cannabidiol and Epileptic-Syndromes

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

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

Add-on cannabidiol (CBD) reduced seizures associated with Dravet syndrome (DS) in two randomized, double-blind, placebo-controlled trials: GWPCARE1 Part B (NCT02091375) and GWPCARE2 (NCT02224703). Patients who completed GWPCARE1 Part A (NCT02091206) or Part B, or GWPCARE2, were enrolled in a long-term open-label extension trial, GWPCARE5 (NCT02224573). We present an interim analysis of the safety, efficacy, and patient-reported outcomes from GWPCARE5.. Patients received a pharmaceutical formulation of highly purified CBD in oral solution (100 mg/ml), titrated from 2.5 to 20 mg/kg/day over a 2-week period, added to their existing medications. Based on response and tolerance, CBD could be reduced or increased to 30 mg/kg/day.. Of the 330 patients who completed the original randomized trials, 315 (95%) enrolled in this open-label extension. Median treatment duration was 444 days (range = 18-1535), with a mean modal dose of 22 mg/kg/day; patients received a median of three concomitant antiseizure medications. Adverse events (AEs) occurred in 97% patients (mild, 23%; moderate, 50%; severe, 25%). Commonly reported AEs were diarrhea (43%), pyrexia (39%), decreased appetite (31%), and somnolence (28%). Twenty-eight (9%) patients discontinued due to AEs. Sixty-nine (22%) patients had liver transaminase elevations >3 × upper limit of normal; 84% were on concomitant valproic acid. In patients from GWPCARE1 Part B and GWPCARE2, the median reduction from baseline in monthly seizure frequency assessed in 12-week periods up to Week 156 was 45%-74% for convulsive seizures and 49%-84% for total seizures. Across all visit windows, ≥83% patients/caregivers completing a Subject/Caregiver Global Impression of Change scale reported improvement in overall condition.. We show that long-term CBD treatment had an acceptable safety profile and led to sustained, clinically meaningful reductions in seizure frequency in patients with treatment-resistant DS.

Topics: Anticonvulsants; Cannabidiol; Double-Blind Method; Epilepsies, Myoclonic; Epileptic Syndromes; Humans; Seizures; Treatment Outcome

Epilepsy of Infancy with Migrating Focal Seizures (EIMFS) is a rare, developmental and epileptic encephalopathy most commonly associated with mutations in KCNT1, a potassium channel. Polymorphous migrating focal seizures begin within 6 months of life and are pharmacoresistant to standard anticonvulsants. Additional therapies are needed to decrease seizure frequency and subsequent developmental deterioration associated with EIMFS. Cannabidiol (CBD) has recently arisen in public interest due to its potential in treatment-resistant epilepsies as demonstrated in randomized controlled trials for Dravet Syndrome and Lennox-Gastaut Syndrome. Here we evaluate the response of three patients, all diagnosed with EIMFS secondary to KCNT1 mutations, to pharmaceutical grade CBD. Two patients showed no benefit and have since voluntarily stopped CBD. One patient showed no overall reduction in seizure frequency, however showed a notable reduction in seizure intensity with possible developmental progression. Further studies are needed to assess the potential benefit of CBD in treatment-resistant epilepsies such as EIMFS, with a focus on early identification and intervention.

Topics: Adolescent; Anticonvulsants; Cannabidiol; Child, Preschool; Epileptic Syndromes; Female; Humans; Infant; Male; Mutation; Nerve Tissue Proteins; Potassium Channels, Sodium-Activated; Prospective Studies; Seizures; Spasms, Infantile

Febrile infection-related epilepsy syndrome (FIRES) is a prolonged refractory status epilepticus (SE) that develops among healthy individuals after a febrile infection. FIRES treatment is challenging due to its poor response to antiseizure medications (ASMs) and anesthetic drugs. The use of cannabidiol (CBD) as an adjunctive treatment has been suggested, albeit data about its role in the acute phase is lacking. This report describes the use of purified CBD in the acute phase of two pediatric cases of FIRES and their long-term outcome. Both children were treated with several ASMs, immunomodulators, anesthetics, and nonpharmacological treatment (ketogenic diet). CBD was administered, as an adjunctive treatment, through nasogastric tube about 30 days after onset. SE resolved within 3 days of reaching the target dose and both were seizure-free for 1 year after. Although it is difficult to define the extent to which each previous therapy contributed to recovery, in both cases CBD therapy was a turning point, reinforcing its potential role as add-on treatment in the acute phase of FIRES.

