Abstracts

Rationale: Interest in the use of cannabidiol (CBD) for the management of treatment resistant epilepsy (TRE) has driven the need to evaluate its effects on seizures and brain functional networks. Resting state fMRI (rs-fMRI) studies have shown epilepsy to be a network/systems disorder. In the present study, we evaluate the effects of adjunct treatment with pharmaceutical grade cannabidiol (CBD; Epidiolex®) on rs-fMRI functional connectivity (rs-FC) in patients with TRE and the relationship between treatment and network changes when compared to healthy controls. We hypothesized that CBD may normalize rs-FC in TRE along the seizure improvements. Methods: Out of 169 patients with TRE recruited into the UAB CBD Program (www.uab.edu/cbd), 27 were able and received fMRI prior to initiation of treatment with CBD. Out of those patients, 4 had withdrawn from the study prior to the second fMRI and 1 died of SUDEP. The remaining 22 patients (8M/14F, mean age=36.2±15.9 years, mean illness duration=18.3±12.6 years) returned for a second fMRI after attaining a stable CBD dose for at least 2 weeks (13 at 25 mg/kg/day, 5 at 20 mg/kg/day, 4 at 15 mg/kg/day; mean time between fMRIs=11 weeks). Pre- and on-CBD assessments included seizure frequency (SF), Chalfont Seizure Severity Scale (CSSS), Lifetime Columbia Suicide Rating Severity Scale (C-SSRS), Adverse Events Profile (AEP), and Profile of Mood States (POMS). Functional connectivity was assessed by correlating time-courses of Automated Anatomical Labelling atlas regions. Additionally, 23 healthy controls (HC) were recruited and received the same rs-fMRI scan once and POMS. Epilepsy patients and HCs did not differ in age (p=0.99) and in sex (Chi-square = 2.07, p=0.15). Results: Patients showed overall decreased SF, with the median percent change of -71.2% total seizures/2-week period (p<0.0001); 19/22 had decreased SF from their pre- to on-CBD visit with 6/22 attaining seizure freedom. No significant differences were found between group of patients with SF reduction and groups of patients with no SF reduction in age (p=0.14), CBD dosage (p=0.56), age of onset (p=0.25), years of epilepsy (p=0.7) or pre-CBD monthly SF (p=0.62). Significant decreases were found for CSSS, AEP, and POMS confusion, depression, and fatigue sub-scores (all p<0.05). No significant changes were found for other behavioral scores. Paired t-tests showed significant changes in rs-FC from pre- to on-CBD in cerebellum, frontal areas, temporal areas, hippocampus and amygdala; some rs-FC changes were significantly correlated with behavioral score improvements (Figure 1). Additionally, significant differences in rs-FC between pre-CBD and healthy controls were found in cerebellum, frontal areas and occipital areas (see Figure 2), indicating cerebellum may play a crucial role in cognitive deficits induced by epilepsy. No significant difference was found between on-CBD and healthy controls suggesting, as hypothesized, a normalization of rs-FC in epilepsy patients associated with CBD treatment. Conclusions: In this cohort, we found that CBD induced several positive behavioral changes and significantly reduced CSSS and SF in patients with TRE and that some of those behavioral changes were significantly correlated with changes in resting-state functional connectivity between various brain regions. Further, treatment with CBD appeared to normalize previously aberrant network connectivity in TRE. This confirms the positive epilepsy outcomes with CBD and shows that CDB has an extended effect on functional brain connectivity. Funding: No funding