Is highly purified cannabidiol a treatment opportunity for drug-resistant epilepsy in subjects with typical Rett syndrome and CDKL5 deficiency disorder?
Aglaia Vignoli 1 2, Giulia Prato 3, Enrico Alfei 4, Irene Bagnasco 5, Alberto Danieli 6, Massimiliano Celario 7 8, Jacopo Favaro 9 10, Sara Matricardi 11, Francesca Felicia Operto 12, Alessandro Orsini 13, Davide Paolo Bernasconi 14 15, Nicola Pietrafusa 16, Emilia Ricci 2 17, Luca Manfredini 18, Giulia Balletto 3, Paolo Bonanni 6, Maria Paola Canevini 2 17, Valentina De Giorgis 7 8, Lino Nobili 3, Stefano Sartori 9 10, Miriam Nella Savini 17, Ilaria Viganò 17, Nicola Specchio 16 19
- 1Childhood and Adolescence Neuropsychiatry Unit, Grande Ospedale Metropolitano Niguarda, Milan, Italy.
- 2Health Sciences Department, Università degli Studi di Milano, Milan, Italy.
- 3Unit of Child Neuropsychiatry, IRCCS Istituto Giannina Gaslini, Full Member of European Reference Network EpiCARE, Genoa, Italy.
- 4Pediatric Neurology Unit, Buzzi Children’s Hospital, Milan, Italy.
- 5Division of Child Neuropsychiatry, Martini Hospital, Torino, Italy.
- 6Epilepsy Unit, IRCCS E. Medea Scientific Institute, Conegliano, Italy.
- 7Department of Child Neurology and Psychiatry, IRCCS Mondino Foundation, Pavia, Italy.
- 8Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.
- 9Department of Women’s and Child’s Health, University of Padua, Padova, Italy.
- 10Paediatric Neurology and Neurophysiology Unit – University Hospital of Padua, Padova, Italy.
- 11Department of Pediatrics, University of Chieti, Chieti, Italy.
- 12Department of Science of Health School of Medicine, University Magna Greacia of Catanzaro, Catanzaro, Italy.
- 13Pediatric Neurology, University Hospital of Pisa, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy.
- 14Bicocca Bioinformatics Biostatistics and Bioimaging Center, School of Medicine and Surgery, University of Milano-Bicocca, Italy.
- 15Clinical Research and Innovation Unit, Grande Ospedale Metropolitano Niguarda, Milan, Italy.
- 16Neurology, Epilepsy and Movement Disorders Unit, Bambino Gesù Children’s Hospital IRCCS, Full Member of European Reference Network EpiCARE, Rome, Italy.
- 17Child Neurology Unit, Epilepsy Center, San Paolo Hospital, Member of European Reference Network EpiCARE, Milan, Italy.
- 18Paediatric Chronic Pain and Palliative Care Service, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
- 19University Hospitals KU Leuven, Leuven, Belgium.
Affiliationer
Objective: This study aimed to evaluate the efficacy and safety of adjunctive, highly purified Cannabidiol (Epidiolex®) in individuals with drug-resistant epilepsy (DRE) due to genetically determined typical Rett Syndrome (RTT) and CDKL5 Deficiency Disorder (CDD).
Methods: We recruited subjects with genetically confirmed typical RTT and CDD with drug-resistant seizures who received add-on treatment with highly purified Cannabidiol (CBD) through a national collaboration group. CBD treatment was titrated from 5 to 20 mg/kg/day; concurrent antiseizure medications (ASMs) could have been adjusted as clinically indicated.
Results: We enrolled 27 subjects (26 females), carrying a MECP2 genetic variant (14 subjects, 51.9%) or a CDKL5 genetic variant (13 subjects, 48.1%). Median age [IRQ] of individuals was 10.5 [7.9, 18.5] years. The median dose of CBD [IRQ] at last follow-up was 15 [11.12, 18.8] mg/kg/day, in association with a mean of 3 ASMs (range 2-4). The median duration of treatment was 14 [8.5, 20] months. Although not reaching a significant statistical effect, CBD reduced the incidence of seizures with respect to the baseline in 18/27 (66.6%) subjects, with 7 (25.9%) showing a seizure reduction >75%, and 11 (40.7%) >50%. The most relevant adverse events were somnolence seen in 3 subjects, irritability/agitation in 2 subjects, loss of appetite in 2 subjects, and insomnia in 1 individual. Caregivers reported an improvement in attention and reactivity in 12 subjects (44.4%), in sleep quality in 5 subjects (18.5%), and in motor aspects in 3 patients (11.1%).
Significance: CBD resulted effective in reducing seizure frequency in 66.6% of the study sample, regardless of the pathogenic variant; side effects were mild, and caregivers reported an improvement in behavioral and motor features.
Plain language summary: This study explored the use of highly purified Cannabidiol (CBD, Epidiolex®) as an add-on therapy for individuals with drug-resistant epilepsy due to Rett Syndrome (RTT) or CDKL5 Deficiency Disorder (CDD). Twenty-seven participants received CBD alongside their usual ASMs. After a median treatment duration of 14 months, 66.6% experienced fewer seizures, with some showing over 75% reduction. Side effects were generally mild, mainly sleepiness or irritability. Notably, caregivers reported improvements in attention, responsiveness, sleep, and motor function. While results were not statistically significant, they suggest CBD may benefit seizure control and quality of life in RTT and CDD patients.