Topics: Anesthetics; Cannabidiol; Child; Drug Resistant Epilepsy; Encephalitis; Epileptic Syndromes; Humans; Seizures; Status Epilepticus

Dravet syndrome is a severe developmental and epileptic encephalopathy characterised by refractory seizures and cognitive dysfunction. The treatment is challenging, not least because the seizures are highly drug resistant, requiring multiple anti-seizure medications (ASMs), while some ASMs can exacerbate seizures. Initial treatments include the broad-spectrum ASMs valproate (VPA), and clobazam (CLB) in some regions; however, they are generally insufficient to control seizures. With this in mind, three adjunct ASMs have been approved specifically for the treatment of seizures in patients with Dravet syndrome: stiripentol (STP) in 2007 in the European Union and 2018 in the USA, cannabidiol (CBD) in 2018/2019 (in combination with CLB in the European Union) and fenfluramine (FFA) in 2020. These "add-on" therapies (mostly to VPA/CLB) are used as escalation therapies, with the choice dependent on availability in different countries, patient characteristics and caregiver preferences. Topiramate is also frequently used, with evidence of efficacy in Dravet syndrome, and there is anecdotal evidence of efficacy with bromide, which is frequently used in Germany and Japan. With a growing treatment landscape for Dravet syndrome, there can be practical challenges for clinicians, particularly with issues associated with polypharmacy. This practical guide provides an overview of these main ASMs including their indications/contraindications, mechanism of action, efficacy, safety and tolerability profile, dosage requirements, and laboratory and clinical parameters to be evaluated. Standard laboratory and clinical parameters include blood counts, liver function tests, serum concentrations of ASMs, monitoring the growth of children, as well as weight loss and acceleration of behavioural problems. Regular cardiac monitoring is also important with FFA as it has previously been associated with cases of cardiac valve disease when used in adults at high doses (up to 120 mg/day) in combination with phentermine as a therapy for obesity. Importantly, no signs of heart valve disease have been documented to date at the low doses used in patients with developmental and epileptic encephalopathies. In addition, potential drug-drug interactions and their consequences are a key consideration in everyday practice. Interactions that potentially require dosage adjustments to alleviate adverse events include the following: STP + CLB resulting in increased plasma concentrations of CLB and its ac

Topics: Adult; Anticonvulsants; Cannabidiol; Child; Clobazam; Drug Therapy, Combination; Epilepsies, Myoclonic; Epileptic Syndromes; Fenfluramine; Humans; Sleepiness; Spasms, Infantile; Topiramate

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

Febrile infection-related epilepsy syndrome (FIRES) is a rare catastrophic epileptic encephalopathy that presents suddenly in otherwise normal children and young adults causing significant neurological disability, chronic epilepsy, and high rates of mortality. To suggest a therapy protocol to improve outcome of FIRES, workshops were held in conjunction with American Epilepsy Society annual meeting between 2017 and 2019. An international group of pediatric epileptologists, pediatric neurointensivists, rheumatologists and basic scientists with interest and expertise in FIRES convened to propose an algorithm for a standardized approach to the diagnosis and treatment of FIRES. The broad differential for refractory status epilepticus (RSE) should include FIRES, to allow empiric therapies to be started early in the clinical course. FIRES should be considered in all previously healthy patients older than two years of age who present with explosive onset of seizures rapidly progressing to RSE, following a febrile illness in the preceding two weeks. Once FIRES is suspected, early administrations of ketogenic diet and anakinra (the IL-1 receptor antagonist that blocks biologic activity of IL-1β) are recommended.

Topics: Adolescent; Cannabidiol; Child; Child, Preschool; Diet, Ketogenic; Drug Resistant Epilepsy; Encephalitis; Epileptic Syndromes; Humans; Immune System Diseases; Infant; Interleukin 1 Receptor Antagonist Protein; Seizures, Febrile; Status Epilepticus

