatment of seizures associated with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS). The mechanisms underlying the antiseizure effects of CBD are unclear but may involve, among others, antagonism of G protein-coupled receptor 55 (GPR55), desensitization of transient receptor potential of vanilloid type 1 (TRPV1) channels, and inhibition of adenosine reuptake. CBD has complex and variable pharmacokinetics, with a prominent first-pass effect and a low oral bioavailability that increases fourfold when CBD is taken with a high-fat/high-calorie meal. In four randomized, double-blind, parallel-group, adjunctive-therapy trials, CBD given at doses of 10 and 20 mg/kg/day administered in two divided administrations was found to be superior to placebo in reducing the frequency of drop seizures in patients with LGS and convulsive seizures in patients with DS. Preliminary results from a recently completed controlled trial indicate that efficacy also extends to the treatment of seizures associated with the tuberous sclerosis complex. The most common adverse events that differentiated CBD from placebo in controlled trials included somnolence/sedation, decreased appetite, increases in transaminases, and diarrhea, behavioral changes, skin rashes, fatigue, and sleep disturbances. About one-half of the patients included in the DS and LGS trials were receiving concomitant therapy with clobazam, and in these patients a CBD-induced increase in serum levels of the active metabolite norclobazam may have contributed to improved seizure outcomes and to precipitation of some adverse effects, particularly somnolence.

Topics: Animals; Cannabidiol; Double-Blind Method; Epilepsies, Myoclonic; Epilepsy; Humans; Lennox Gastaut Syndrome; Randomized Controlled Trials as Topic; Seizures

Over the past decade there has been an increasing interest in using cannabinoids to treat a range of epilepsy syndromes following reports of some remarkable responses in individual patients. The situation is complicated by the fact that these agents do not appear to work via their attachment to endogenous cannabinoid receptors. Their pharmacokinetics are complex, and bioavailability is variable, resulting in difficulty in developing a suitable formulation for oral delivery. Drug interactions also represent another complication in their everyday use. Nevertheless, recent randomized, placebo-controlled trials with cannabidiol support its efficacy in Dravet and Lennox-Gastaut syndromes. Further placebo-controlled studies are underway in adults with focal epilepsy using cannabidivarin. The many unanswered questions in the use of cannabinoids to treat epileptic seizures are briefly summarized in the conclusion.

Topics: Anticonvulsants; Biological Availability; Cannabidiol; Cannabinoids; Drug Interactions; Epilepsies, Myoclonic; Epilepsies, Partial; Epilepsy; Humans; Lennox Gastaut Syndrome

Lennox-Gastaut syndrome (LGS) is a severe developmental epileptic encephalopathy, and available interventions fail to control seizures in most patients. Cannabidiol (CBD) is a major chemical of marijuana, which has anti-seizure properties and different mechanisms of action compared with other approved antiepileptic drugs (AEDs).. The aim was to evaluate the efficacy and safety of CBD as adjunctive treatment for seizures in patients with LGS using meta-analytical techniques.. Randomized, placebo-controlled, single- or double-blinded trials were identified. Main outcomes included the ≥ 50% reduction in baseline drop and non-drop seizure frequency, and the incidence of treatment withdrawal and adverse events (AEs). Risk ratios (RRs) with 95% confidence intervals (CIs) were estimated through the inverse variance method.. Two trials were included involving 396 participants. Patients presenting ≥ 50% reduction in drop seizure frequency during the treatment were 40.0% with CBD and 19.3% with placebo [RR 2.12 (95% CI 1.48-3.03); p < 0.001]. The rate of non-drop seizure frequency was reduced by 50% or more in 49.4% of patients in the CBD and 30.4% in the placebo arms [RR 1.62 (95% CI 1.09-2.43); p = 0.018]. The RR for CBD withdrawal was 4.93 (95% CI 1.50-16.22; p = 0.009). The RR to develop any AE during CBD treatment was 1.24 (95% CI 1.11-1.38; p < 0.001). AEs significantly associated with CBD were somnolence, decreased appetite, diarrhea and increased serum aminotransferases.. Adjunctive CBD resulted in a greater reduction in seizure frequency and a higher rate of AEs than placebo in patients with LGS presenting seizures uncontrolled by concomitant AEDs.

Topics: Anticonvulsants; Cannabidiol; Double-Blind Method; Humans; Lennox Gastaut Syndrome; Odds Ratio; Randomized Controlled Trials as Topic; Seizures; Transaminases

For millennia, there has been interest in the use of cannabis for the treatment of epilepsy. However, it is only recently that appropriately powered controlled studies have been completed. In this review, we present an update on the research investigating the use of cannabidiol (CBD), a non-psychoactive component of cannabis, in the treatment of epilepsy.. While the anticonvulsant mechanism of action of CBD has not been entirely elucidated, we discuss the most recent data available including its low affinity for the endocannabinoid receptors and possible indirect modulation of these receptors via blocking the breakdown of anandamide. Additional targets include activation of the transient receptor potential of vanilloid type-1 (TRPV1), antagonist action at GPR55, targeting of abnormal sodium channels, blocking of T-type calcium channels, modulation of adenosine receptors, modulation of voltage-dependent anion selective channel protein (VDAC1), and modulation of tumor necrosis factor alpha release. We also discuss the most recent studies on various artisanal CBD products conducted in patients with epilepsy in the USA and internationally. While a high percentage of patients in these studies reported improvement in seizures, these studies were either retrospective or conducted via survey. Dosage/preparation of CBD was either unknown or not controlled in the majority of these studies. Finally, we present data from both open-label expanded access programs (EAPs) and randomized placebo-controlled trials (RCTs) of a highly purified oral preparation of CBD, which was recently approved by the FDA in the treatment of epilepsy. In the EAPs, there was a significant improvement in seizure frequency seen in a large number of patients with various types of treatment-refractory epilepsy. The RCTs have shown significant seizure reduction compared to placebo in patients with Dravet syndrome and Lennox-Gastaut syndrome. Finally, we describe the available data on adverse effects and drug-drug interactions with highly purified CBD. While this product is overall well tolerated, the most common side effects are diarrhea and sedation, with sedation being much more common in patients taking concomitant clobazam. There was also an increased incidence of aspartate aminotransferase and alanine aminotransferase elevations while taking CBD, with many of the patients with these abnormalities also taking concomitant valproate. CBD has a clear interaction with clobazam, significantly increasing the levels of its active metabolite N-desmethylclobazam in several studies; this is felt to be due to CBD's inhibition of CYP2C19. EAP data demonstrate other possible interactions with rufinamide, zonisamide, topiramate, and eslicarbazepine. Additionally, there is one case report demonstrating need for warfarin dose adjustment with concomitant CBD. U

Topics: Anticonvulsants; Cannabidiol; Cannabis; Drug Resistant Epilepsy; Endocannabinoids; Epilepsies, Myoclonic; Epilepsy; Epileptic Syndromes; Humans; Lennox Gastaut Syndrome; Medical Marijuana; Randomized Controlled Trials as Topic; Retrospective Studies; Seizures; Spasms, Infantile; Treatment Outcome; TRPV Cation Channels

Approximately one-third of patients with epilepsy presents seizures despite adequate treatment. Hence, there is the need to search for new therapeutic options. Cannabidiol (CBD) is a major chemical component of the resin of Cannabis sativa plant, most commonly known as marijuana. The anti-seizure properties of CBD do not relate to the direct action on cannabinoid receptors, but are mediated by a multitude of mechanisms that include the agonist and antagonist effects on ionic channels, neurotransmitter transporters, and multiple 7-transmembrane receptors. In contrast to tetra-hydrocannabinol, CBD lacks psychoactive properties, does not produce euphoric or intrusive side effects, and is largely devoid of abuse liability.. The aim of the study was to estimate the efficacy and safety of CBD as adjunctive treatment in patients with epilepsy using meta-analytical techniques.. Randomized, placebo-controlled, single- or double-blinded add-on trials of oral CBD in patients with uncontrolled epilepsy were identified. Main outcomes included the percentage change and the proportion of patients with ≥ 50% reduction in monthly seizure frequency during the treatment period and the incidence of treatment withdrawal and adverse events (AEs).. Adjunctive CBD in patients with LGS or DS experiencing seizures uncontrolled by concomitant anti-epileptic treatment regimens is associated with a greater reduction in seizure frequency and a higher rate of AEs than placebo.

Topics: Adolescent; Adult; Anticonvulsants; Cannabidiol; Child; Child, Preschool; Drug Therapy, Combination; Epilepsies, Myoclonic; Epilepsy; Female; Humans; Lennox Gastaut Syndrome; Male; Middle Aged; Randomized Controlled Trials as Topic; Seizures; Treatment Outcome

Treatment-resistant epilepsy (TRE) affects 30% of epilepsy patients and is associated with severe morbidity and increased mortality. Cannabis-based therapies have been used to treat epilepsy for millennia, but only in the last few years have we begun to collect data from adequately powered placebo-controlled, randomized trials (RCTs) with cannabidiol (CBD), a cannabis derivative. Previously, information was limited to case reports, small series, and surveys reporting on the use of CBD and diverse medical marijuana (MMJ) preparations containing: tetrahydrocannabinol (THC), CBD, and many other cannabinoids in differing combinations. These RCTs have studied the safety and explored the potential efficacy of CBD use in children with Dravet Syndrome (DS) and Lennox-Gastaut Syndrome (LGS). The role of the placebo response is of paramount importance in studying medical cannabis products given the intense social and traditional media attention, as well as the strong beliefs held by many parents and patients that a natural product is safer and more effective than FDA-approved pharmaceutical agents. We lack valid data on the safety, efficacy, and dosing of artisanal preparations available from dispensaries in the 25 states and District of Columbia with MMJ programs and online sources of CBD and other cannabinoids. On the other hand, open-label studies with 100mg/ml CBD (Epidiolex®, GW Pharmaceuticals) have provided additional evidence of its efficacy along with an adequate safety profile (including certain drug interactions) in children and young adults with a spectrum of TREs. Further, Phase 3 RCTs with Epidiolex support efficacy and adequate safety profiles for children with DS and LGS at doses of 10- and 20-mg/kg/day. This article is part of a Special Issue titled "Cannabinoids and Epilepsy".

