The efficacy and safety of cannabidiol (CBD) in pediatric patients with Dravet Syndrome: a narrative review of clinical trials.

BACKGROUND: Dravet Syndrome (DS) is a rare and severe form of childhood epilepsy that is often refractory to conventional antiepileptic drugs. Emerging evidence suggests that Cannabidiol (CBD) offer therapeutic benefits for DS. This review aims to evaluate the efficacy and safety of CBD in pediatric patients with DS based on data from ten clinical trials. METHODS: A review was conducted to identify clinical trials assessing the efficacy and safety of CBD in pediatric patients diagnosed with DS. PubMed, MEDLINE, Scopus, Web of Science, and relevant grey literature were systematically searched for relevant articles up to October 2023, and clinical trials within the last 10 years were included. The search strategy incorporated controlled vocabulary terms and keywords related to "Cannabidiol," "Dravet Syndrome," and "pediatric patients." RESULTS: The analysis revealed promising efficacy outcomes. Notably, CBD demonstrated substantial reductions in seizure frequency, with some patients achieving seizure freedom. The findings emphasised the consistency of CBD's efficacy across different patient subgroups. The safety profile of CBD was generally acceptable, with adverse events often being manageable. CONCLUSION: This review consolidates evidence from multiple clinical trials, affirming the potential of CBD as a promising treatment option for pediatric patients with DS. While further research is needed to address existing knowledge gaps, CBD's efficacy and acceptable safety profile make it a valuable addition to the therapeutic tools for DS.

Brain network reconstruction of abnormal functional connectivity in Lennox-Gastaut syndrome according to drug responsiveness: A retrospective study.

OBJECTIVE: Functional network effects of resective or palliative epilepsy surgery in Lennox-Gastaut syndrome (LGS) patients are different according to the seizure outcome. This study aimed to clarify whether the response to antiseizure medications (ASM) can affect to alteration of brain network connectivity. METHODS: In this retrospective study, 37 patients with LGS who underwent 1st electroencephalography (EEG) and 40 healthy controls were enrolled. Among them, 24 LGS patients had follow-up EEG data and were classified as drug responders and non-responders according to the ASM response. Graphical theoretical analysis was used to assess functional connectivity using resting-state EEG. RESULTS: The 1st EEG showed a decreased radius in patients with LGS compared with that in healthy controls (3.987 vs. 4.279, P = 0.003). Follow-up EEG data of patients with LGS revealed significant differences in functional connectivity depending on the ASM response. On follow-up EEG, non-responders (n = 11) demonstrated significant increases in global network parameters, whereas responders (n = 13) showed no significant difference in functional connectivity compared with healthy controls. CONCLUSIONS: The functional connectivity patterns in patients with LGS differed from those in healthy controls. Functional connectivity in drug-responsive patients with LGS tended to preserve the network of brain connections in a pattern similar to that in healthy controls, whereas non-responders showed more disrupted functional connectivity.

Evaluating fenfluramine hydrochloride as an oral solution for the treatment of seizures associated with Lennox-Gastaut syndrome.

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

Efficacy and safety of six new antiseizure medications for adjunctive treatment of focal epilepsy and epileptic syndrome: A systematic review and network meta-analysis.

