A. Key points from the clinical management of DRE
1. Failure of two appropriate and tolerated treatments reduces but does not preclude seizure freedom in response to a different antiseizure medication.
2. Some epilepsies or etiologies are drug resistant from the start or do not have treatments leading to seizure freedom and are therefore not addressed by the current DRE definition.
3. Earlier diagnosis of resistance to a drug or of DRE, before the failure of two appropriate and tolerated treatments, could accelerate decisions to direct care to more effective treatment choices, when these are available.
4. Clinical assessments of treatment response are not absolute and may be confounded by the natural history of epilepsy or comorbidities, or other pharmacological or contextual factors influencing target relevance or modification by the drug.
5. “Appropriate treatment” is usually extrapolated by data from responses of populations with similar seizure types and may not necessarily be effective for a given individual with such seizures or across etiologies.
6. The efficacy of a treatment in a patient may change over time, as diverse factors that control the biological effects of a drug may change.
7. The current DRE definition relies on seizure freedom as readout of success which is a delayed endpoint; search for tools to monitor earlier effects on the epileptogenic substrate that predict treatment response might accelerate the diagnosis of DRE.
8. Treatments with incomplete efficacy on seizures may still be useful in improving quality of life or informing on future successful combination treatments.
B. Framework for future research on DRE
1. Further research on the multifactorial mechanisms of DRE is needed to expand current knowledge, on: (a) drug pharmacokinetics-pharmacodynamics, (b) transport and access to brain targets, (c) effects on drug targets, networks and off target sites, (d) genetic and epigenetic mechanisms, (e) other co-occurring biological processes or medical conditions, (f) exogenous or environmental factors.
2. Better define appropriate and effective treatments for a person with epilepsy at early stages after diagnosis, so as to inform and accelerate treatment decisions.
3. Define and monitor the biological substrates and biomarkers of drug response and drug resistance for a given individual with epilepsy, to enable early prediction of treatment response.
4. Determine patterns of DRE and critical windows for interventions to maximize therapeutic effects and prevent adverse consequences (cognitive, SUDEP, etc) for DRE across the lifespan.
5. Develop treatments targeting drug resistance substrates that are also effective in the context of specific epileptogenic processes.