Topics: Adult; Anticonvulsants; Cannabidiol; Cannabinoids; Child; Clinical Trials as Topic; Dronabinol; Drug Combinations; Drug Resistant Epilepsy; Epilepsies, Myoclonic; Humans; Lennox Gastaut Syndrome; Medical Marijuana; Young Adult

States and the federal government are under growing pressure to legalize the use of cannabis products for medical purposes in the United States. Sixteen states have legalized (or decriminalized possession of) products high in cannabidiol (CBD) and with restricted ∆(9) -tetrahydrocannabinol (∆(9) -THC) content. In most of these states, the intent is for use in refractory epileptic seizures in children, but in a few states, the indications are broader. This review provides an overview of the pharmacology and toxicology of CBD; summarizes some of the regulatory, safety, and cultural issues relevant to the further exploitation of its antiepileptic or other pharmacologic activities; and assesses the current status and prospects for clinical development of CBD and CBD-rich preparations for medical use in the United States. Unlike Δ(9) -THC, CBD elicits its pharmacologic effects without exerting any significant intrinsic activity on the cannabinoid receptors, whose activation results in the psychotropic effects characteristic of Δ(9) -THC, and CBD possesses several pharmacologic activities that give it a high potential for therapeutic use. CBD exhibits neuroprotective, antiepileptic, anxiolytic, antipsychotic, and antiinflammatory properties. In combination with Δ(9) -THC, CBD has received regulatory approvals in several European countries and is currently under study in trials registered by the U.S. Food and Drug Administration in the United States. A number of states have passed legislation to allow for the use of CBD-rich, limited Δ(9) -THC-content preparations of cannabis for certain pathologic conditions. CBD is currently being studied in several clinical trials and is at different stages of clinical development for various medical indications. Judging from clinical findings reported so far, CBD and CBD-enriched preparations have great potential utility, but uncertainties regarding sourcing, long-term safety, abuse potential, and regulatory dilemmas remain.

Topics: Cannabidiol; Dronabinol; Endocannabinoids; Epilepsies, Myoclonic; Epilepsy; Humans; Lennox Gastaut Syndrome; Receptors, Cannabinoid

To present a summary of current scientific evidence about the cannabinoid, cannabidiol (CBD) with regard to its relevance to epilepsy and other selected neuropsychiatric disorders. We summarize the presentations from a conference in which invited participants reviewed relevant aspects of the physiology, mechanisms of action, pharmacology, and data from studies with animal models and human subjects. Cannabis has been used to treat disease since ancient times. Δ(9) -Tetrahydrocannabinol (Δ(9) -THC) is the major psychoactive ingredient and CBD is the major nonpsychoactive ingredient in cannabis. Cannabis and Δ(9) -THC are anticonvulsant in most animal models but can be proconvulsant in some healthy animals. The psychotropic effects of Δ(9) -THC limit tolerability. CBD is anticonvulsant in many acute animal models, but there are limited data in chronic models. The antiepileptic mechanisms of CBD are not known, but may include effects on the equilibrative nucleoside transporter; the orphan G-protein-coupled receptor GPR55; the transient receptor potential of vanilloid type-1 channel; the 5-HT1a receptor; and the α3 and α1 glycine receptors. CBD has neuroprotective and antiinflammatory effects, and it appears to be well tolerated in humans, but small and methodologically limited studies of CBD in human epilepsy have been inconclusive. More recent anecdotal reports of high-ratio CBD:Δ(9) -THC medical marijuana have claimed efficacy, but studies were not controlled. CBD bears investigation in epilepsy and other neuropsychiatric disorders, including anxiety, schizophrenia, addiction, and neonatal hypoxic-ischemic encephalopathy. However, we lack data from well-powered double-blind randomized, controlled studies on the efficacy of pure CBD for any disorder. Initial dose-tolerability and double-blind randomized, controlled studies focusing on target intractable epilepsy populations such as patients with Dravet and Lennox-Gastaut syndromes are being planned. Trials in other treatment-resistant epilepsies may also be warranted. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Topics: Animals; Anticonvulsants; Brain; Cannabidiol; Cannabinoids; Epilepsies, Myoclonic; Epilepsy; Humans; Intellectual Disability; Lennox Gastaut Syndrome; Mental Disorders; Phytotherapy; Plant Extracts; Seizures; Spasms, Infantile

The United States Food and Drug Administration recently approved the use of Cannabis sativa derived cannabidiol (CBD) in the treatment of Dravet Syndrome and Lennox-Gastaut Syndrome, under the trade name, Epidiolex. In double-blinded, placebo-controlled clinical trials, elevated ALT levels were observed in some patients, but these findings could not be uncoupled from the confounds of potential drug-drug interactions with co-administration of valproate and clobazam. Given the uncertainty of the potential hepatatoxic effects of CBD, the objective of the present study was to determine a point of departure for CBD, using human HepaRG spheroid cultures, followed by transcriptomic benchmark dose analysis. Treatment of HepaRG spheroids with CBD for 24 and 72 h, resulted in EC50 concentrations for cytotoxicity of 86.27 µM and 58.04 µM, respectively. Subsequent transcriptomic analysis at these timepoints demonstrated little alteration of gene and pathway data sets at a CBD concentration at or below 10 µM. Although this current analysis was conducted using liver cells, interestingly the findings at 72 h post CBD treatment showed suppression of many genes more commonly associated with immune regulation. Indeed, the immune system is a well-established target for CBD based on immune function assays. Collectively, in the present studies a point of departure was derived using transcriptomic changes produced by CBD in a human cell-based model system, which has been shown to accurately translate to human hepatotoxicity modeling.

Topics: Anticonvulsants; Cannabidiol; Chemical and Drug Induced Liver Injury; Double-Blind Method; Humans; Lennox Gastaut Syndrome; Seizures; United States

Epidiolex® (CBD) is FDA-approved for seizures associated with Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), and tuberous sclerosis complex (TSC). Phase III studies suggest that certain adverse effects (AEs), possibly linked to pharmacokinetic/pharmacodynamic (PK/PD) interactions may be therapy-limiting. We sought to identify these factors that contribute to treatment success and retention of therapy.. A single-center, retrospective review of patients with refractory epilepsy taking Epidiolex® was performed. Kaplan-Meier analysis was performed to describe Epidiolex® retention, as a measure of overall effectiveness.. One hundred and twelve patients were screened; 4 were excluded due to loss to follow-up or never starting Epidiolex®. Of 108 patients, mean age was 20.3 years (13.1, range 2 to 63), and 52.8% were female. Mean initial and maintenance doses were 5.3 mg/kg/day (1.3) and 15.3 mg/kg/day (5.8), respectively. At the final evaluation, 75% of patients remained on Epidiolex®. The 25th percentile for discontinuation was 19 months. 46.3% of patients experienced at least one treatment-emergent adverse effect (TEAE) with 14.5% d/c Epidiolex® due to treatment emerging adverse effects (TEAE). The most common reasons for discontinuation were lack of efficacy (37%), increased seizure activity (22%), worsened behavior (22%), and sedation (22%). One out of 27 discontinuations was due to liver function test (LFT) elevations (3.7%). At initiation, 47.2% were concurrently taking clobazam, and 39.2% of those patients had an initial clobazam dose decrease. 53% of patients were able to either discontinue or lower the dose of at least one other antiseizure medication.. Epidiolex® is generally well-tolerated and the majority continued long-term treatment. Patterns of adverse effects were similar to clinical trials, however gastrointestinal complaints, and significant LFT elevations were less common. Our data suggest most patients discontinue within the first several months of treatment and suggest that further studies designed to evaluate early identification and potential mitigation of adverse effects and including drug interactions are warranted.

Topics: Adolescent; Adult; Anticonvulsants; Cannabidiol; Child; Child, Preschool; Clobazam; Drug Resistant Epilepsy; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Lennox Gastaut Syndrome; Male; Middle Aged; Seizures; Young Adult

To estimate time to onset of cannabidiol (CBD) treatment effect (seizure reduction and adverse events [AEs]), we conducted post hoc analyses of data from two randomized, placebo-controlled, Phase 3 trials, GWPCARE3 (NCT02224560) and GWPCARE4 (NCT02224690), of patients with Lennox-Gastaut syndrome.. Patients received plant-derived pharmaceutical formulation of highly purified CBD (Epidiolex, 100 mg/ml oral solution) at 10 mg/kg/day (CBD10; GWPCARE3) or 20 mg/kg/day (CBD20; both trials) or placebo for 14 weeks. Treatment started at 2.5 mg/kg/day for all groups and reached 10 mg/kg/day on Day 7 and 20 mg/kg/day (CBD20 and matching placebo only) on Day 11. Percentage change from baseline in drop seizure frequency was calculated by cumulative day (i.e., including all previous days). Time to onset and resolution of AEs were evaluated.. Overall, 235 patients received CBD (CBD10 [GWPCARE3 only], n = 67; CBD20 [pooled GWPCARE3&4], n = 168) and 161 received placebo. Mean (range) age was 15.3 years (2.6-48.0). Patients had previously discontinued a median (range) of six (0-28) antiepileptic drugs (AEDs) and were currently taking a median of three (0-5) AEDs. Differences in drop seizure reduction between placebo and CBD emerged during the titration period and became nominally significant by Day 6 (p = .008) for pooled CBD treatment groups. Separation between placebo and CBD in ≥50% responder rate emerged by Day 6. Onset of the first reported AE occurred during the titration period in 45% of patients (CBD10, 46%; CBD20, 52%; placebo, 38%). In patients with AEs, resolution occurred within 4 weeks of onset in 53% of placebo and 39% of CBD patients and by end of study in 63% of placebo and 61% of CBD patients.. Treatment effect (efficacy and AEs) of CBD may occur within 1 week of starting treatment. Although AEs lasted longer for CBD than placebo, most resolved within the 14-week period.