OBJECTIVE: This study aimed to evaluate the efficacy and safety of six new antiseizure medications (ASMs) for adjunctive treatment in adult patients with focal epilepsy and adolescents with Dravet syndrome (DS), Lennox-Gastaut syndrome (LGS), or tuberous sclerosis complex (TSC). METHODS: A comprehensive literature search was performed using PubMed, Medline, Embase, and Cochrane library databases from inception to October 13, 2023. We included published studies for a systematic review and a network meta-analysis (NMA). The efficacy and safety were reported in terms of a 50% response rate and dropout rate along with serious adverse events (SAEs). The outcomes were ranked with the surface under the cumulative ranking curve (SUCRA). RESULTS: Twenty eligible trials with 5516 patients and 21 interventions, including placebo, contributed to the analysis. Included ASMs were brivaracetam (BRV), cenobamate (CBM), cannabidiol (CBD), fenfluramine (FFM), everolimus (ELM), and soticlestat (SLT). The six new ASMs were compared in four different epilepsy subtypes. In focal epilepsy treatment, BRV seemed to be safe [vs placebo, risk ratio (RR) = 0.69, 95 % confidence interval (CI): 0.25-1.91] and effective (vs placebo, RR = 2.18, 95 % CI: 1.25-3.81). In treating focal epilepsy, CBM 300 mg was more effective at a 50 % response rate (SUCRA 91.8 %) compared with BRV and CBD. However, with the increase in dosage, more SAEs (SUCRA 85.6 %) appeared compared with other ASMs. CBD had good efficacy on LGS (SUCRA 88.4) and DS (SUCRA 66.2), but the effect on adult focal epilepsy was not better than that of placebo [vs placebo, RR = 0.83 (0.36-1.93)]. The NMA indicated that the likelihood of the most appropriate intervention (SUCRA 91.2 %) with minimum side effects（SUCRA 12.5 %）for the DS was FFM. Compared with CBD, high exposure to ELM demonstrated a more effective treatment of TSC (SUCRA 89.7 %). More high-quality SLT studies are needed to further evaluate the efficacy and safety. The comparison-adjusted funnel plots of annualized relapse rate and side effects in the included studies revealed no significant funnel plot asymmetry. CONCLUSIONS: This NMA indicated that the most effective treatment strategy for focal epilepsy, DS, Lennox-Gastaut syndrome, and TSC, respectively, included CBM 300 mg, FFM, CBD, and ELM. However, the aforementioned findings need further confirmation.

What have we learned from the real-world efficacy of FFA in DS and LGS? A post-marketing study in clinical practice.

OBJECTIVE: To evaluate the effectiveness and tolerability of fenfluramine (FFA) in routine clinical practice treating real-world populations with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS). METHODS: This was a retrospective analysis of patients with DS or LGS who initiated FFA treatment from 2018 to 2022 at a single center. Patient demographics, medical history, seizure characteristics, and treatment outcomes were collected from electronic medical records. Duration of FFA treatment, dosage regimens, seizure frequency, seizure severity, improvements in cognitive, social, and motor outcomes, and adverse events were extracted and analyzed. Effectiveness was assessed using ≥50 % sustained reduction in monthly seizure frequency vs baseline for ≥2 consecutive months at 12 months; seizure freedom was a secondary measure. RESULTS: Seizure frequency data was available for 56 of 68 patients included in the study. At 12 months, 50 patients (89.3 %) remained on FFA treatment; 58 % of these patients achieved a ≥50 % sustained response and 10 % experienced seizure freedom. Cognitive, motor, and social improvement were noted in 70.7 %, 36.2 %, and 27.6 % of patients, respectively. The total number of concomitant antiseizure medications was reduced by ≥1 in 29.4 % of patients. No differences were found between DS and LGS patients in these outcomes; age at start of FFA and age at the 12-month timepoint did not have an effect. At least one AE was experienced by 59.7% of patients; in 86.5% of the cases, AEs were plausibly related to treatment. While 70.3% of AEs were self-resolving and 81.8% of the remaining patients experienced mild AEs, 1 patient experienced a serious AE unrelated to FFA which resulted in the patient's death. There were no cases of pulmonary arterial hypertension or ventricular heart disease. SIGNIFICANCE: The effectiveness and tolerability of FFA treatment in patients with DS or LGS in this retrospective analysis of real-world data were consistent with those seen in randomized clinical trials.

Caregiver-reported outcomes with real-world use of cannabidiol in Lennox-Gastaut syndrome and Dravet syndrome from the BECOME survey.

