Abstracts

Rationale: Epilepsy and autism have been estimated to coexist in 20-30% of patients with either disorder. The wide prevalence and association of these two disorders suggest common genetic factors and pathway correlations along with an increased predisposition for other pathologies. Lack of evidence-based recommendations for people afflicted by both these disorders suggest that insights into the common signaling systems of both disorders is needed. The endocannabinoid system plays a key role in synaptic homeostasis and likely modulates GABAergic neurons in autism and epilepsy patients. The recent success of the compound cannabidiol (Epidiolex® from GW Pharmaceuticals) in developmental epilepsies suggests that phytocannabinoids may be a good class of compounds to search for modulators of both excitability and behavioral/cognitive phenotypes. Methods: An expanded access protocol was developed via collaboration between the University of Louisville Autism Center and GW Pharmaceuticals. Although planned for 20 subjects, an initial pilot cohort of 5 subjects (ages 6-18 years) with documented autism and epilepsy was recruited. Autism spectrum disorder (ASD) was verified via Autism Diagnostic Observation Schedule (ADOS) testing and treatment resistant epilepsy (defined as 2 or more countable seizures per month) was verified via clinical history, initial 28-day seizure diary, and sleep eeg/polysomnogram. Clinical phenotyping by a senior psychologist and research team included seizure diary, actigraphy, Children’s Sleep Habit Questionnaire, Children Behavioral Checklist, Vineland scales, Mean Length Utterance, Differential Ability Scales, Social Communication Questionnaire, ADOS Severity Score, Pervasive Developmental Disorder Behavioral Inventory (PDD-BI), and motor battery. Subjects were titrated from 1 mg/kg/day to 10mg/kg/day cannabidivarin (CBDV) (GWP42006; GW Pharmaceuticals) divided BID. Safety profiles for side effects, antiepileptic drug levels, liver function, basic metabolic panel, amylase/lipase, CBCs, ECG, and Columbia Suicide Scale were monitored. Results: ADOS severity score was an average of 8 (range 4-13) and the baseline 2 week seizure frequency was 15 (range 2-50). Safety profiles of all 5 subjects suggest that CBDV is well tolerated at 10 mg/kg/day dosing through 12 weeks. No major laboratory abnormalities were noted. Gastroesophageal reflux, aggression, and sedation were the most common adverse events upon CBDV initiation. Valproic acid and zonisamide levels were elevated in two patients with GI or behavioral side effects, which resolved with lowering of AED dosing. No subjects have withdrawn to date.  We report seizure and cognitive/behavioral data at the 8 week time point when all 5 subjects were treated with 6mg/kg/d CBDV. Two subjects are seizure free, another subject has a 70% seizure reduction, and 2 subjects have no major effects on seizure activity. Caretakers of all subjects report consistent gains in social engagement and communication regardless of seizure frequency. Initial testing at 8 weeks (dose of 6 mg/kg/day) suggest statistically significant reductions in the generalized seizure frequency (from 22 to 6 per 2 week epoch) p=0.026) and PDD-BI Autism T score (p=0.039). Suggestions of increased communication were documented by the increased Mean Length Utterance score (p=0.048). Conclusions: The initial data suggest that CBDV 10 mg/kg is well tolerated and certainly has potential as an AED in the autism/epilepsy population. Interestingly, the initial cohort suggest CBDV may impact communication, social interactions, and core autism symptoms. Our current plan is to expand our cohort and increase CBDV dosing up to 20 mg/kg/day in children 6 years of age and older. Funding: GW Pharmaceuticals