Topics: Adolescent; Adult; Anticonvulsants; Cannabidiol; Child; Child, Preschool; Double-Blind Method; Female; Humans; Lennox Gastaut Syndrome; Male; Middle Aged; Seizures; Time Factors; Treatment Outcome; Young Adult

Lennox-Gastaut syndrome (LGS) is an epileptic encephalopathy that is often treatment resistant. Efficacy and safety of add-on cannabidiol (CBD) to treat seizures associated with LGS was demonstrated in two randomized controlled trials (RCTs). Patients who completed the RCTs were invited to enroll in this long-term open-label extension (OLE) trial, GWPCARE5 (NCT02224573). We present the final analysis of safety and efficacy outcomes from GWPCARE5.. Patients received plant-derived highly purified CBD (Epidiolex in the United States; Epidyolex in the European Union; 100 mg/ml oral solution), titrated to a target maintenance dose of 20 mg/kg/day over 2 weeks. Based on response and tolerability, CBD could then be reduced or increased up to 30 mg/kg/day.. Of 368 patients with LGS who completed the RCTs, 366 (99.5%) enrolled in this OLE. Median and mean treatment duration were 1090 and 826 days (range = 3-1421), respectively, with a mean modal dose of 24 mg/kg/day. Adverse events (AEs) occurred in 96% of patients, serious AEs in 42%, and AE-related discontinuations in 12%. Common AEs were convulsion (39%), diarrhea (38%), pyrexia (34%), and somnolence (29%). Fifty-five (15%) patients experienced liver transaminase elevations more than three times the upper limit of normal; 40 (73%) were taking concomitant valproic acid. Median percent reductions from baseline ranged 48%-71% for drop seizures and 48%-68% for total seizures through 156 weeks. Across all 12-week visit windows, 87% or more of patients/caregivers reported improvement in the patient's overall condition on the Subject/Caregiver Global Impression of Change scale.. Long-term add-on CBD treatment had a similar safety profile as in the original RCTs. Sustained reductions in drop and total seizure frequency were observed for up to 156 weeks, demonstrating long-term benefits of CBD treatment for patients with LGS.

Topics: Anticonvulsants; Cannabidiol; Epilepsies, Myoclonic; Humans; Lennox Gastaut Syndrome; Seizures

Patients with Lennox-Gastaut syndrome (LGS) who completed 1 of 2 randomized, double-blind, placebo-controlled trials of add-on cannabidiol (CBD) (GWPCARE3, NCT02224560 or GWPCARE4, NCT02224690) were invited to enroll in an open-label extension (OLE) study evaluating the long-term safety and efficacy of CBD (GWPCARE5, NCT02224573). Herein we present an interim analysis of the safety, efficacy, and patient-reported outcomes from this trial.. Patients received a pharmaceutical formulation of highly purified CBD oral solution (Epidiolex; 100 mg/mL), titrated from 2.5 to 20 mg/kg/d over a 2-week titration period, in addition to their existing medications. Doses could be reduced if not tolerated or increased up to 30 mg/kg/d if thought to be of benefit.. This interim analysis was based on a November 2016 data cut. Of 368 patients who completed treatment in GWPCARE3 and GWPCARE4, 366 (99.5%) enrolled in the OLE study (GWPCARE5). Median treatment duration was 38 weeks at a mean modal dose of 23 mg/kg/d. Most patients (92.1%) experienced adverse events (AEs), primarily of mild (32.5%) or moderate (43.4%) severity. The most common AEs were diarrhea (26.8%), somnolence (23.5%), and convulsion (21.3%). Thirty-five patients (9.6%) discontinued treatment due to AEs. Liver transaminase elevations were reported in 37 patients (10.1%), of whom 29 were receiving concomitant valproic acid; 34 cases resolved spontaneously or with dose modification of CBD or concomitant medication. Median reduction from baseline in drop seizure frequency (quantified monthly over 12-week periods) ranged from 48% to 60% through week 48. Median reduction in monthly total seizure frequency ranged from 48% to 57% across all 12-week periods through week 48. Eighty-eight percent of patients/caregivers reported an improvement in the patient's overall condition per the Subject/Caregiver Global Impression of Change scale.. In this study, long-term add-on CBD treatment had an acceptable safety profile in patients with LGS and led to sustained reductions in seizures.

Topics: Adolescent; Adult; Cannabidiol; Child; Child, Preschool; Double-Blind Method; Female; Humans; Lennox Gastaut Syndrome; Male; Middle Aged; Seizures; Treatment Outcome; Young Adult

Since 2014, patients with severe treatment-resistant epilepsies (TREs) have been receiving add-on cannabidiol (CBD) in an ongoing, expanded access program (EAP), which closely reflects clinical practice. We conducted an interim analysis of long-term efficacy and tolerability in patients with Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS) who received CBD treatment through December 2016.. Children and adults with LGS/DS taking stable doses of antiepileptic drugs (AEDs) at baseline were included from 25 EAP sites across the United States. During the 4-week baseline period, parents/caregivers kept diaries of all countable seizure types. Patients received a pharmaceutical formulation of highly purified CBD (Epidiolex®; 100 mg/mL) in oral solution at 2-10 mg/kg/day, titrated until tolerability limit or a maximum dose of 25-50 mg/kg/day. Patient visits were every 2-4 weeks. The percentage change from baseline in median monthly convulsive (ie, major motor) and total seizures was evaluated at 12-week intervals through 96 weeks. The percentages of patients who had ≥50%, ≥75%, and 100% reduction in monthly seizures relative to the baseline period were also evaluated. Adverse events (AEs) were monitored and summarized for the safety analysis set (SAS) through 144 weeks.. Of the 607 patients in the SAS, 58 had DS and 94 had LGS (N = 152); 455 patients had other TREs. Twenty-eight percent of LGS/DS patients withdrew, primarily owing to lack of efficacy (20%). LGS/DS patients were taking a median of 3 (0-10) concomitant AEDs. Median treatment duration was 78.3 (range, 4.1-146.4) weeks. Between weeks 12 and 96, median CBD dose ranged from 21 to 25 mg/kg/day. At 12 weeks, add-on CBD reduced median monthly major motor seizures by 50% and total seizures by 44%, with consistent reductions in both seizure types through 96 weeks. At 12 weeks, the proportions of patients with ≥50%, ≥75%, and 100% reductions in major motor seizures were 53%, 23%, and 6%; the proportions with corresponding reductions in total seizures were 46%, 26%, and 5%. Responder rates for both seizure types were consistent through 96 weeks. CBD had an acceptable safety profile; the most common AEs were somnolence (30%) and diarrhea (24%).. Results from this interim analysis support add-on CBD as an effective long-term treatment option in LGS or DS.

Topics: Adolescent; Adult; Anticonvulsants; Cannabidiol; Child; Child, Preschool; Diarrhea; Drug Resistant Epilepsy; Duration of Therapy; Epilepsies, Myoclonic; Female; Humans; Infant; Lennox Gastaut Syndrome; Male; Middle Aged; Sleepiness; Treatment Outcome; Young Adult

Patients with Lennox-Gastaut syndrome, a rare, severe form of epileptic encephalopathy, are frequently treatment resistant to available medications. No controlled studies have investigated the use of cannabidiol for patients with seizures associated with Lennox-Gastaut syndrome. We therefore assessed the efficacy and safety of cannabidiol as an add-on anticonvulsant therapy in this population of patients.. In this randomised, double-blind, placebo-controlled trial done at 24 clinical sites in the USA, the Netherlands, and Poland, we investigated the efficacy of cannabidiol as add-on therapy for drop seizures in patients with treatment-resistant Lennox-Gastaut syndrome. Eligible patients (aged 2-55 years) had Lennox-Gastaut syndrome, including a history of slow (<3 Hz) spike-and-wave patterns on electroencephalogram, evidence of more than one type of generalised seizure for at least 6 months, at least two drop seizures per week during the 4-week baseline period, and had not responded to treatment with at least two antiepileptic drugs. Patients were randomly assigned (1:1) using an interactive voice response system, stratified by age group, to receive 20 mg/kg oral cannabidiol daily or matched placebo for 14 weeks. All patients, caregivers, investigators, and individuals assessing data were masked to group assignment. The primary endpoint was percentage change from baseline in monthly frequency of drop seizures during the treatment period, analysed in all patients who received at least one dose of study drug and had post-baseline efficacy data. All randomly assigned patients were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02224690.. Between April 28, 2015, and Oct 15, 2015, we randomly assigned 171 patients to receive cannabidiol (n=86) or placebo (n=85). 14 patients in the cannabidiol group and one in the placebo group discontinued study treatment; all randomly assigned patients received at least one dose of study treatment and had post-baseline efficacy data. The median percentage reduction in monthly drop seizure frequency from baseline was 43·9% (IQR -69·6 to -1·9) in the cannibidiol group and 21·8% (IQR -45·7 to 1·7) in the placebo group. The estimated median difference between the treatment groups was -17·21 (95% CI -30·32 to -4·09; p=0·0135) during the 14-week treatment period. Adverse events occurred in 74 (86%) of 86 patients in the cannabidiol group and 59 (69%) of 85 patients in the placebo group; most were mild or moderate. The most common adverse events were diarrhoea, somnolence, pyrexia, decreased appetite, and vomiting. 12 (14%) patients in the cannabidiol group and one (1%) patient in the placebo group withdrew from the study because of adverse events. One patient (1%) died in the cannabidiol group, but this was considered unrelated to treatment.. Add-on cannabidiol is efficacious for the treatment of patients with drop seizures associated with Lennox-Gastaut syndrome and is generally well tolerated. The long-term efficacy and safety of cannabidiol is currently being assessed in the open-label extension of this trial.. GW Pharmaceuticals.