PURPOSE: Plant-derived highly purified cannabidiol (CBD) reduced the frequency of seizures associated with Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) and improved the overall condition of patients in placebo-controlled phase 3 clinical trials. Anecdotal reports also suggest a positive effect on nonseizure outcomes. In this study, we aimed to identify, through a caregiver survey which nonseizure outcomes were most likely to change in these patients. METHODS: The BEhavior, COgnition, and More with Epidiolex® (BECOME) was a 20-minute, cross-sectional, online survey that was developed with extensive input from caregivers, healthcare professionals, and epilepsy researchers, and was based on questions from validated measures and previously published caregiver reports. US-based caregivers (from Jazz Pharmaceuticals patient/caregiver database) of people with LGS or DS who were treated with CBD (Epidiolex®, 100 mg/mL oral solution) for ≥3 months were asked to compare the past month to the period before CBD initiation and rate their impression of changes using symmetrical Likert scales. RESULTS: A total of 498 caregivers (97% parents) of patients with LGS (80%) or DS (20%) completed the survey. Mean (range) age of patients was 16 (1-73) years, and 52% were male. Patients were taking a median CBD dose of 14 mg/kg/d and median 4 concomitant antiseizure medications. A large proportion of respondents reported improvements in ≥1 survey question for all nonseizure-related domains: alertness, cognition, and executive function (85%); emotional functioning (82%); language and communication (79% in nonverbal patients and 74% in verbal); activities of daily living (51%); sleep (51%); and physical functioning (46%). Respondents reported improvements in seizure-related domains, including overall seizure frequency (85%), overall seizure severity (76%), seizure-free days per week for ≥1 seizure type (67%), and seizure freedom during the past month (16%). The majority of respondents who reported reduction in seizure frequency also reported improvements in nonseizure outcomes domains (51-80%). However, improvements in nonseizure outcomes (18-56%) were also reported in patients who either had no change or worsening of seizure frequency. CONCLUSIONS: This survey characterized and quantified caregiver impression of changes in the seizure and nonseizure outcomes in patients taking add-on CBD treatment. Overall, 93% of caregivers reported planning to continue CBD treatment, primarily because of reduced seizure burden but also because of improvements in nonseizure-related outcomes. Despite the limitations that are associated with a retrospective survey-based study design, these results support further evaluation of the effect of CBD treatment on nonseizure outcomes among patients with LGS or DS.

Real-Life Experience With Purified Cannabidiol Treatment for Refractory Epilepsy: A Multicenter Retrospective Study.

BACKGROUND: Drug-resistant epilepsy (DRE) affects the development and quality of life of children and young adults. We analyzed the effectiveness and safety of purified CBD in this population. METHODS: A retrospective analysis of medical records of 139 children and young adults (54.7% female, median age 12.0 years) with DRE treated with purified CBD from 2018 to 2022 at five medical centers in Israel. RESULTS: The most common diagnosis was Lennox-Gastaut syndrome (37.4%) followed by Dravet syndrome (16.5%) and tuberous sclerosis complex (16.5%). Median purified CBD dose was 12.5 mg/kg (range 2.5 to 20.0), and median treatment duration was 9.0 months (range 0.5 to 48.0). Most patients (92.2%) had a reduced seizure frequency following treatment initiation; 41.1% had >50% reduction. Fifty-three patients (38.1%) had positive effects: improved alertness (31.7%), improved speech (10.1%), and achievement of new developmental milestones (2.2%). A multivariate linear model assessing predictive factors for seizure reduction demonstrated that patients previously treated with CBD oils, especially those with >50% seizure reduction on prior treatment, were also more likely to have a reduced seizure frequency while they were treated with purified CBD (P = 0.01, P < 0.0001). Development, diagnosis, age, purified CBD dose (0 to 10 mg/kg/day vs 10 to 20 mg/kg/day), and concomitant treatment with clobazam, valproic acid, or everolimus did not affect seizure reduction by purified CBD. The most common adverse events were irritability (20.9%) and drowsiness (12.9%). CONCLUSION: Purified CBD is well-tolerated and effective in reducing seizure frequency in children and young adults with DRE.

Real-world evidence on the use of cannabidiol for the treatment of drug resistant epilepsy not related to Lennox-Gastaut syndrome, Dravet syndrome or Tuberous Sclerosis Complex.

INTRODUCTION: 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. MATERIALS AND METHODS: 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. RESULTS: 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%. CONCLUSIONS: 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.

Lennox-Gastaut syndrome characterized by super-refractory status epilepticus treated with high-dose anesthetics: A case report.

