Northwell Study Offers Nuanced Hope for Long-Term Seizure Reduction in Chronic, Treatment-Resistant Epilepsy
For millions of individuals worldwide, epilepsy remains one of the most challenging chronic neurological disorders to manage. Although many patients achieve seizure control through medication, roughly one-third continue to experience frequent, often disabling episodes despite receiving appropriate medical care. Among these patients, those with a particularly stubborn subtype—focal treatment-resistant epilepsy (FTRE)—continue to struggle with recurrent seizures originating from a specific region of the brain, despite trying multiple anti-seizure medications and advanced treatment approaches.
A new study led by researchers at Northwell Health’s Feinstein Institutes for Medical Research, and recently published in JAMA Neurology, brings both encouragement and complexity to the conversation. The research suggests that a significant proportion of individuals with FTRE may experience a meaningful reduction in seizures over time. However, the underlying reasons for this improvement remain difficult to interpret, raising key questions about whether clinical interventions are directly responsible for these advances or whether some improvement may be attributed to the natural progression of the condition.
Understanding FTRE: A Challenging Subtype of Epilepsy
Epilepsy encompasses a wide spectrum of disorders characterized by abnormal electrical activity in the brain leading to seizures of varied frequency, severity, and duration. While many forms respond well to anti-seizure medications, FTRE is defined by persistent seizures despite optimal medical therapeutic efforts.
Patients with FTRE often try multiple drug regimens—sometimes in combination—as well as surgical interventions or implantable neuromodulation technologies. Yet, even with these advanced options, consistent seizure control remains elusive, and the condition can take a profound toll on quality of life. Individuals may face limitations in employment, education, mobility, and social independence, with many remaining at elevated risk for injury and long-term disability.
Against this backdrop, new evidence suggesting that meaningful seizure reduction is possible—even without clear, singular interventions—has the potential to reshape how clinicians and patients think about FTRE.
Inside the Human Epilepsy Project 2 (HEP2): A Longitudinal Look at FTRE
The study forms part of the Human Epilepsy Project 2 (HEP2), a longitudinal investigation designed to analyze real-world outcomes among patients with chronic, difficult-to-treat seizure disorders. HEP2 was co-led by Dr. Ruben Kuzniecky, a neurologist at Northwell’s Lenox Hill Hospital and member of The Feinstein Institutes.
The research enrolled 146 adults across the United States, all diagnosed with FTRE. What made this group particularly significant was their extensive treatment history: each participant had previously taken at least four anti-seizure medications, none of which successfully controlled their condition. This profile placed them at the severe end of treatment resistance.
Over the course of 18 months to three years, participants were closely monitored. Researchers gathered detailed data on:
- Daily seizure frequency
- Medication additions or modifications
- Use of implanted neuromodulation devices, including:
- Deep brain stimulation (DBS)
- Responsive neurostimulation (RNS)
- Vagal nerve stimulation (VNS)
This depth of monitoring enabled researchers to examine seizure trajectories over time and evaluate whether changes could be correlated with therapeutic interventions.
Key Findings: Broad Seizure Reduction, Sparse Complete Remission
The most compelling finding from the study was that nearly 70% of participants experienced a significant reduction in seizure frequency over the study period. For individuals whose lives are often disrupted by unpredictable seizure events, even moderate improvements can Epilepsy translate into more independence, fewer injuries, and greater social and emotional well-being.
However, while broad improvement was notable, sustained seizure freedom was relatively rare:
| Duration of Seizure Freedom | Percentage of Participants |
|---|---|
| 3 months | ~13% |
| 6 months | 7.8% |
| 12+ months | ~3% |
Although a small minority achieved lasting seizure remission, these rates underscore that chronic FTRE remains deeply challenging, even in the context of multifaceted clinical care.
Role of Anti-Seizure Medications: Newer Drugs Show promise
More than half of the study participants received new anti-seizure medications during the observation window. Within this subgroup, approximately two-thirds experienced further reductions in seizure activity, suggesting that newer pharmaceutical options may be contributing to improved disease management.
