Benchmarks to Breakthroughs: How the 2007 Epilepsy Research Benchmarks Reframed Scientific and Clinical Trajectories of 21st-Century Epilepsy Care

At the dawn of the 21st century, a group of patient advocates, scientists, and healthcare providers gathered in Washington, D.C. In the shadows of Y2 K, a booming Dot-com bubble, and with N'Sync's latest hit undoubtedly blaring on taxicab radios enroute to the meeting, this event coalesced key stakeholders to set forth an ambitious goal: “no seizures, no side effects, and the prevention of epilepsy in those at risk.” This was the first of what would become a roughly septennial conference. A conference driven by optimism and hope; hope for innovation, hope for progress, hope for a cure. It represented a discrete generational shift in epilepsy research strategy—the focus transitioned from symptomatic treatments to curative approaches. The resulting “Benchmarks,” the tangible outcomes of this meeting (https://www.ninds.nih.gov/about-ninds/what-we-do/strategic-plans-evaluations/strategic-plans/benchmarks-epilepsy-research), have transformed into something that now, 25 years later, represents a critical moment in epilepsy history. Seemingly in the dark ages—prior to the human genome project's initial release in 2001 and without any glimmer of CRISPR/Cas9 gene editing capabilities—this meeting laid forth a trailblazing road map of key research and clinical development priorities for the 21st century. And the field has largely answered this call.

The National Institute of Neurological Disorders and Stroke (NINDS) has sponsored a Curing Epilepsy conference in 2000, 2007, 2013, and again in 2021 (delayed due to the COVID-19 pandemic). The 2007 meeting, entitled “Translating Discoveries into Therapies,” and summary, ¹ provides historical context to illustrate just how far the field has come in a quarter century. A major deliverable from these conferences has been the Epilepsy Research Benchmarks, which reflect the key epilepsy research priorities for the ensuing 5 to 7 years. At each conference, research progress against goals is assessed, and new milestones established for the next 5 to 7 years. In short, this conference serves as a way for the field to routinely assess and gauge progress, ensure efficient use of federal and foundation resources, and convey progress to patients and advocates. Few other chronic neurological diseases have such a tight-knit community striving continuously to innovate, and few other diseases have a community that has made such remarkable progress towards disease-modifying treatments in such a short time. ² With a changing funding landscape, it is important to highlight how instrumental this conference and the Epilepsy Research Benchmarks have been toward the goal of curing epilepsy, and just how prescient those pioneers were in March 2000.

The NINDS has made visionary contributions to epilepsy in the 25 years since the first Curing Epilepsy conference. Its flagship program—the Anticonvulsant Screening Program (rebranded in 2016 to the Epilepsy Therapy Screening Program [ETSP])—offers a resource to implement the core Benchmarks objectives, including Benchmark II—Develop new therapeutic strategies and optimize current approaches to cure epilepsy. Established in 1975, the ETSP provides a contract testing site at the University of Utah ³ that has repeatedly delivered on its original intention: identify impactful small molecule treatments for people with epilepsy. Moreover, the ETSP offers a dedicated resource to rigorously assess new molecular targets and derisk novel compounds, thereby accelerating potential treatments to first-in-human trials. Each iteration of the Benchmarks shifted ETSP priorities and approaches, including integrating rodent comorbidity models,^4,5 prioritizing pharmacoresistant epilepsy treatment discovery,^3,6 generating a public database on nonproprietary structure response data (NINDS PANAChE database—https://panache.ninds.nih.gov/Compound),^1,3 and developing rare epilepsies screening platforms. ⁷ Over 9 marketed small molecule antiseizure medicines owe their origins to the research staff on the Wasatch Front in Utah,^3,6 a testament to the tangible impact that public investment can have on individual patients. Without the Benchmarks calling for the discovery of novel molecular targets, improvements in epilepsy genetics, and refined animal models to reproduce the many clinical facets by which epilepsy arises, it is unlikely that the wealth of compounds in the preclinical pipeline would exist today.