Topics: Adolescent; Adult; Anticonvulsants; Cannabidiol; Child; Child, Preschool; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Lennox Gastaut Syndrome; Male; Middle Aged; Seizures; Treatment Outcome; Young Adult

Cannabidiol has been used for treatment-resistant seizures in patients with severe early-onset epilepsy. We investigated the efficacy and safety of cannabidiol added to a regimen of conventional antiepileptic medication to treat drop seizures in patients with the Lennox-Gastaut syndrome, a severe developmental epileptic encephalopathy.. In this double-blind, placebo-controlled trial conducted at 30 clinical centers, we randomly assigned patients with the Lennox-Gastaut syndrome (age range, 2 to 55 years) who had had two or more drop seizures per week during a 28-day baseline period to receive cannabidiol oral solution at a dose of either 20 mg per kilogram of body weight (20-mg cannabidiol group) or 10 mg per kilogram (10-mg cannabidiol group) or matching placebo, administered in two equally divided doses daily for 14 weeks. The primary outcome was the percentage change from baseline in the frequency of drop seizures (average per 28 days) during the treatment period.. A total of 225 patients were enrolled; 76 patients were assigned to the 20-mg cannabidiol group, 73 to the 10-mg cannabidiol group, and 76 to the placebo group. During the 28-day baseline period, the median number of drop seizures was 85 in all trial groups combined. The median percent reduction from baseline in drop-seizure frequency during the treatment period was 41.9% in the 20-mg cannabidiol group, 37.2% in the 10-mg cannabidiol group, and 17.2% in the placebo group (P=0.005 for the 20-mg cannabidiol group vs. placebo group, and P=0.002 for the 10-mg cannabidiol group vs. placebo group). The most common adverse events among the patients in the cannabidiol groups were somnolence, decreased appetite, and diarrhea; these events occurred more frequently in the higher-dose group. Six patients in the 20-mg cannabidiol group and 1 patient in the 10-mg cannabidiol group discontinued the trial medication because of adverse events and were withdrawn from the trial. Fourteen patients who received cannabidiol (9%) had elevated liver aminotransferase concentrations.. Among children and adults with the Lennox-Gastaut syndrome, the addition of cannabidiol at a dose of 10 mg or 20 mg per kilogram per day to a conventional antiepileptic regimen resulted in greater reductions in the frequency of drop seizures than placebo. Adverse events with cannabidiol included elevated liver aminotransferase concentrations. (Funded by GW Pharmaceuticals; GWPCARE3 ClinicalTrials.gov number, NCT02224560 .).

Topics: Adolescent; Adult; Anticonvulsants; Cannabidiol; Child; Child, Preschool; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Humans; Lennox Gastaut Syndrome; Male; Middle Aged; Odds Ratio; Seizures; Transaminases; Young Adult

Almost a third of patients with epilepsy have a treatment-resistant form, which is associated with severe morbidity and increased mortality. Cannabis-based treatments for epilepsy have generated much interest, but scientific data are scarce. We aimed to establish whether addition of cannabidiol to existing anti-epileptic regimens would be safe, tolerated, and efficacious in children and young adults with treatment-resistant epilepsy.. In this open-label trial, patients (aged 1-30 years) with severe, intractable, childhood-onset, treatment-resistant epilepsy, who were receiving stable doses of antiepileptic drugs before study entry, were enrolled in an expanded-access programme at 11 epilepsy centres across the USA. Patients were given oral cannabidiol at 2-5 mg/kg per day, up-titrated until intolerance or to a maximum dose of 25 mg/kg or 50 mg/kg per day (dependent on study site). The primary objective was to establish the safety and tolerability of cannabidiol and the primary efficacy endpoint was median percentage change in the mean monthly frequency of motor seizures at 12 weeks. The efficacy analysis was by modified intention to treat. Comparisons of the percentage change in frequency of motor seizures were done with a Mann-Whitney U test.. Between Jan 15, 2014, and Jan 15, 2015, 214 patients were enrolled; 162 (76%) patients who had at least 12 weeks of follow-up after the first dose of cannabidiol were included in the safety and tolerability analysis, and 137 (64%) patients were included in the efficacy analysis. In the safety group, 33 (20%) patients had Dravet syndrome and 31 (19%) patients had Lennox-Gastaut syndrome. The remaining patients had intractable epilepsies of different causes and type. Adverse events were reported in 128 (79%) of the 162 patients within the safety group. Adverse events reported in more than 10% of patients were somnolence (n=41 [25%]), decreased appetite (n=31 [19%]), diarrhoea (n=31 [19%]), fatigue (n=21 [13%]), and convulsion (n=18 [11%]). Five (3%) patients discontinued treatment because of an adverse event. Serious adverse events were reported in 48 (30%) patients, including one death-a sudden unexpected death in epilepsy regarded as unrelated to study drug. 20 (12%) patients had severe adverse events possibly related to cannabidiol use, the most common of which was status epilepticus (n=9 [6%]). The median monthly frequency of motor seizures was 30.0 (IQR 11.0-96.0) at baseline and 15.8 (5.6-57.6) over the 12 week treatment period. The median reduction in monthly motor seizures was 36.5% (IQR 0-64.7).. Our findings suggest that cannabidiol might reduce seizure frequency and might have an adequate safety profile in children and young adults with highly treatment-resistant epilepsy. Randomised controlled trials are warranted to characterise the safety profile and true efficacy of this compound.. GW Pharmaceuticals, Epilepsy Therapy Project of the Epilepsy Foundation, Finding A Cure for Epilepsy and Seizures.

Topics: Adolescent; Adult; Age of Onset; Anticonvulsants; Cannabidiol; Child; Child, Preschool; Drug Resistant Epilepsy; Drug Therapy, Combination; Epilepsies, Myoclonic; Female; Humans; Infant; Lennox Gastaut Syndrome; Male; Outcome Assessment, Health Care; Seizures; Young Adult

Marijuana-based therapies (MBTs) have been shown to reduce seizure frequency in patients with severe and drug-resistant epilepsy (DRE). Pharmaceutical-grade CBD (Epidiolex. Thirty patients were identified as taking more than 1 type of MBT. Our findings suggest that seizure frequencies do not change significantly from baseline to after the first MBT and to after the second MBT (p = .4). However, we did find that patients with greater baseline seizure frequency were significantly more likely to respond to treatment after the second MBT (p = .03). To our second endpoint of side effect profile, we found that patients who experienced side effects after a second MBT had significantly greater seizure frequency compared to those who did not (p = .04).. We found no significant seizure frequency reduction from baseline to after a second MBT in patients who tried at least 2 different formulations of MBT. This suggests a low probability of seizure frequency reduction with a second MBT therapy in patients with epilepsy who tried at least two different MBTs. While these findings need to be replicated in a larger sample, they suggest that clinicians should not delay care by trying alternative MBT formulations after a patient has already tried one. Instead, it may be more prudent to attempt an alternative class of therapy.

Topics: Anticonvulsants; Cannabidiol; Cannabis; Child, Preschool; Drug Resistant Epilepsy; Epilepsy; Humans; Lennox Gastaut Syndrome; Retrospective Studies; Seizures

Lennox-Gastaut syndrome (LGS) is a severe developmental epileptic encephalopathy associated with numerous neurological signs and symptoms. Altered postural tone and the need for a caregiver-assisted wheelchair are features characterizing patients with LGS. Highly purified cannabidiol (CBD) is a novel antiseizure medication (ASM) recommended for seizure treatment, in combination with clobazam, in patients with LGS. Adding CBD to the previous ASM treatment helps in reducing seizure frequency, specifically drop seizures, in patients with LGS in both clinical trials and real-world studies. However, no data about drug effects on postural tone, motor activity, gait, and stability are available. In this case series, three adult patients diagnosed with LGS were treated with CBD as an add-on. During the follow-up, a slight improvement in seizure frequency was observed. Unexpectedly, an amelioration in postural tone and stability, measured using the validated Gross Motor Function Classification System, was also detected. Our case series suggests that CBD may help in managing patients with LGS regarding seizure control and in improving other aspects of the clinical spectrum of the disease, such as postural tone and stability. The mechanisms at the basis of this improvement may be related, other than seizure reduction, to the drug's effect on the brain locomotor centers, as demonstrated in animal model studies.

Topics: Animals; Anticonvulsants; Cannabidiol; Epilepsy; Humans; Lennox Gastaut Syndrome; Seizures

Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) currently present a therapeutic challenge. A pharmaceutical cannabidiol (CBD) specialty (Epidyolex®) has been approved by the FDA and EMA for the treatment of seizures in these syndromes. However, in Italy, the use of galenic formulations versus the pharmaceutical CBD has not been clearly regulated.. To share and disseminate expert' opinions on how to use and administer pharmaceutical CBD in patients with DS and LGS as well as identifying a possible strategy for the switch from galenic to pharmaceutical specialty.. A nominal group technique (NGT) was used, involving eight Italian adult and pediatric neurologists. Two questionnaires were consecutively administered and the Clinician' responses were discussed in a final meeting in order to draw the own conclusions.. The use of a pharmaceutical CBD is considered preferable to galenic formulations, in terms of reproducibility, safety, and control of the delivered dose.. The use of a pharmaceutical CBD in DS and LGS patients is useful for both seizure treatment and quality of life (QoL) improvement. However, further studies are needed to confirm the improvement in QoL and the best strategy for switching from a galenic formulation to pharmaceutical CBD.

