• We suggest the epilepsy field make concerted efforts to specifically apply BRAIN Initiative discoveries towards the epilepsies.
• Grand Challenge idea: Precision diagnosis – right now there are a large number of people with epilepsy with an unknown cause. This means that our understanding of the phenotypes that we currently associate with a specific etiology (such as genetic) may be skewed to only the most severe phenotypes, which are often also the most rare, and therefore understudied. A grand challenge is to develop ways to rapidly diagnose an epilepsy etiology—whether that is genetic, infectious, autoimmune, etc. – for every person so that the full spectrum of phenotypes associated with those etiologies can be determined. This foundational project has the potential to impact basic science, clinical development, and clinical care in the epilepsies.
Basic Science opportunities related to Precision Diagnosis
• Understand the mechanistic rationale(s) for the large phenotypic variability within an etiology (for examples, phenotypic spectrum associated with TSC1 and TSC2 mutations, or SCN1A causing both Dravet and GEFS+).
• Map convergent pathways that are involved in multiple specific causes (for example, the mTORopathies) that provide a new way to classify the epilepsies by molecular etiology rather than by seizure type, epilepsy syndrome, or individual etiologies
• Relate molecular etiology to seizure network activity
Clinical development opportunities related to "Etiology for Everyone"
• Expand current interests in biotech/pharma industry toward development for an indication across multiple epilepsy syndromes that share a convergent molecular pathway can lead to more effective, rational therapies with larger market share (going from narrow indications to broad indications).
• Identify the next-generation assays useful in screening for candidate therapeutics (going beyond immediate impacts on synaptic excitability)
• Develop animal models that better represent a range of phenotypic impacts
• Re-design clinical trials to enroll larger numbers of participants with more homogeneous molecular basis for epilepsy
Clinical care opportunities related to Precision Diagnosis
• Rapid determination of etiology is likely to reduce time to accurate diagnosis and appropriate treatment, leading to improved outcomes
• Establishing large populations of patient with confirmed molecular etiology will enable more rapid recruitment into clinical trials for rational therapies.
• Offers the opportunity to identify individuals with a potentially progressive course (such as Lafora Disease presenting as JME, or Dravet Syndrome presenting with febrile seizures, or early identification of risk of LGS) for studies of early intervention.