We conducted a post hoc analysis of two randomized controlled trials, GWPCARE1 (NCT02091375) and GWPCARE2 (NCT02224703), to estimate the time to onset of cannabidiol (CBD) treatment effects (seizure reduction and adverse events [AEs]) in patients with Dravet syndrome (DS).. Patients received either plant-derived highly purified CBD (Epidiolex in the United States; 100 mg/ml oral solution) 10 mg/kg/day (CBD10; GWPCARE2) or 20 mg/kg/day (CBD20; GWPCARE1&2), or matching placebo for 14 weeks. Treatment started at 2.5 mg/kg/day, reached 10 mg/kg/day on Day 7, and went up to 20 mg/kg/day on Day 11 during the 14-day titration period. Percentage change from baseline in convulsive seizure frequency was calculated by cumulative day (i.e., including all previous days). Time to onset and resolution of AEs were also evaluated.. Overall, 124 patients received placebo and 194 received CBD (CBD10, n = 64; CBD20, n = 130). Mean age was 9.5 years (range = 2.2-18.9). Patients had discontinued a median of four antiepileptic drugs (range = 0-26) and were currently taking a median of three (range = 1-5). Differences in convulsive seizure reduction between placebo and CBD emerged during titration and became nominally significant by Day 12 for CBD20 (p = .02) and Day 13 for CBD10 (p = .03). Additionally, differences in the 50% responder rate between placebo and CBD became apparent during titration. Onset of the first reported AE occurred during the titration period in 48.4% of placebo patients and 54.1% of CBD patients. The three most common AEs of somnolence, decreased appetite, and diarrhea resolved within 4 weeks of onset in the majority of CBD-treated patients (56.3%-72.9%).. The therapeutic effect of CBD in DS may start within 2 weeks of treatment in some patients. Although AEs lasted longer for CBD than placebo, most resolved within the 14-week study period.

Topics: Adolescent; Anticonvulsants; Cannabidiol; Child; Child, Preschool; Double-Blind Method; Epilepsies, Myoclonic; Epileptic Syndromes; Humans; Randomized Controlled Trials as Topic; Seizures; Spasms, Infantile; Treatment Outcome

We studied our collective open-label, compassionate use experience in using cannabidiol (CBD) to treat epilepsy in patients with CDKL5 deficiency disorder and Aicardi, Doose, and Dup15q syndromes.. We included patients aged 1-30 years with severe childhood-onset epilepsy who received CBD for ≥10 weeks as part of multiple investigator-initiated expanded access or state access programs for a compassionate prospective interventional study: CDKL5 deficiency disorder (n = 20), Aicardi syndrome (n = 19), Dup15q syndrome (n = 8), and Doose syndrome (n = 8). These patients were treated at 11 institutions from January 2014 to December 2016.. The percent change in median convulsive seizure frequency for all patients taking CBD in the efficacy group decreased from baseline [n = 46] to week 12 (51.4% [n = 35], interquartile range (IQR): 9-85%) and week 48 (59.1% [n = 27], IQR: 14-86%). There was a significant difference between the percent changes in monthly convulsive seizure frequency during baseline and week 12, χ. This open-label drug trial provides class III evidence for the long-term safety and efficacy of CBD administration in patients with treatment-resistant epilepsy (TRE) associated with CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes. Adjuvant therapy with CBD showed similar safety and efficacy for these four syndromes as reported in a diverse population of TRE etiologies. This study extended analysis of the prior report from 12 weeks to 48 weeks of efficacy data and suggested that placebo-controlled randomized trials should be conducted to formally assess the safety and efficacy of CBD in these epileptic encephalopathies.

Topics: Adolescent; Adult; Aicardi Syndrome; Anticonvulsants; Cannabidiol; Child; Child, Preschool; Chromosomes, Human, 13-15; Epilepsies, Myoclonic; Epileptic Syndromes; Female; Humans; Infant; Male; Middle Aged; Prospective Studies; Protein Serine-Threonine Kinases; Spasms, Infantile; Trisomy; Young Adult

Topics: Cannabidiol; Drug Resistant Epilepsy; Epilepsy; Epileptic Syndromes; Humans; Seizures

Febrile infection-related epilepsy syndrome (FIRES) is a devastating epilepsy affecting normal children after a febrile illness. FIRES presents with an acute phase with super-refractory status epilepticus and all patients progress to a chronic phase with persistent refractory epilepsy. The typical outcome is severe encephalopathy or death. The authors present 7 children from 5 centers with FIRES who had not responded to antiepileptic drugs or other therapies who were given cannabadiol (Epidiolex, GW Pharma) on emergency or expanded investigational protocols in either the acute or chronic phase of illness. After starting cannabidiol, 6 of 7 patients' seizures improved in frequency and duration. One patient died due to multiorgan failure secondary to isoflourane. An average of 4 antiepileptic drugs were weaned. Currently 5 subjects are ambulatory, 1 walks with assistance, and 4 are verbal. While this is an open-label case series, the authors add cannabidiol as a possible treatment for FIRES.

Topics: Acute Disease; Anticonvulsants; Cannabidiol; Child; Chronic Disease; Drug Resistant Epilepsy; Epileptic Syndromes; Fever; Humans; Infections; Male; Status Epilepticus; Treatment Outcome