RATIONALE: Super-refractory status epilepticus is a serious illness with high morbidity and mortality, which is defined as an SE that continues or recurs 24 hours or more after the onset of anesthesia. Anesthetic agents can be either pro-convulsant or anticonvulsant or both. PATIENT CONCERNS: Epilepsy occurred at the age of 3 years. At the age of 4 years, generalized tonic-clonic seizure occurred for the first time. The patient was hospitalized at the age of 27 and 28 years for treating status epilepticus. At the age of 33 years, antiepileptic drugs were stopped due to poor appetite. In an early morning, the patient was found delirious with reduced speech. DIAGNOSIS: Occasionally, the patient blinked his eyelids, or deflected his eyeballs to 1 side. When propofol was lowered to 10 mL/H, the epileptic wave reduced obviously. Afterwards, the patient opened his eyes autonomously and his consciousness gradually recovered. The patient could answer questions, and the limbs had voluntary movements. The patient breathing also gradually recovered, and his urine gradually returned to pale yellow from green. After anesthetic was stopped for 10 days, the patient lost his consciousness again. The patient eyes turned upward frequently, which was relieved in 1 to 2 seconds with an attack once every 2 to 5 minutes. INTERVENTIONS: Clonazepam was gradually reduced to 2 mg qn, and the patient gradually woke up during this process. The patient was also treated with levetiracetam 1.5 g bid, oxcarbazepine 0.6 g bid, topiramate 50 mg bid and valproate 0.4 g tid. OUTCOMES: After 1 month follow-up, status epilepticus did not appear again. LESSONS: Propofol aggravated the tonic seizures. As tonic seizures occur during natural sleep and after sleep induced by various narcotic drugs, the decrease of consciousness level induced by excessive sedation of narcotic drugs has been suggested as the reason for poor seizure control.

Caregivers' Perspectives on the Impact of Cannabidiol (CBD) Treatment for Dravet and Lennox-Gastaut Syndromes: A Multinational Qualitative Study.

OBJECTIVE: To increase understanding of the impact of cannabidiol (CBD) on outcomes beyond seizure control among individuals with Dravet syndrome or Lennox-Gastaut syndrome. METHODS: 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. RESULTS: 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. CONCLUSION: In addition to reduced seizure frequency, CBD may have a wide range of beneficial effects beyond seizure control that warrant further investigation.

Safety of Diazepam Nasal Spray in Pediatric Patients With Developmental Epileptic Encephalopathies: Results From a Long-term Phase 3 Safety Study.

Pediatric developmental epileptic encephalopathies are often refractory to treatment despite stable antiseizure therapy. The safety profile of diazepam nasal spray (Valtoco) as rescue therapy for seizure clusters was described in a long-term safety study. This post hoc analysis assessed safety and effectiveness within a subpopulation of patients with developmental epileptic encephalopathies. Of 163 treated patients, 64 were diagnosed with ≥1 pediatric developmental epileptic encephalopathy. Among the most common developmental epileptic encephalopathies were Rett syndrome (n = 16), Lennox-Gastaut syndrome (n = 9), and Dravet syndrome (n = 7). In the broad pediatric developmental epileptic encephalopathy group, 10.6% of seizure clusters were treated with a second dose, with similar proportions in the 3 individual encephalopathies. Across groups, treatment-emergent adverse event rates ranged from 66.7% to 100%. Only epistaxis (n = 2) was treatment-related and reported in >1 patient. In this long-term safety analysis in patients with developmental epileptic encephalopathies, diazepam nasal spray demonstrated a consistent safety profile, supporting its use in these hard-to-treat patients (ClinicalTrials.gov NCT02721069).

Proposed anti-seizure medication combinations with rufinamide in the treatment of Lennox-Gastaut syndrome: Narrative review and expert opinion.