Topics: Adult; Anticonvulsants; Cannabidiol; Child; Epilepsies, Myoclonic; Humans; Lennox Gastaut Syndrome; Pharmaceutical Preparations; Quality of Life; Reproducibility of Results; Seizures

In this post hoc analysis, we aimed to assess seizure-free days as a potential new outcome measure to use in randomized placebo-controlled trials (RCTs) of patients with Lennox-Gastaut syndrome (LGS).. In two phase 3 RCTs (GWPCARE3, GWPCARE4), eligible patients were randomized to receive plant-derived highly purified cannabidiol (CBD; Epidiolex® in the USA; 100 mg/mL oral solution) at 10 mg/kg/day (CBD10; GWPCARE3 only), at 20 mg/kg/day (CBD20), or matched placebo. The treatment period comprised a 2-week dose titration and a 12-week maintenance period. This post hoc analysis evaluated the least-squares (LS) mean changes from baseline and difference versus placebo in the number of drop or total seizure-free days per 28 days during the treatment period or maintenance period alone. LS mean changes were estimated using an analysis of covariance model, with categorical age and baseline number of drop or total seizure-free days as covariates, and treatment group as a fixed factor.. A total of 396 patients were included in this post hoc analysis. During the 14-week treatment period, LS mean changes from baseline in number of drop seizure-free days per 28 days for patients receiving placebo (n = 161), CBD10 (n = 73), and CBD20 (n = 162) were 2.81 (95% confidence interval [CI] = 1.75-3.88), 5.64 (95% CI = 4.08-7.20), and 6.45 (95% CI = 5.39-7.52), respectively. The LS mean differences in number of drop seizure-free days versus placebo were 2.83 (95% CI = .98-4.68) for CBD10 and 3.64 (95% CI = 2.18-5.10) for CBD20. For total seizure-free days, LS mean differences versus placebo were 2.63 (95% CI = .92-4.34) for CBD10 and 3.50 (95% CI = 2.16-4.85) for CBD20. The improvements from baseline in seizure-free days during the maintenance period alone were similar to the entire treatment period.. Drop and total seizure-free days represent potential new and clinically meaningful endpoints for future RCTs in patients with LGS.

Topics: Anticonvulsants; Cannabidiol; Clinical Trials, Phase III as Topic; Humans; Lennox Gastaut Syndrome; Randomized Controlled Trials as Topic; Seizures; Treatment Outcome

Cannabidiol oil (CBD) has been approved as an anti-seizure medication for the treatment of uncommon types of epilepsy, occurring in children: Dravet syndrome, Lennox-Gastaut syndrome, and Tuberous Sclerosis Complex. There are few publications in relation to use the CBD in adult patients with focal drug-resistant epilepsy. The objective of this study was to evaluate the efficacy, tolerability, safety, and quality of life, of adjuvant treatment with CBD, in adult patients with drug-resistant focal epilepsy for at least 6 months. An open, observational, prospective cohort study was conducted using a before-after design (time series) in adult patients undergoing outpatient follow-up in a public hospital in Buenos Aires, Argentina. From a total of 44 patients, 5% of patients were seizure-free, 32% of patients reduced more than 80% of their seizures and 87% of patients reduced 50% of their monthly seizures. Eleven percent presented a decrease of less than 50% in seizure frequency. The average final dose was 335 mg/d orally administered. Thirty-four percent of patients reported mild adverse events and no patient reported severe adverse effects. At the end of the study, we found in most patients a significant improvement in the quality of life, in all the items evaluated. Adjuvant treatment with CBD in adult patients with drug-resistant focal epilepsy was effective, safe, well tolerated, and associated with a significant improvement in their quality of life.

Topics: Adult; Anticonvulsants; Cannabidiol; Child; Drug Resistant Epilepsy; Epilepsies, Myoclonic; Epilepsies, Partial; Epilepsy; Humans; Lennox Gastaut Syndrome; Prospective Studies; Quality of Life

This retrospective chart review study (GWEP20052) evaluated plant-derived highly purified cannabidiol (CBD; Epidyolex®; 100 mg/mL oral solution) use without clobazam as add-on therapy in patients aged ≥2 years with Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS) enrolled in a European Early Access Program.. Data were extracted from patient charts covering a period starting 3 months before CBD treatment and concluding after 12 months of CBD treatment, or sooner if a patient discontinued CBD or started clobazam.. Of 114 enrolled patients, data were available for 107 (92 LGS, 15 DS) who received CBD without clobazam for ≥3 months. Mean age: 14.5 (LGS) and 10.5 (DS) years; female: 44% (LGS) and 67% (DS). Mean time-averaged CBD dose: 13.54 (LGS) and 11.56 (DS) mg/kg/day. Median change from baseline in seizure frequency per 28 days over 3-month intervals varied from -6.2% to -20.9% for LGS and 0% to -16.7% for DS. Achievement of ≥50% reduction in drop (LGS) or convulsive (DS) seizures at 3 and 12 months: LGS, 19% (n = 69) and 30% (n = 53); DS, 21% (n = 14) and 13% (n = 8). Retention on CBD without clobazam (enrolled set): 94%, 80%, 69%, and 63% at 3, 6, 9, and 12 months. Adverse event (AE) incidence was 31%, most commonly somnolence, seizure, diarrhea, and decreased appetite. Two patients discontinued CBD owing to AEs, and four patients with LGS experienced elevated liver enzymes.. Results support favorable effectiveness and retention of CBD without concomitant clobazam for up to 12 months in clinical practice.

Topics: Adolescent; Anticonvulsants; Cannabidiol; Clobazam; Epilepsies, Myoclonic; Humans; Lennox Gastaut Syndrome; Retrospective Studies; Seizures; Treatment Outcome

To increase understanding of the impact of cannabidiol (CBD) on outcomes beyond seizure control among individuals with Dravet syndrome or Lennox-Gastaut syndrome.. Qualitative interviews were conducted with caregivers of individuals with Dravet syndrome or Lennox-Gastaut syndrome treated with plant-derived, highly purified CBD medicine (Epidiolex in the USA; Epidyolex in Europe; 100 mg/mL oral solution). Symptoms and impacts of Dravet syndrome and Lennox-Gastaut syndrome on individuals were explored, as were the effects of CBD. Data were analyzed using thematic analysis.. Twenty-one caregivers of individuals with Dravet syndrome (n = 14) and Lennox-Gastaut syndrome (n = 7) aged 4-22 years participated. Health-related quality of life improvements associated with CBD included cognitive function, communication, behavior, mobility, and participation in daily activities. Seizure frequency reduction was commonly reported (n = 12), resulting in caregivers having greater freedom and family life being less disrupted. Adverse events were reported by 10 caregivers.. In addition to reduced seizure frequency, CBD may have a wide range of beneficial effects beyond seizure control that warrant further investigation.

Topics: Adolescent; Adult; Behavioral Symptoms; Cannabidiol; Caregivers; Child; Child, Preschool; Cognition; Communication; Epilepsies, Myoclonic; Female; Humans; Interviews as Topic; Lennox Gastaut Syndrome; Male; Middle Aged; Qualitative Research; Quality of Life; Seizures; Verbal Behavior; Young Adult

Highly purified cannabidiol (CBD) has a broad spectrum of action and could be useful for the treatment of drug resistant epilepsy regardless of etiology or syndrome.. Multicenter retrospective study that evaluated the efficacy and safety of CBD for the treatment of drug resistant epilepsy of different etiologies in patients >2 years of age.. Seventy-eight patients with a median age of 24 years and a wide spectrum of mainly structural and genetic etiologies were included. Patients were using a median of 3 antiseizure drugs (IQR=2-4) and had a median of 30 monthly seizures (IQR=12-100) before starting CBD. The median treatment time with CBD was 14 months (IQR=10-17). The efficacy analysis at the last available visit showed that mean percent reduction in seizures, ≥50% reduction in seizure frequency and seizure freedom was 67.8%, 68.8% and 11.5% respectively. We found no significant impact of concomitant clobazam use on the efficacy and safety of CBD. In the safety analysis, 28.2% (n = 22) of patients presented adverse events related to CBD and drug-retention rate was 78.2%.. In a real-world setting, highly purified CBD has been shown to be safe and effective for the treatment of drug resistant epilepsy not related to Lennox-Gastaut syndrome, Dravet syndrome or Tuberous Sclerosis Complex. Based on these findings, highly purified CBD should be considered as an adjuvant therapy for drug resistant epilepsy, regardless of its underlying cause or specific syndrome. Nevertheless, this assumption should be validated through further controlled trials.

Topics: Adult; Anticonvulsants; Cannabidiol; Drug Resistant Epilepsy; Epilepsies, Myoclonic; Humans; Lennox Gastaut Syndrome; Retrospective Studies; Seizures; Tuberous Sclerosis; Young Adult

Cannabis sativa has been cultivated for human use for about 5,000 years, and has likewise been used in the treatment of epilepsy for thousands of years.. Cannabidiol (CBD), which was isolated from cannabis sativa in 1940, has an anti-seizure effect and no psychoactive activity. Its effectiveness in reducing various types of seizures has been proven in animal seizure and epilepsy models. Recent randomised, placebo-controlled trials have confirmed its effectiveness in patients with drug-resistant epilepsy.. The aim of this position paper was to present the specific mechanism of CBD's anti-seizure action and current indications for CBD's use in epilepsy. The only cannabis-derived drug that has successfully passed clinical trials and has obtained United States Food and Drug Administration and European Medicines Agency approval for epilepsy is Epidiolex®. This paper presents the outcomes of the completed clinical trials with the use of this drug.. CBD may be an effective drug in drug-resistant epilepsy, particularly in Dravet Syndrome, Lennox- Gastaut Syndrome and seizures associated with tuberous sclerosis complex. Additional randomised, placebo-controlled studies with CBD are needed.

