Authors :
Presenting Author: Zoltan Chadaide, MD – University of Szeged
Daniel Fabo, MD PhD – Semmelweis University
Miklos Szoboszlay, MSc PhD – Neunos ZRt
Livia Barcsai, MSc – University of Szeged
Andrea Pejin, MD – University of Szeged
Balint Horvath, MD – Neunos ZRt
Marton Gorog, MSC – Neunos ZRt
Tamas Foldi, MD – Neunos ZRt
Lili Ambruzs, MD – Semmelweis University
Tamas Laszlovszky, MSc PhD – Neunos ZRt
Laszlo Halasz, MD PhD – Semmelweis University
Marton Kis, MSc – Neunos ZRt
Nora Forgo, MSc – Neunos ZRt
Anna Kelemen, MD PhD – Semmelweis University
Zsofia Jordan, MD – Semmelweis University
Akos Ujvari, MD – Semmelweis University
Anna Sakovics, MD – Semmelweis University
Gabor Szilagyi, MD – Neunos ZRt
Anita Kamondi, MD PhD – Semmelweis University
György Buzsáki, MD PhD – New York University, Grossman School of Medicine
Orrin Devinsky, MD – NYU Comprehensive Epilepsy Center, NYU Langone Medical Center
Lorand Eross, MD PhD – Semmelweis University
Antal Berenyi, MD, PhD – University of Szeged
Rationale:
Approximately one-third of epilepsy patients are resistant to antiseizure medications and may not qualify for surgical interventions. Current neuromodulation therapies, including deep brain stimulation (DBS), vagus nerve stimulation (VNS), and responsive neurostimulation (RNS), exhibit limitations such as invasiveness, restricted spatial targeting, limited adaptability, and delayed therapeutic onset. Thus, there is an unmet need for immediate seizure termination. Methods:
We developed a novel minimally invasive neurostimulation method termed Intersectional Short-Pulse (ISP) stimulation, delivered through implanted subgaleal electrode strips. ISP stimulation involves brief, high-intensity electrical pulses arranged in succession spatially and temporally to maximize stimulation intensity at targeted seizure onset zones while minimizing stimulation of non-targeted brain regions. Preclinical studies demonstrated ISP stimulation’s capacity to disrupt pathological brain oscillations and terminate seizures in animal models. This first-in-human clinical study enrolled fourteen adult patients with therapy-resistant epilepsy, primarily assessing the safety and feasibility of personalized ISP stimulation, with a secondary aim of evaluating its acute effects on clinical seizure manifestation and neurophysiological epileptiform activity. Seizures were detected using a machine-learning-based algorithm, and stimulation was delivered following validation of patient-specific tolerance thresholds. Results:
ISP stimulation demonstrated a significant reduction in seizure duration, shortening episodes by approximately 61% compared to unstimulated seizures. Additionally, spectral analyses revealed a consistent decrease in the spectral power during stimulated seizures, indicating effective modulation of ictal EEG patterns. ISP stimulation also effectively prevented secondary seizure generalization in two of the three susceptible patients. The minimally invasive procedure was highly tolerated by patients, who reported minimal discomfort, validating its safety and feasibility. Compared to existing therapies such as DBS and RNS, ISP stimulation provided immediate therapeutic effects without necessitating prolonged adaptation periods, potentially enhancing patient outcomes pending confirmation from larger, long-term studies. Conclusions:
ISP stimulation emerges as minimally-invasive neurostimulation method for managing therapy-resistant epilepsy, offering immediate seizure termination and personalized stimulation adaptability. The primary outcomes of safety and feasibility were robustly demonstrated, alongside substantial acute reductions in seizure severity and duration, favorably positioning ISP stimulation compared to existing neuromodulatory therapies. Future studies focusing on larger patient populations and extended treatment periods are warranted to establish long-term efficacy data. Funding:
KKP133871/KKP20 and 151490/EXCELLENCE_24 - NKFIH, Hungary, EU Horizon 2020 (No. 739593—HCEMM), Ministry of Innovation and Technology of Hungary grant (TKP2021-EGA-28)
Hungarian Brain Research Program (grant NAP2022-I-7/2022)