These Benchmarks have also challenged the field to routinely reassess critical unmet needs for people with epilepsy. Reviewing the 2007 Benchmarks ¹ while drafting this commentary in November 2025, the authors were struck by the numerous successes that have occurred in just a generation. For example, the 2007 Curing Epilepsy meeting and Benchmarks reframed our understanding of the cognitive comorbidities surrounding epilepsy, encouraging care beyond simply treating the symptomatic seizures. ¹ These 2007 Benchmarks gave us greater insight into the constellation of neuropsychiatric symptoms associated with epilepsy. ⁸ It helped advance new animal models to understand the mechanistic basis of these comorbidities ⁹ and improved clinical management. ¹⁰ Comorbidity research has expanded dramatically, reflecting Benchmark III's emphasis on overall outcomes rather than merely symptom control. Large studies have characterized cognitive, psychiatric, and behavioral trajectories across epilepsies, revealing that comorbidities often arise from shared neurobiological mechanisms rather than secondary consequences. Integration of neuropsychology, quality-of-life measures, and behavioral assessments into the NINDS clinical Common Data Elements (CDEs) framework has standardized measurement and enabled multicenter comorbidity research, strengthening the shift toward comprehensive patient-centered care. Methodological modernization further advanced Benchmark II. Contemporaneous efforts evaluating electronic seizure diaries demonstrated advantages in reliability, adherence, time-stamping, and real-time data access. As digital platforms integrate with sensors and electronic health records, they will enhance trial rigor and expand real-world evidence. Further, we can now increase preclinical data harmonization because of the preclinical CDEs that were modeled after these clinical CDEs. ¹¹

The clinical developments since 2007 to address Benchmark I—Prevent epilepsy and its progression—have been especially impactful. Neuroimaging innovations—including high-resolution structural MRI, quantitative MRI, and machine learning–assisted lesion detection—now reveal subtle cortical dysplasias and network disruptions previously undetected on conventional scans. PET ligands and advanced MRI sequences provide insight into neuroinflammatory processes within an epileptogenic cortex, strengthening mechanistic links between immune pathways, gliosis, and epileptogenesis. These tools have also been pivotal in characterizing epileptogenesis across diverse biological states. Late-onset epilepsy- (eg, Alzheimer's disease), inflammation- (eg, infectious and autoimmune encephalitis), and neurodevelopment-related (eg, focal cortical dysplasia) brain disorders are now recognized to exhibit conserved network hyperexcitability, emphasizing that epileptogenesis arises from heterogeneous yet interconnected processes. Increasing attention to peripheral-to-central immune interactions—including systemic inflammation, blood–brain barrier dysfunction, and innate immune activation—has highlighted the importance of systemic–neuroimmune crosstalk in facilitating seizure occurrence. One of the most profoundly improved 2007 Benchmarks was Area III—Prevent, limit, and reverse the comorbidities associated with epilepsy and its treatment—section 3—sudden unexpected death in epilepsy (SUDEP). Significant progress has been made in understanding the fundamental basis of SUDEP. ¹² Real-world registries (eg, North American SUDEP Registry, U.K. Epilepsy Deaths Register, and international SUDEP Action databases) have clarified modifiable risk factors—particularly generalized tonic–clonic seizure frequency—informing patient counseling and preventive strategies. Enhanced nocturnal monitoring, wearable cardiorespiratory devices, and sleep-related biomarkers represent meaningful translation toward real-world SUDEP risk mitigation. Altogether, the 2007 Benchmarks provided multifaceted guidance to meaningfully prevent epilepsy and its progression.

As mid-career investigators ourselves, much of this progress occurred first through the efforts of our mentors and colleagues, but now with our trainees. The first epilepsy conference that Dr Barker-Haliski attended was the 2013 Curing Epilepsy meeting, and both our professional careers have been molded by these leaders and the original 2000 and 2007 Benchmarks. It is likely that the next 25 years will lead to as transformational of a shift as has occurred in the last 25 years. An increasingly connected planet means that the influence of these Benchmarks now extends across the globe. Many countries have developed tiered epilepsy-care networks linking comprehensive tertiary centers with regional and community sites (eg, China), improving referral pathways and access. International adoption of CDEs, global SUDEP registries, and multinational consortia (eg, Epi4 K) foster data harmonization, shared outcomes, and collaborative translational pipelines. These efforts reflect an increasingly interconnected global epilepsy research ecosystem focused on shared goals, progressively improving the Benchmarks on a regular basis and building on the impact of that small group of trailblazers who came together in March 2000.