Topics: Animals; Anticonvulsants; Cannabidiol; Epilepsies, Myoclonic; Epilepsy; Humans; Lennox Gastaut Syndrome

Although international guidelines exist, the clinical heterogeneity of Lennox-Gastaut syndrome (LGS) and the increasing availability of new and repurposed drugs (e.g., fenfluramine and cannabidiol) requires a practical guide to patient management in the clinical context. We report the results of a consensus survey among 42 Italian experts in the diagnosis and treatment of LGS.. The consensus procedure followed a modified Delphi approach. Statements were formulated, based on the most recent published evidence and the clinicians' personal experience, then discussed, and agreed upon by the experts through a two-round voting procedure. Approval of a statement was reached with an average score ≥7.. Thirteen statements dealing with three main topics (i.e., clinical diagnosis and prognosis, impact on the Quality of Life (QoL), and treatment strategies) were generated. Six statements achieved a level of agreement sufficient for approval on the first voting round. Following the discussion and a few consequent amendments, most of the statements increased their level of agreement and all 13 were approved.. Overall, the statements draw a slightly more benign picture of this rare and severe disease, highlighting the possibility of remission - albeit modest -, an apparent trend towards lower mortality, and the availability of several effective drugs, to which greater accessibility would be hoped for. Valproate remains a major therapeutic option in LGS patients although lamotrigine, rufinamide, topiramate, cannabidiol, and clobazam are popular therapeutic options in Italy, allowing for a tailor-made antiseizure therapy.

Topics: Anticonvulsants; Cannabidiol; Clobazam; Consensus; Fenfluramine; Humans; Lamotrigine; Lennox Gastaut Syndrome; Quality of Life; Topiramate; Valproic Acid

To evaluate the effectiveness and tolerability of cannabidiol (CBD) in patients with developmental and epileptic encephalopathies, including Dravet syndrome (DS), and Lennox-Gastaut syndrome (LGS), in a Spanish Expanded Access Program (EAP).. This was a multicenter, retrospective, observational study of patients treated with purified CBD in 14 hospitals across Spain. Patients with (1) written informed consent and (2) at least 6 months follow-up before the closure of the database were included. Primary effectiveness endpoints included reductions (100 %, ≥75 %, ≥50 %, ≥25 %, or 0 %) or worsening in seizure frequency (all seizure types and most disabling seizures) at 1-, 3-, 6-, and 12-month visits and at the last visit, and median relative seizure reduction between baseline and last visit. Secondary effectiveness endpoints included retention rate, reduction in seizure severity, status epilepticus, healthcare utilization, and quality of life. Primary safety endpoints included rates of adverse events (AEs) and AEs leading to discontinuation.. One hundred and two patients (DS 12 %; LGS 59 %; other epilepsy syndromes 29 %) with a mean age of 15.9 years were enrolled. Patients were highly refractory to antiseizure medications (ASMs); mean number of prior failed ASMs was 7.5 (SD 3.7). The mean CBD dose was 13.0 mg/kg/day at the last visit. The proportion of patients with ≥50 % reduction in the total number of seizures from baseline was 44.9 % at 6 months and 38.9 % at 12 months. The median number of total seizures per month reduced by 47.6 % from baseline to the last visit. At 12 months, seizure severity was lower in 33/54 patients (61.1 %) and unchanged in 17/54 patients (31.5 %). Quality of life, based on the CAVE scale, increased from a mean score of 17.9 ± 4.7 (n = 54) at baseline to 21.7 ± 5.5 (n = 51) at the last patient visit (21.2 % improvement). The mean treatment retention time was 10.3 months. There were no statistically significant changes in the number of status epilepticus episodes, but lower healthcare utilization was observed. Adverse events occurred in sixty-eight patients (66.7 %), and the most common were somnolence (34.3 %) and diarrhea (12.7 %). Cannabidiol was discontinued exclusively due to AEs in 7.8 % of patients, increasing to 25.5 % when both lack of efficacy and AEs were considered together.. Cannabidiol demonstrated promising effectiveness and tolerability in patients with developmental and epileptic encephalopathies taking part in a Spanish EAP.

Topics: Adolescent; Adult; Anticonvulsants; Cannabidiol; Child; Epilepsies, Myoclonic; Epilepsy; Humans; Lennox Gastaut Syndrome; Quality of Life; Retrospective Studies; Seizures; Status Epilepticus; Treatment Outcome

Lennox Gastaut Syndrome (LGS) is an epilepsy syndrome presenting in childhood, classically characterised by a triad of cognitive or developmental impairment, multiple seizure types and EEG features of slow-spike waves (SWW), with or without paroxysmal fast activity (PFA) in sleep. There is increasing scientific opinion in favour of a less rigid approach to LGS diagnosis and this clinical audit attempts to shed light on how the LGS diagnostic criteria used may have changed over time, in a large tertiary paediatric neurology unit (Great Ormond Street Hospital (GOSH), London, UK).. Electronic patient records were reviewed for patients with a diagnosis of LGS made at GOSH within two time periods, 2014-2017 and 2018-2021. Patient demographics, aetiology, clinical features, EEG features, investigation results and medications were reviewed. Findings were compared against the International League Against Epilepsy (ILAE) Diagnostic Manual criteria for LGS diagnosis (the classical triad plus PFA in sleep). Existing GOSH data regarding total number of new epilepsy referrals to GOSH and ICD10 codes (including all epilepsy and epilepsy syndromes) per year were also used to review LGS diagnoses as proportions of new epilepsy referrals and total number of epilepsy diagnoses.. 5 LGS diagnoses were made in 2014-2017 compared to 40 diagnoses made in 2018-2021. There was a steep increase in the number of LGS diagnoses and LGS diagnoses as a proportion of total epilepsy diagnoses in the last 4 years, coinciding with the licensing of cannabidiol for management of LGS in the UK in 2018. There was a much less marked increase in LGS diagnoses as a proportion of epilepsy referrals from 2018 (and an as yet unexplained high proportion in 2014). The 2014-17 cohort fit a more classical LGS diagnostic criteria of the triad plus presence of PFA on sleep EEG (100% in 2014-17 vs 68% in 2018-21), with a more classical preceding history of infantile spasms (80% in 2014-17 vs 23% in 2018-21). Common seizure types were similar in both groups and a male preponderance was also noted in both groups. Cannabidiol use in LGS patients has also increased over time, all prescribed after 2018.. Despite the limitations of the small numbers of patients in each group, the results of this clinical audit are in keeping with changing clinical trends in favour of a broader LGS diagnostic criteria. The combination of this less rigid diagnostic criteria, the steep increase in diagnosis seen from 2018 onwards (coinciding with UK cannabidiol licencing for LGS in 2018) and the fact that most of the LGS patients in both groups are currently prescribed cannabidiol, may reflect a strategic shift in attitude towards LGS diagnosis or an increase in referrals for LGS, possibly to help facilitate access to novel treatments.

Topics: Cannabidiol; Child; Electroencephalography; Epilepsy; Epileptic Syndromes; Humans; Lennox Gastaut Syndrome; Male; Seizures; Spasms, Infantile

Growing interest in the clinical use of cannabidiol (CBD) as adjuvant therapy for pediatric refractory epileptic encephalopathy emphasizes the need for drug treatment optimization. The aim of this study was to characterize the pharmacokinetics of CBD in pediatric patients with refractory epileptic encephalopathy receiving an oil-based oral solution. To evaluate CBD concentrations, six serial blood samples per patient were collected after the morning dose of CBD, at least 21 days after the beginning of treatment. Twelve patients who received a median (range) dose of 12.2 (5.3-19.4) mg/kg/d (twice daily) were included in the analysis. Median (range) CBD time to maximum plasma concentration, maximum plasma concentration, and area under the concentration versus time curve up to 6 hours after dosing were 3.2 hours (1.9-6.2), 49.6 ng/mL (14.4-302.0), and 226.3 ng ⋅ h/mL (70.5-861.3), respectively. CBD systemic exposure parameters were in the lower range of previous reports in pediatric patients receiving doses in a similar range. Most of our patients (83%) showed little CBD plasma level fluctuation during a dosing interval, comparable to that encountered after oral administration of an extended release drug delivery system. CDB administration was generally safe and well tolerated, and a novel levothyroxine-CBD interaction was recorded. Similar to other studies, large interindividual variability in CBD exposure was observed, encouraging the use of CBD therapeutic drug monitoring.

