Authors :
Presenting Author: Aurelie Hanin, PharmD, PhD – Paris Brain Institute
Clemence Marois, MD – Hopital Pitie-Salpetriere
Martin Guillemaud, BS – Paris Brain Institute
Gwen Goudard, Ms – Hopital Pitie-Salpetriere
Louis Cousyn, MD, PhD – Hopital Pitie-Salpetriere
Jerome Denis, PharmD, PhD – Hopital Pitie-Salpetriere
Rana Alkouri, PharmD – Hopital Pitie-Salpetriere
Foudil Lamari, PharmD, PhD – Hopital Pitie-Salpetriere
Francesca Bisulli, MD – Department of Biomedical and NeuroMotor Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy
Krista Eschbach, MD – Children Hospital Colorado
Raquel Farias-Moeller, MD – Medical College Wisconsin
Nicolas Gaspard, MD – Department of Neurology, Hopital Universitaire de Bruxelles–Hopital Erasme, Universite Libre de Bruxelles, Belgium
Teneille Gofton, MD – Schulich School of Medicine and Dentistry, Western University, London Health Sciences Center, Ontario, Canada
Margaret Gopaul, PhD, MSCP – Yale University | VA-Connecticut Healthcare System
Matthew Gruen, BS – Yale University
Marissa Kellogg, MD, MPH, FAES – Portland VA HCS & Oregon Health & Science Univ (OHSU)
Lorenzo Muccioli, MD – Department of Biomedical and Neuromotor Sciences, University of Bologna
Elena Pasini, MD – IRCCS Istituto delle Scienze Neurologiche di Bologna, Epilepsy Center (full member of the European Reference Network EpiCARE), Bologna, Italy
Olga Taraschenko, MD – Department of Neurological Sciences, University of Nebraska Medical Center, Omaha, NE
Nathan Torcida Sedano, MD – Hôpital Universitaire de Bruxelles
Dominique Bonnefont-Rousselot, PharmD, PhD – Hopital Pitie-Salpetriere
Lawrence Hirsch, MD – Yale University School of Medicine
Sophie Demeret, MD – Hopital Pitie-Salpetriere
Vincent Navarro, MD – Epilepsy Unit and Department of Clinical Neurophysiology, APHP, Hopital de la Pitie-Salpetrere, Sorbonne Universite, ERN-Epicare, Paris, France
Rationale:
Drug-resistant epilepsy develops in over 70% of patients within the first year following cryptogenic new-onset refractory status epilepticus (cNORSE). Despite its high prevalence, the mechanisms driving seizure recurrence remain poorly understood. It is unclear whether dysregulation of innate immunity, observed during the acute phase of status epilepticus, persists or re-emerges in patients who develop drug-resistant epilepsy.
Methods:
We included patients enrolled in the French biorepository (COLETTE) or the Yale NORSE/FIRES biorepository. We first assessed whether clinical (including preceding fever, defining FIRES, a subtype of NORSE), MRI, and biological markers identified during the acute phase can predict the development of post-cNORSE epilepsy and 12-month functional outcomes. We then characterized the immune and brain-injury profiles of patients with drug-resistant post-cNORSE epilepsy, comparing them to control patients with chronic temporal lobe epilepsy associated with hippocampal sclerosis (TLE-HS) or with chronic encephalitis (GAD65 and Rasmussen encephalitis). We measured a panel of 15 biological markers in both serum and CSF, including 11 cytokines covering innate and adaptive immune responses, as well as neuron-specific enolase (NSE), protein S100beta (pS100B), progranulin, and neurofilament light chain (NfL).
Results:
In part one, 93 eligible patients were identified, including 74 NORSE survivors. Among survivors, 52/74 developed drug-resistant epilepsy, and 29/73 had poor functional outcomes (Glasgow Outcome Extended Score ≤ 4). Post-cNORSE epilepsy was more common in patients with cFIRES than in non-febrile cNORSE. Patients with post-cNORSE epilepsy also experienced longer SE duration and prolonged ICU stays, received more anesthetics, anti-seizure medications, or immunotherapies, and more frequently showed cortical hyperintensities on MRI. None of the tested biological markers significantly distinguished patients who did or did not develop drug-resistant epilepsy. In contrast, poor 12-month functional outcomes were associated with elevated serum CXCL8 and increased CSF levels of IL6, CXCL8, CCL2, MIP1a, GCSF, NSE, and progranulin. Survivors with poor outcomes also had higher serum NfL.
In part two, we compared 39 patients (28 yo [21-36]) with post-cNORSE epilepsy (median 2.2 years [IQR 1-5.9] after SE onset) to 40 with TLE-HS (45 yo [32-53]) and 19 with encephalitis (25 yo [19-39]). Paired analysis showed significant decreases in serum IL6, progranulin, and NfL between the acute and chronic phases. Inter-group analysis revealed significant differences in serum CCL2, IL17A, and NFL levels. Notably, patients with post-cNORSE epilepsy had lower T-cell-related cytokines but higher NfL compared to TLE-HS, with no evidence of ongoing innate immune activation.
Conclusions:
These findings suggest that post-cNORSE epilepsy is more likely driven by SE-related brain injury rather than persistent immune dysregulation. Further analyses are needed to confirm these findings and explore potential individual mechanisms of epileptogenesis.
Funding:
CURE Epilepsy, NORSE Institute, Swebilius Foundation, FFRE-Paratonnerre NORSE grant.