Though the study did not evaluate the comparative effectiveness of individual drugs, the data indicate that medical innovation remains an important driver of improved outcomes for patients who have not responded to earlier treatments.
Neuromodulation Devices: Ambiguous Outcome Patterns
A growing number of FTRE Epilepsy patients undergo surgical implantation of devices designed to alter brain activity and reduce seizures. These include DBS, RNS, and VNS technologies, each involving targeted electrical stimulation.
While a portion of the study population used these devices, a notable finding was that patients with neuromodulation implants did not show substantially different seizure frequency trends than those who did not receive such devices.
This unexpected observation suggests that although neuromodulation remains an important option in the arsenal of treatment strategies, its statistical impact within this dataset remains unclear. It also Epilepsy reinforces the complexity of parsing the effects of individual interventions when patients receive multiple overlapping forms of care over time.
A Major Question Emerges: Treatment Effect or Natural Disease Course?
One of the most consequential findings of the study lies not only in the outcomes, but in their interpretation. Because FTRE patients often receive multiple new therapies over time—from medication adjustments to device implantation—isolating the cause of seizure reduction is inherently challenging.
The study’s conclusion raises a critical question:
Are long-term improvements driven by specific treatment interventions, or do seizure patterns naturally lessen in some FTRE patients over time?
This is not merely an academic point. Understanding whether FTRE follows a self-modifying trajectory could influence how clinicians recommend and sequence treatments. It may also affect how researchers design future drug trials, evaluate surgical techniques, or refine neuromodulatory approaches.
Expert Perspectives
“This research sheds light on the challenges patients living with chronic, treatment-resistant epilepsy face,” said Dr. Ruben Kuzniecky, who also serves as a professor and vice chair of academic affairs at the Barbara and Donald Zucker School of Medicine at Hofstra/Northwell.
Our findings confirm that seizure frequency can decrease significantly over time, but they also raise important questions about whether these improvements stem from the natural history of the condition or from the active management strategies employed. Discovering this distinction is crucial for developing more precise and effective treatment approaches.”
Similarly, Dr. Souhel Najjar, chair of Neurology at Lenox Hill Hospital and Staten Island University Hospital, emphasized the implications for ongoing research.
By challenging conventional assumptions about intervention-specific ‘disease-modifying effects,’ this study sets the stage for more rigorous research to unravel the true drivers of improvement, ultimately guiding us toward more personalized and effective treatments for patients.”
Related Research from Northwell Experts
This work builds on previous influential research published in JAMA by Dr. Kuzniecky and colleagues examining predictors of drug resistance in epilepsy. That study found that patients who experience frequent seizures early in their disease course, and those with co-existing psychiatric conditions, are significantly less likely to achieve successful seizure control through standard anti-seizure medications.
Together, these research efforts contribute to a growing body of evidence aimed at improving diagnostic precision, therapeutic planning, and long-term management.
Implications for Patients and Clinicians
The results of this study may provide a sense of cautious optimism for patients with FTRE. While outcomes vary widely, many may take comfort in the possibility of natural improvement over time, even when seizures appear stubbornly resistant to treatment.
For clinicians, the findings reinforce the importance of:
- Continual reassessment of patient outcomes
- Careful, data-driven treatment adjustments
- Surveillance for natural changes in disease patterns
- Judicious use of neuromodulation and next-generation pharmaceuticals
Moreover, the research highlights the need for future controlled studies capable of isolating the effects of individual interventions. Such clarity may help guide more tailored treatment strategies for FTRE patients.
The Northwell-led HEP2 study adds an important chapter to the understanding of focal treatment-resistant epilepsy. Its results, showing widespread improvement in seizure frequency but limited sustained remission, emphasize both the progress made and the complexity that remains.
While many patients may experience meaningful reductions over time, the drivers of this improvement remain unclear—highlighting the need for deeper investigation into the interplay between disease biology and therapeutic intervention.
Ultimately, this research provides a nuanced but hopeful message: even for individuals with the most stubborn forms of epilepsy, improvement is possible. Continued research may yield the clarity required to transform possibility into predictability, allowing clinicians to better guide patients along their treatment journey.
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