Topics: Administration, Oral; Adolescent; Anticonvulsants; Brain Diseases; Cannabidiol; Child; Child, Preschool; Drug Interactions; Drug Resistant Epilepsy; Epilepsies, Myoclonic; Epileptic Syndromes; Female; Humans; Lennox Gastaut Syndrome; Male; Oils; Thyroxine

Topics: Anticonvulsants; Cannabidiol; Epilepsies, Myoclonic; Humans; Lennox Gastaut Syndrome

Topics: Anticonvulsants; Cannabidiol; Cost-Benefit Analysis; Humans; Lennox Gastaut Syndrome; Seizures

Topics: Cannabidiol; Cost-Benefit Analysis; Humans; Lennox Gastaut Syndrome; Pharmaceutical Preparations; Rare Diseases; Seizures

Topics: Anticonvulsants; Cannabidiol; Cost-Benefit Analysis; Humans; Lennox Gastaut Syndrome; Seizures

Since 2016, the Paediatric Department of the Filadelfia Epilepsy Hospital, Denmark, has been treating patients with cannabidiol for severe refractory epilepsy. This study describes treatment results, evaluates the effect of clobazam co-medication and compares findings in Dravet and Lennox-Gastaut patients with results in patients with other epilepsies.. This was a retrospective cohort study including 78 patients treated with off-label cannabidiol in 2016-2019. Diagnoses, previous and concomitant treatment, and presence of motor seizures were assessed. Effect on seizures was evaluated by seizure frequency registration or perceived effect in patients without seizure frequency registration.. In 51 patients with seizure frequency registration, 31.4% had ≥ 50% seizure reduction at three months, 31.1% at six months, 28.1% at 12 months and 20.0% at 24 months. At the same periods, some degree of seizure reduction was: 68.6%, 57.8%, 46.9% and 20.0%, respectively. Seizure reduction was higher with clobazam co-medication. In Dravet and Lennox-Gastaut patients, 70.0% had ≥ 50% seizure reduction at three months compared with 22.0% in patients with other epilepsies, where some degree of seizure reduction at three months were 80.0% and 65.9%, respectively.. Cannabidiol is a treatment option in children and young adults with severe refractory epilepsy other than Dravet and Lennox-Gastaut syndromes, but close evaluation of its effects is important to taper off treatment in case a treatment effect is lacking. Clobazam co-medication increases seizure reduction.. none.. not relevant.

Topics: Anticonvulsants; Cannabidiol; Child; Drug Resistant Epilepsy; Humans; Lennox Gastaut Syndrome; Retrospective Studies; Young Adult

Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) are rare treatment-resistant epileptic encephalopathies with limited data describing the relationship between seizures and quality of life (QoL). The objective of this cross-sectional pilot study was to assess the impact on QoL of seizures and seizure-free days for the generation of utility values.. Surveys were conducted in the UK and France, whereby patients and/or caregivers of patients with LGS, DS, or other epilepsies were asked to score health state vignettes for a hypothetical patient with LGS or DS. Respondents evaluated QoL for health states based on the number of seizures and seizure-free days per month, using a visual analog scale (VAS). Visual analog scale scores were converted to the 0-1 scale as a proxy estimate for utility values. Surveys were pilot tested and respondents were recruited from October 2018 to August 2019.. Patient respondents were mainly treatment-responsive (n = 43/55) whereas caregiver respondents mainly cared for patients with treatment-resistant epilepsy (n = 38/43). Most respondents and patients were aged ≥18 years. Results from LGS and DS surveys in the UK (n = 58) and France (n = 40) suggested that health states with fewer seizures and more seizure-free days had higher QoL scores for hypothetical patients. For DS, QoL scores for patient health states ranged from 0.20 (32 convulsive seizures and 4 seizure-free days/month, UK) to 0.92 (seizure-free, France). For LGS, scores ranged from 0.14 (130 drop seizures and 1 seizure-free day/month, France) to 0.83 (seizure-free, UK). In all surveys, seizure-free days had a greater impact on QoL than seizure frequency (P < 0.001).. Fewer seizures and additional seizure-free days improved QoL in patients with LGS or DS; seizure-free days had the greatest impact on QoL.

Topics: Adolescent; Adult; Anticonvulsants; Cannabidiol; Cross-Sectional Studies; Epilepsies, Myoclonic; Humans; Lennox Gastaut Syndrome; Pilot Projects; Quality of Life; Seizures; Spasms, Infantile

With this study, we aim to test the hypothesis that the effect of cannabidiol on drop-seizure frequency in patients with Lennox-Gastaut syndrome and Dravet syndrome could be attributed to a drug-drug interaction with clobazam. We performed clinical trial simulations for the effect of 20 mg/kg/day cannabidiol on drop-seizure frequency in patients with Lennox-Gastaut syndrome. We assumed that patients taking 10 or 20 mg clobazam would have a 2- to 7-fold increase in N-desmethylclobazam exposure, whereas patients not taking clobazam would have a median reduction in drop-seizure frequency and a variability in the percent reduction similar to the placebo group. The results show that the effect of cannabidiol on the median reduction in drop-seizure frequency in patients with Lennox-Gastaut syndrome may be explained by a drug-drug interaction with clobazam. This may have important implications for the use of cannabidiol and its Food and Drug Administration registration.

Topics: Anticonvulsants; Cannabidiol; Clobazam; Humans; Lennox Gastaut Syndrome; Seizures

Epidiolex™, a form of highly purified cannabidiol (CBD) derived from Cannabis plants, has demonstrated seizure control activity in patients with Dravet syndrome, without a fully elucidated mechanism of action. We have employed an unbiased approach to investigate this mechanism at a cellular level.. We use a tractable biomedical model organism, Dictyostelium, to identify a protein controlling the effect of CBD and characterize this mechanism. We then translate these results to a Dravet syndrome mouse model and an acute in vitro seizure model.. CBD activity is partially dependent upon the mitochondrial glycine cleavage system component, GcvH1 in Dictyostelium, orthologous to the human glycine cleavage system component H protein, which is functionally linked to folate one-carbon metabolism (FOCM). Analysis of FOCM components identified a mechanism for CBD in directly inhibiting methionine synthesis. Analysis of brain tissue from a Dravet syndrome mouse model also showed drastically altered levels of one-carbon components including methionine, and an in vitro rat seizure model showed an elevated level of methionine that is attenuated following CBD treatment.. Our results suggest a novel mechanism for CBD in the regulating methionine levels and identify altered one-carbon metabolism in Dravet syndrome and seizure activity.

Topics: Animals; Anticonvulsants; Cannabidiol; Carbon Cycle; Dictyostelium; Epilepsy; Humans; Lennox Gastaut Syndrome; Methionine; Rats

Cannabinoids include a variety of substances, of which cannabidiol (CBD) is the main substance investigated for the treatment of epilepsy, and this will be the focus in the present review. CBD preparations exist in various forms. There are significant differences in quality control regarding content and reproducibility for an approved drug versus herbal preparations. Cannabidiol has challenging pharmacological properties, and pharmaceutical and pharmacokinetic aspects will depend on the formulation or preparation of a certain product. This article will focus on the characteristics, pharmacokinetic challenges, and interactions of standardised CBD-containing drugs based on evidence from clinical and pharmacokinetic studies.

Topics: Anticonvulsants; Cannabidiol; Cannabinoids; Drug Interactions; Drug Resistant Epilepsy; Epilepsy; Humans; Lennox Gastaut Syndrome; Seizures

Cannabis sativa L. is an ancient medicinal plant wherefrom over 120 cannabinoids are extracted. In the past two decades, there has been increasing interest in the therapeutic potential of cannabis-based treatments for neurological disorders such as epilepsy, and there is now evidence for the medical use of cannabis and its effectiveness for a wide range of diseases. Cannabinoid treatments for pain and spasticity in patients with multiple sclerosis (Nabiximols) have been approved in several countries. Cannabidiol (CBD), in contrast to tetra-hydro-cannabidiol (THC), is not a controlled substance in the European Union, and over the years there has been increasing use of CBD-enriched extracts and pure CBD for seizure disorders, particularly in children. No analytical controls are mandatory for CBD-based products and a pronounced variability in CBD concentrations in commercialized CBD oil preparations has been identified. Randomized controlled trials of plant-derived CBD for treatment of Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) have provided evidence of anti-seizure effects, and in June 2018, CBD was approved by the Food and Drug Administration as an add-on antiepileptic drug for patients two years of age and older with LGS or DS. Medical cannabis, with various ratios of CBD and THC and in different galenic preparations, is licensed in many European countries for several indications, and in July 2019, the European Medicines Agency also granted marketing authorisation for CBD in association with clobazam, for the treatment of seizures associated with LGS or DS. The purpose of this article is to review the availability of cannabis-based products and cannabinoid-based medicines, together with current regulations regarding indications in Europe (as of July 2019). The lack of approval by the central agencies, as well as social and political influences, have led to significant variation in usage between countries.

Topics: Anticonvulsants; Cannabidiol; Cannabinoids; Child; Child, Preschool; Dronabinol; Drug Combinations; Epilepsies, Myoclonic; Epilepsy; Humans; Lennox Gastaut Syndrome; Plant Extracts; Seizures

Cannabidiol is a cannabinoid-derived product that has recently been approved for the treatment of pharmacoresistant seizures in patients with epileptic encephalopathies such as Dravet Syndrome and Lennox-Gastaut Syndrome. Short-term side effects of cannabidiol are well know and well-documented in the clinical trials that lead to its approval. Generally, is a well tolerated drug with transitory, dose-dependent mild to moderate effects like somnolence, decreased appetite or diarrhoea. However severe life-threatening reactions can also occur, and are often related to the non-controlled toxic combination with other antiseizure drugs that are widely used in this type of patients like sodium valproate or clobazam. In this brief review we summarize the available data about the short-term adverse events of cannabidiol. Further studies are required to assess the long-term outcome and final resolution of these conditions regarding safety of these patients.