Lennox-Gastaut syndrome (LGS) is a severe, chronic, complex form of early childhood-onset epilepsy characterized by multiple seizure types, generalized slow (≤2.5 Hz) spike-and-wave activity and other electroencephalography abnormalities, and cognitive impairment. A key treatment goal is early seizure control, and several anti-seizure medications (ASMs) are available. Due to the low success rate in achieving seizure control with monotherapy and an absence of efficacy data supporting any particular combination of ASMs for treating LGS, a rational approach to selection of appropriate polytherapy should be applied to maximize benefit to patients. Such "rational polytherapy" involves consideration of factors including safety (including boxed warnings), potential drug-drug interactions, and complementary mechanisms of action. Based on the authors' clinical experience, rufinamide offers a well-considered first adjunctive therapy for LGS, particularly in combination with clobazam and other newer agents for LGS, and may be particularly useful for reducing the frequency of tonic-atonic seizures associated with LGS.

Fenfluramine: A Review in Dravet and Lennox-Gastaut Syndromes.

Fenfluramine (Fintepla®) is an oral anti-seizure medication (ASM) with a novel mechanism of action consisting of activity in the serotonergic system coupled with positive allosteric modulation effects at sigma-1 receptors. Originally approved for use at high doses as an appetite suppressant, it was subsequently withdrawn after being linked to valvular heart disease (VHD) and pulmonary arterial hypertension (PAH), before being investigated for use at low doses as an adjunctive ASM in patients with developmental epileptic encephalopathies, including Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) who have pharmacoresistant seizures. In clinical trials, treatment with adjunctive fenfluramine markedly reduced convulsive seizure frequency in patients with DS that were sustained for up to 3 years, and reduced drop seizure frequency in patients with LGS that were sustained for up to 1 year. Notably, fenfluramine was also associated with clinically meaningful improvements in aspects of everyday executive functioning (EF) not entirely explainable by seizure reduction alone. Furthermore, it was generally well tolerated with, importantly, no reports of VHD or PAH. Thus, adjunctive fenfluramine is a novel and effective treatment for pharmacoresistant seizures associated with DS and LGS that may also improve aspects of everyday EF in some patients.

Emerging in infancy and childhood, respectively, Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) are severe developmental and epileptic encephalopathies. They are characterized by seizures that are frequently 'pharmacoresistant' [i.e. cannot be controlled by ≥ 2 anti-seizure medications (ASMs)] and that, along with cognitive and behavioural comorbidities, can have a major impact on the quality of life of patients (and their caregivers/family members) as they grow. Fenfluramine (Fintepla^®) is an oral ASM with a distinctive dual mechanism of action, that is used at low doses. In clinical trials in patients with DS or LGS, adding fenfluramine to the existing ASM regimen produced significant and sustained reductions in pharmacoresistant seizures and was associated with clinically meaningful improvements in aspects of everyday executive functioning (EF; i.e. the ability to regulate cognition, emotions and/or behaviour). Importantly, there was no evidence of the heart complications previously observed with the use of high doses of fenfluramine as an appetite suppressant. Adjunctive fenfluramine is an effective and generally well-tolerated treatment for pharmacoresistant seizures associated with DS and LGS that may also improve aspects of everyday EF in some patients.

Retrospective chart review study of use of cannabidiol (CBD) independent of concomitant clobazam use in patients with Lennox-Gastaut syndrome or Dravet syndrome.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: Results support favorable effectiveness and retention of CBD without concomitant clobazam for up to 12 months in clinical practice.

Current and emerging pharmacotherapy for the treatment of Lennox-Gastaut syndrome.

INTRODUCTION: Lennox-Gastaut syndrome (LGS) is a severe childhood-onset epileptic encephalopathy, characterized by multiple seizure types, generalized slow spike-and-wave complexes in the EEG, and cognitive impairment. Seizures in LGS are typically resistant to treatment with antiseizure medications (ASMs). Tonic/atonic ('drop') seizures are of particular concern, due to their liability to cause physical injury. AREAS COVERED: We summarize evidence for current and emerging ASMs for the treatment of seizures in LGS. The review focuses on findings from randomized, double-blind, placebo-controlled trials (RDBCTs). For ASMs for which no double-blind trials were identified, lower quality evidence was considered. Novel pharmacological agents currently undergoing investigation for the treatment of LGS are also briefly discussed. EXPERT OPINION: Evidence from RDBCTs supports the use of cannabidiol, clobazam, felbamate, fenfluramine, lamotrigine, rufinamide, and topiramate as adjunct treatments for drop seizures. Percentage decreases in drop seizure frequency ranged from 68.3% with high-dose clobazam to 14.8% with topiramate. Valproate continues to be considered the first-line treatment, despite the absence of RDBCTs specifically in LGS. Most individuals with LGS will require treatment with multiple ASMs. Treatment decisions should be individualized and take into account adverse effects, comorbidities, general quality of life, and drug interactions, as well as individual efficacy.

