Authors :
Presenting Author: Katie Angione, MS, CGC – University of Colorado
Megan Abbott, MD – University of Colorado; Andrea Miele, PhD, ABPP-CN – Pediatrics, Neurology – University of Colorado; Megan Stringfellow, BS – Pediatrics, Neurology – University of Colorado; Lacie Taylor, DO, MS – Rocky Vista University; Kourtney Santucci, MD – Pediatrics, Special Care – University of Colorado; Kristina Malik, MD – Pediatrics, Special Care – University of Colorado; Kilby Mann, MD – Physical Medicine and Rehabilitation – University of Colorado; Ann Reynolds, MD – Pediatrics, Developmental Pediatrics – University of Colorado; Lauren Treat, MD – Pediatrics, Palliative Medicine – University of Colorado; Tristen Dinkel, MSPC, BSN – Children's Hospital Colorado; Margarita Saenz, MD – Pediatrics, Genetics – University of Colorado; Scott Demarest, MD, MSCS – Pediatrics, Neurology – University of Colorado
Rationale:
Gene therapies are on the horizon for a number of Developmental and Epileptic Encephalopathies (DEEs); however, clinical trial readiness is dependent on reliable assessment of the efficacy of potential treatments. DEEs often lack appropriate outcome measures aside from seizure frequency. We piloted the use of both a clinician and caregiver-reported clinical severity assessment previously developed for CDKL5 Deficiency Disorder (CDKL5 Clinical Severity Assessment [CCSA]) on four populations housed within a neurogenetic multidisciplinary clinic: STXBP1, SLC6A1, Ring 14, and chromosome 8p-related disorders. Methods:
The CCSA includes both clinician and caregiver reported outcome measures. The clinician-reported CCSA covers three domains: Communication, Vision, and Motor. The caregiver-reported CCSA covers four domains: Seizures, Behavior, Alertness, and Autonomic. While initially developed for CDKL5 Deficiency Disorder, these measures were piloted by a trained assessor for the other DEEs served by our clinic. Scores for each item ranged from 0-100, with 100 being the most severe impairment. Results were recorded in a secure REDCap database. Descriptive statistical analysis was performed on the group as a whole and each disorder sub-group.Results:
Clinician CCSAs were completed on 17 patients with 8p, 13 with STXBP1, four with Ring 14, and three with SLC6A1. Mean total scores for the clinician CCSA were: SLC6A1: 19.34, 8p: 27.67, STXBP1: 32.25, Ring 14: 32.35. SLC6A1 had the lowest domain score means (Communication: 17.5, Vision: 0, Motor: 19.37), indicating possibly milder impairments. Many scores had large ranges, such as the 8p communication subdomain (6.25-46.25), suggesting a broad clinical spectrum. Others had narrow ranges, such as the Ring 14 motor subdomain (29.05-45.71).
Of those patients with Clinician CCSAs, Caregiver CCSAs were completed for 10 patients with 8p, eight with STXBP1, three with Ring 14, and two with SLC6A1. Mean total score for the caregiver CCSA were as follows: 8p: 15.70, STXBP1: 22.44, Ring 14: 30.77, SLC6A1: 24.41. The total mean score for SLC6A1 was higher for the caregiver measure when compared to the clinician measure, likely due to a high behavior subdomain score on the caregiver reports (mean: 57.5). Seizure subdomain score means varied widely amongst conditions (8p: 6.14, STXBP1: 11.00, Ring 14: 23.21, SLC6A1: 2.5).
Conclusions:
Clinician and caregiver-reported outcome measures for DEEs will be crucial moving forward as new gene therapy clinical trials are initiated. Many components of the CCSA seem to capture a broad range of severity both across disorders and within individual conditions. These measures may be able to distinguish between disorders by capturing relative severity of subdomains. Other subdomains have similar scores across conditions as well as within a disorder. This could indicate these items are less sensitive at representing change across a spectrum of phenotypes, or that there is a common severity of these features. Further investigation with larger cohorts is required to understand the potential and limitations of these measures for DEEs. Funding:
Research was supported by Project 8P, SLC6A1 Connect, Ring 14 USA, and STXBP1 Foundation.