Topics: Anticonvulsants; Cannabidiol; Cannabinoids; Drug Resistant Epilepsy; Humans; Lennox Gastaut Syndrome; Seizures

Highly purified cannabidiol (CBD) (approved as Epidiolex

Topics: Anticonvulsants; Cannabidiol; Drug Resistant Epilepsy; Epilepsies, Myoclonic; Epilepsy; Humans; Lennox Gastaut Syndrome; Seizures; TRPV Cation Channels

Topics: Antiemetics; Antineoplastic Agents; Cannabidiol; Cannabinoid Receptor Agonists; Chronic Pain; Decision Making, Shared; Dronabinol; Drug and Narcotic Control; Drug Resistant Epilepsy; Epilepsies, Myoclonic; Humans; Lennox Gastaut Syndrome; Medical Marijuana; Multiple Sclerosis; Muscle Spasticity; Nausea; Needs Assessment; Physicians, Primary Care; Practice Guidelines as Topic; Specialization; United Kingdom; Vomiting

In January 2019, a new plant-derived purified cannabidiol preparation, approved by the US Food and Drug Administration, became commercially available for patients ≥2 years old with Lennox-Gastaut syndrome or Dravet syndrome. Among our patients who were prescribed the new cannabidiol formulation, we observed several cases of thrombocytopenia and therefore embarked on this study. We conducted a single-center systematic chart review of all pediatric patients (<21 years old) who were prescribed cannabidiol from January to August 2019. We evaluated salient features of the patients' epilepsy syndrome, age, concurrent medications, and surveillance laboratory results before and after cannabidiol initiation. Among 87 patients, nine (10%) developed thrombocytopenia (platelet nadir range = 17 000-108 000) following initiation of cannabidiol. Each of these nine children was on combination therapy of cannabidiol with valproic acid. Whereas no children on cannabidiol without valproic acid (0/57) developed thrombocytopenia, nine of 23 treated with combination valproic acid and cannabidiol developed platelets < 110 000/µL (P < .0001). We report a novel and clinically important side effect of thrombocytopenia in one-third of patients treated concurrently with cannabidiol and valproic acid. If this finding is confirmed, clinicians should perform close monitoring for thrombocytopenia when adding cannabidiol to a regimen that includes valproic acid.

Topics: Adolescent; Anticonvulsants; Cannabidiol; Child; Child, Preschool; Drug Resistant Epilepsy; Drug Therapy, Combination; Epilepsies, Myoclonic; Epilepsy; Female; Humans; Infant; Lennox Gastaut Syndrome; Male; Thrombocytopenia; Valproic Acid; Young Adult

Cannabidiol (CBD) is a novel therapy for the treatment of Lennox-Gastaut Syndrome (LGS), a rare, treatment-refractory epileptic encephalopathy. Two pivotal trials found CBD 20 mg/kg/day conferred a reduction from baseline in median drop seizure frequency of 44% and 42%, respectively, compared with 22% and 17%, respectively, in the usual care arms. No economic evaluations have been published to date. This analysis assessed the cost effectiveness of CBD adjunct therapy compared with usual care alone in LGS from the US payer perspective.. We developed a lifetime horizon Markov decision analytic model. Efficacy, healthcare costs (2020 US$), and health state utilities were ascertained from published clinical trials, retrospective analyses, and time trade-off interviews conducted in the UK, respectively. Fifteen-year-old patients entering the model transitioned to states representing a percentage reduction in drop seizure frequency from baseline, where they remained until reverting back to baseline drop seizure frequency, or death. One-way and probabilistic sensitivity analyses were conducted to evaluate parameter uncertainty, and scenario analyses investigated the impact of various assumptions. Costs and outcomes were discounted at 3%.. Compared with usual care alone, CBD yielded 0.7 additional quality-adjusted life-years (QALYs) and $314,900 additional healthcare expenditure, resulting in $451,800 per QALY. Uncertainty in health state utilities were the largest contributor to uncertainty in the results. Results from the 5000-simulation probabilistic sensitivity analysis indicated a 0% chance of CBD being cost effective at a $150,000 per QALY willingness-to-pay threshold, with a 95% credible range for the incremental cost-effectiveness ratio of $325,300-$690,000 per QALY.. CBD does not appear to be a cost-effective therapeutic option in LGS patients at a willingness-to-pay threshold of $150,000/QALY.

Topics: Adolescent; Cannabidiol; Cost-Benefit Analysis; Humans; Lennox Gastaut Syndrome; Quality-Adjusted Life Years; Retrospective Studies; Seizures

For the first time in Korea, we aimed to study the efficacy and safety of cannabidiol (CBD), which is emerging as a new alternative in treating epileptic encephalopathies.. This study was conducted retrospectively with patients between the ages of 2-18 years diagnosed with Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS) were enrolled from March to October 2019, who visited outpatient unit at 3 and 6 months to evaluate medication efficacy and safety based on caregiver reporting. Additional evaluations, such as electroencephalogram and blood tests, were conducted at each period also. CBD was administered orally at a starting dose of 5 mg/kg/day, and was maintained at 10 mg/kg/day.. We analyzed 34 patients in the LGS group and 10 patients in the DS group between the ages of 1.2-15.8 years. In the 3-month evaluation, the overall reduction of seizure frequency in the LGS group was 52.9% (>50% reduction in 32.3% of the cases), and 29.4% in the 6-month evaluation (more than 50% reduction in 20.6%). In DS group, the reduction of seizure frequency by more than 50% was 30% and 20% in the 3-month and 6-month evaluation, respectively. Good outcomes were defined as the reduction of seizure frequency by more than 50% and similar results were observed in both LGS and DS groups. Adverse events were reported in 36.3% of total patients of which most common adverse events were gastrointestinal problems. However, no life-threatening adverse event was reported in both LGS and DS during the observation period.. In this first Korean study, CBD was safe and tolerable for use and could be expected to potentially reduce the seizure frequency in pediatric patients with LGS or DS.

Topics: Adolescent; Anticonvulsants; Cannabidiol; Caregivers; Child; Child, Preschool; Electroencephalography; Epilepsies, Myoclonic; Epilepsy; Female; Humans; Infant; Lennox Gastaut Syndrome; Male; Patient Safety; Republic of Korea; Retrospective Studies; Treatment Outcome

Topics: Anticonvulsants; Cannabidiol; Clobazam; Humans; Lennox Gastaut Syndrome

Topics: Anticonvulsants; Cannabidiol; Drug Approval; Epilepsies, Myoclonic; Humans; Lennox Gastaut Syndrome; Medical Marijuana; United States; United States Food and Drug Administration

The FDA recently approved the first cannabidiol oral medication to treat refractory epilepsy in patients with Dravet syndrome and Lennox-Gastaut syndrome. This article describes the safety and efficacy of cannabidiol treatment in patients with refractory epilepsy.

Topics: Age Factors; Anticonvulsants; Cannabidiol; Child; Drug Resistant Epilepsy; Epilepsies, Myoclonic; Female; gamma-Aminobutyric Acid; Glutamic Acid; Humans; Lennox Gastaut Syndrome; Mutation; NAV1.1 Voltage-Gated Sodium Channel; Phytotherapy; Treatment Outcome

Topics: Anticonvulsants; Cannabidiol; Humans; Lennox Gastaut Syndrome; Seizures

Topics: Cannabidiol; Humans; Lennox Gastaut Syndrome; Seizures

Topics: Anticonvulsants; Cannabidiol; Epilepsy; Humans; Lennox Gastaut Syndrome; Seizures

Topics: Anticonvulsants; Cannabidiol; Epilepsy; Humans; Lennox Gastaut Syndrome; Seizures

Topics: Anticonvulsants; Cannabidiol; Epilepsy; Humans; Lennox Gastaut Syndrome; Seizures

Topics: Anticonvulsants; Cannabidiol; Child, Preschool; Drug Approval; Humans; Lennox Gastaut Syndrome; Myoclonic Epilepsies, Progressive

Topics: Administration, Oral; Anticonvulsants; Brain; Brain Waves; Cannabidiol; Drug Costs; Drug Interactions; Epilepsies, Myoclonic; Humans; Lennox Gastaut Syndrome; Treatment Outcome

Topics: Anticonvulsants; Cannabidiol; Drug Resistant Epilepsy; Epilepsies, Myoclonic; Female; Humans; Lennox Gastaut Syndrome; Male; Outcome Assessment, Health Care; Seizures

There is a great need for safe and effective therapies for treatment of infantile spasms (IS) and Lennox-Gastaut syndrome (LGS). Based on anecdotal reports and limited experience in an open-label trial, cannabidiol (CBD) has received tremendous attention as a potential treatment for pediatric epilepsy, especially Dravet syndrome. However, there is scant evidence of specific utility for treatment of IS and LGS. We sought to document the experiences of children with IS and/or LGS who have been treated with CBD-enriched cannabis preparations. We conducted a brief online survey of parents who administered CBD-enriched cannabis preparations for the treatment of their children's epilepsy. We specifically recruited parents of children with IS and LGS and focused on perceived efficacy, dosage, and tolerability. Survey respondents included 117 parents of children with epilepsy (including 53 with IS or LGS) who had administered CBD products to their children. Perceived efficacy and tolerability were similar across etiologic subgroups. Eighty-five percent of all parents reported a reduction in seizure frequency, and 14% reported complete seizure freedom. Epilepsy was characterized as highly refractory with median latency from epilepsy onset to CBD initiation of five years, during which the patient's seizures failed to improve after a median of eight antiseizure medication trials. The median duration and the median dosage of CBD exposure were 6.8 months and 4.3mg/kg/day, respectively. Reported side effects were far less common during CBD exposure, with the exception of increased appetite (30%). A high proportion of respondents reported improvement in sleep (53%), alertness (71%), and mood (63%) during CBD therapy. Although this study suggests a potential role for CBD in the treatment of refractory childhood epilepsy including IS and LGS, it does not represent compelling evidence of efficacy or safety. From a methodological standpoint, this study is extraordinarily vulnerable to participation bias and limited by lack of blinded outcome ascertainment. Appropriately controlled clinical trials are essential to establish efficacy and safety.

Topics: Adolescent; Affect; Age of Onset; Anticonvulsants; Attention; Cannabidiol; Cannabis; Child; Drug Resistant Epilepsy; Epilepsy; Female; Health Care Surveys; Humans; Infant; Lennox Gastaut Syndrome; Male; Plant Extracts; Seizures; Sleep; Spasms, Infantile; Syndrome; Young Adult