Consensus panel recommendations for the optimization of EPIDIOLEX® treatment for seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex.

Following the approval of Epidiolex® (cannabidiol; CBD) for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), and tuberous sclerosis complex (TSC), healthcare professionals (HCPs) have had substantial experience in treating patients with Epidiolex. However, confusion still remains among HCPs, caregivers, and patients regarding dosing, drug interactions, safety monitoring, and differentiation between Epidiolex and nonapproved CBD products. To establish consensus recommendations for Epidiolex treatment optimization in LGS, DS, and TSC, a panel of seven HCPs with expertise in epilepsy was convened. Panelists participated in a premeeting survey based on a literature review of Epidiolex for the treatment of LGS, DS, and TSC, and survey responses were compiled for discussion. A modified Delphi method was used to assess agreement among panelists regarding recommendation statements following two rounds of discussion. Panelists identified two broad themes - overcoming barriers to initiation and optimization of treatment for seizures associated with LGS, DS, and TSC - for consensus guidelines. Accurate identification of patients with these rare epilepsies is critical for optimization of Epidiolex treatment. Providers should differentiate Epidiolex from nonapproved CBD products and set expectations for the therapeutic effect and safety/tolerability of Epidiolex. Initial target dose and titration rate should be individualized by baseline variables, prior response to antiseizure medications, and therapeutic goals. Awareness of strategies to manage adverse events and concomitant medications, including drug-drug interactions, is critical. Tracking response to the maximum tolerated dose is an important measure of effectiveness. These consensus recommendations provide real-world experience from neurology HCPs with experience in prescribing Epidiolex and can inform optimal use of Epidiolex for the treatment of seizures associated with LGS, DS, and TSC. PLAIN LANGUAGE SUMMARY: Epidiolex® (cannabidiol) is approved for treating seizures in Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex. Although healthcare professionals have experience in treating patients with Epidiolex, there is a need for better understanding of dosing, drug interactions, and safety of this drug. Therefore, a group of epilepsy experts developed guidelines for best practices in Epidiolex treatment. Two main areas were identified: overcoming barriers to starting Epidiolex and considerations related to Epidiolex dosing. Within these areas, topics, including correct disease identification, managing adverse events, and determining individualized dose, were discussed. These guidelines provide real-world experience to inform optimal Epidiolex use.

Population-based study of rare epilepsy incidence in a US urban population.

OBJECTIVE: This study was undertaken to estimate incidence of rare epilepsies and compare with literature. METHODS: We used electronic health record text search to identify children with 28 rare epilepsies in New York City (2010-2014). We estimated cumulative incidence and compared with literature. RESULTS: Eight of 28 rare epilepsies had five or more prior estimates, and our measurements were within the published range for all. The most common were infantile epileptic spasms syndrome (1 in 2920 live births), Lennox-Gastaut syndrome (1 in 9690), and seizures associated with tuberous sclerosis complex (1 in 14 300). Fifteen of 28 had fewer than five prior estimates, and of these, we provided additional estimates for early infantile developmental and epileptic encephalopathy (1 in 32 700), epilepsy with myoclonic-atonic seizures (1 in 34 100), Sturge-Weber syndrome plus seizures/epilepsy (1 in 40 900), epilepsy in infancy with migrating focal seizures (1 in 54 500), Aicardi syndrome plus seizures/epilepsy (1 in 71 600), hypothalamic hamartoma with seizures (1 in 225 000), and Rasmussen syndrome (1 in 450 000). Five of 28 rare epilepsies had no prior estimates, and of these, we provided a new estimate for developmental/epileptic encephalopathy with spike-and-wave activation in sleep and/or continuous spikes and waves during sleep (1 in 34 100). Data were limited for the remaining 12 rare epilepsies, which were all genetic epilepsies, including PCDH19, CDKL5, Alpers disease, SCN8A, KCNQ2, SCN2A, GLUT1 deficiency, Phelan-McDermid syndrome, myoclonic epilepsy with ragged-red fibers, dup15q syndrome, ring chromosome 14, and ring chromosome 20. SIGNIFICANCE: We estimated the incidence of rare epilepsies using population-based electronic health record data and literature review. More research is needed to better estimate the incidence of genetic epilepsies with nonspecific clinical features. Electronic health records may be a valuable data source for studying rare epilepsies and other rare diseases, particularly as genetic testing becomes more widely adopted.

Real-world use of the updated refractory epilepsy screening tool for Lennox-Gastaut syndrome.

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

Feasibility and safety of stereoelectroencephalography in young children.

PURPOSE: Stereoelectroencephalography (SEEG) is a diagnostic surgery that implants electrodes to identify areas of epileptic onset in patients with drug-resistant epilepsy (DRE). SEEG is effective in identifying the epileptic zone; however, placement of electrodes in very young children has been considered contraindicated due to skull thinness. The goal of this study was to evaluate if SEEG is safe and accurate in young children with thin skulls. METHODS: Four children under the age of two years old with DRE underwent SEEG to locate the region of seizure onset. Presurgical planning and placement of electrodes were performed using ROSA One Brain. Preoperative electrode plans were merged with postoperative CT scans to determine accuracy. Euclidean distance between the planned and actual trajectories was calculated using a 3D coordinate system at both the entry and target points for each electrode. RESULTS: Sixty-three electrodes were placed among four patients. Mean skull thickness at electrode entry sites was 2.34 mm. The mean difference between the planned and actual entry points was 1.12 mm, and the mean difference between the planned and actual target points was 1.73 mm. No significant correlation was observed between planned and actual target points and skull thickness (Pearson R = - 0.170). No perioperative or postoperative complications were observed. CONCLUSIONS: This study demonstrates that SEEG can be safe and accurate in children under two years of age despite thin skulls. SEEG should be considered for young children with DRE, and age and skull thickness are not definite contraindications to the surgery.