Severity Assessment in CDKL5 Deficiency Disorder.

BACKGROUND: Pathologic mutations in cyclin-dependent kinase-like 5 cause CDKL5 deficiency disorder, a genetic syndrome associated with severe epilepsy and cognitive, motor, visual, and autonomic disturbances. This disorder is a relatively common genetic cause of early-life epilepsy. A specific severity assessment is lacking, required to monitor the clinical course and needed to define the natural history and for clinical trial readiness. METHODS: A severity assessment was developed based on clinical and research experience from the International Foundation for CDKL5 Research Centers of Excellence consortium and the National Institutes of Health Rett and Rett-Related Disorders Natural History Study consortium. An initial draft severity assessment was presented and reviewed at the annual CDKL5 Forum meeting (Boston, 2017). Subsequently it was iterated through four cycles of a modified Delphi process by a group of clinicians, researchers, industry, patient advisory groups, and parents familiar with this disorder until consensus was achieved. The revised version of the severity assessment was presented for review, comment, and piloting to families at the International Foundation for CDKL5 Research-sponsored family meeting (Colorado, 2018). Final revisions were based on this additional input. RESULTS: The final severity assessment comprised 51 items that comprehensively describe domains of epilepsy; motor; cognition, behavior, vision, and speech; and autonomic functions. Parental ratings of therapy effectiveness and child and family functioning are also included. CONCLUSIONS: A severity assessment was rapidly developed with input from multiple stakeholders. Refinement through ongoing validation is required for future clinical trials. The consensus methods employed for the development of severity assessment may be applicable to similar rare disorders.

CMR imaging with rapid visual T1 assessment predicts mortality in patients suspected of cardiac amyloidosis.

OBJECTIVES: This study tested the diagnostic and prognostic utility of a rapid, visual T1 assessment method for identification of cardiac amyloidosis (CA) in a "real-life" referral population undergoing cardiac magnetic resonance for suspected CA. BACKGROUND: In patients with confirmed CA, delayed-enhancement cardiac magnetic resonance (DE-CMR) frequently shows a diffuse, global hyperenhancement (HE) pattern. However, imaging is often technically challenging, and the prognostic significance of diffuse HE is unclear. METHODS: Ninety consecutive patients referred for suspected CA and 64 hypertensive patients with left ventricular hypertrophy (LVH) were prospectively enrolled and underwent a modified DE-CMR protocol. After gadolinium administration a method for rapid, visual T1 assessment was used to identify the presence of diffuse HE during the scan, allowing immediate optimization of settings for the conventional DE-CMR that followed. The primary endpoint was all-cause mortality. RESULTS: Among patients with suspected CA, 66% (59 of 90) demonstrated HE, with 81% (48 of 59) of these meeting pre-specified visual T1 assessment criteria for diffuse HE. Among hypertensive LVH patients, 6% (4 of 64) had HE, with none having diffuse HE. During 29 months of follow-up (interquartile range: 12 to 44 months), there were 50 (56%) deaths in patients with suspected CA and 4 (6%) in patients with hypertensive LVH. Multivariable analysis demonstrated that the presence of diffuse HE was the most important predictor of death in the group with suspected CA (hazard ratio: 5.5, 95% confidence interval: 2.7 to 11.0; p < 0.0001) and in the population as a whole (hazard ratio: 6.0, 95% confidence interval 3.0 to 12.1; p < 0.0001). Among 25 patients with myocardial histology obtained during follow-up, the sensitivity, specificity, and accuracy of diffuse HE in the diagnosis of CA were 93%, 70%, and 84%, respectively. CONCLUSIONS: Among patients suspected of CA, the presence of diffuse HE by visual T1 assessment accurately identifies patients with histologically-proven CA and is a strong predictor of mortality.

A checklist for medication compliance and persistence studies using retrospective databases.

The increasing number of retrospective database studies related to medication compliance and persistence (C&P), and the inherent variability within each, has created a need for improvement in the quality and consistency of medication C&P research. This article stems from the International Society of Pharmacoeconomics and Outcomes Research (ISPOR) efforts to develop a checklist of items that should be either included, or at least considered, when a retrospective database analysis of medication compliance or persistence is undertaken. This consensus document outlines a systematic approach to designing or reviewing retrospective database studies of medication C&P. Included in this article are discussions on data sources, measures of C&P, results reporting, and even conflict of interests. If followed, this checklist should improve the consistency and quality of C&P analyses, which in turn will help providers and payers understand the impact of C&P on health outcomes.