Cannabidiol as an adjuvant treatment in adults with drug-resistant focal epilepsy.

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.

Efficacy analysis of oral dexamethasone in the treatment of infantile spasms and infantile spasms related Lennox-Gastaut syndrome.

OBJECTIVE: Treatment with adrenocorticotropic hormone (ACTH) or a corticosteroid is the first choice for infantile spasms (IS), and vigabatrin is the first choice for children with tuberous sclerosis. Although corticosteroids may be also effective against IS and IS-related Lennox-Gastaut syndrome (LGS), the use of dexamethasone (DEX), a kind of corticosteroid, for these diseases has been rarely reported. This retrospective study aimed to evaluate the efficacy and tolerability of DEX for the treatment of IS and IS-related LGS. METHODS: Patients diagnosed as having IS (including patients whose condition evolved to LGS after the failure of early treatment) in our hospital between May 2009 and June 2019 were treated with dexamethasone after failure of prednisone treatment. The oral dose of DEX was 0.15-0.3 mg/kg/d. Thereafter, the clinical efficacy, electroencephalogram (EEG) findings, and adverse effects were observed every 4-12 weeks depending on the individual patient's response. Then, the efficacy and safety of DEX in the treatment of IS and IS-related LGS were retrospectively evaluated. RESULTS: Among 51 patients (35 cases of IS; 16 cases of IS-related LGS), 35 cases (68.63%) were identified as responders to DEX treatment, comprising 20 cases (39.22%) and 15 cases (29.41%) with complete control and obvious control, respectively. To discuss the syndromes individually, complete control and obvious control were achieved in 14/35 and 9/35 IS cases and in 6/16 and 6/16 IS-related LGS cases, respectively. During DEX withdrawal, 11 of the 20 patients with complete control relapsed (9/14 IS; 2/6 LGS). The duration of dexamethasone treatment (including weaning) in most of the 35 responders was less than 1 year. However, 5 patients were treated with prolonged, low-dose maintenance therapy, which continued for more than 1.5 years. These 5 patients showed complete control, and 3 patients had no recurrence. Except for one child who died of recurrent asthma and epileptic status 3 months after stopping DEX, there were no serious or life-threatening adverse effects during DEX treatment. CONCLUSION: Oral DEX is effective and tolerable for IS and IS-related LGS. all LGS patients were evolved from IS in this study. The conclusion may not apply to patients with other etiology and courses of LGS. Even when prednisone or ACTH is failed, DEX may still be considered as a treatment option. For children who respond to DEX but do not show complete control after 6 months of treatment, prolonged treatment with low-dose DEX administered in the morning might be considered.

Cannabidiol use in patients with Dravet syndrome and Lennox-Gastaut syndrome: experts' opinions using a nominal group technique (NGT) approach.

BACKGROUND: 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. AIM: 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. METHODS: 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. RESULTS: The use of a pharmaceutical CBD is considered preferable to galenic formulations, in terms of reproducibility, safety, and control of the delivered dose. CONCLUSION: 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.

Seizure-free days as a novel outcome in patients with Lennox-Gastaut syndrome: Post hoc analysis of patients receiving cannabidiol in two randomized controlled trials.

OBJECTIVE: 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). METHODS: 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. RESULTS: 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. SIGNIFICANCE: Drop and total seizure-free days represent potential new and clinically meaningful endpoints for future RCTs in patients with LGS.

Highly purified cannabidiol improves stability and postural tone in adult patients with Lennox-Gastaut syndrome: A case series.

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.