Journal
NEUROTHERAPEUTICS
Volume 18, Issue 3, Pages 1432-1444Publisher
SPRINGER
DOI: 10.1007/s13311-021-01133-3
Keywords
Natural history studies; Epilepsy; Developmental and epileptic encephalopathies; Clinical trials; Biomarkers; Clinical outcome assessments
Funding
- National Health and Medical Research Council of Australia (Centre for Research Excellence in Developmental and Epileptic Encephalopathies Diagnosis, Australian Medical Research Future Fund)
- National Health and Medical Research Council of Australia (Australian Epilepsy Research Fund)
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Developmental and epileptic encephalopathies (DEEs) are severe epileptic disorders that typically start in early childhood and can result in drug-resistant seizures, developmental delays, and cognitive impairments. Targeted therapies for specific genetic DEE phenotypes are needed to improve health outcomes. Understanding the natural history of the disorder is crucial for assessing treatment efficacy and designing clinical trials.
The developmental and epileptic encephalopathies (DEEs) are the most severe group of epilepsies. They usually begin in infancy or childhood with drug-resistant seizures, epileptiform EEG patterns, developmental slowing or regression, and cognitive impairment. DEEs have a high mortality and profound morbidity; comorbidities are common including autism spectrum disorders. With advances in genetic sequencing, over 400 genes have been implicated in DEEs, with a genetic cause now identified in over 50% patients. Each genetic DEE typically has a broad genotypic-phenotypic spectrum, based on the underlying pathophysiology. There is a pressing need to improve health outcomes by developing novel targeted therapies for specific genetic DEE phenotypes that not only improve seizure control, but also developmental outcomes and comorbidities. Clinical trial readiness relies firstly on a deep understanding of phenotype-genotype correlation and evolution of a condition over time, in order to select appropriate patients for clinical trials. Understanding the natural history of the disorder informs assessment of treatment efficacy in terms of both clinical outcome and biomarker utility. Natural history studies (NHS) provide a high quality, integrated, comprehensive approach to understanding a complex disease and underpin clinical trial design for novel therapies. NHS are pre-planned observational studies designed to track the course of a disease and identify demographic, genetic, environmental, and other variables, including biomarkers, that correlate with the disease's evolution and outcomes. Due to the rarity of individual genetic DEEs, appropriately funded high-quality DEE NHS will be required, with sustainable frameworks and equitable access to affected individuals globally.
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