Authors :
Presenting Author: Kseniia Kriukova, MD – University of Southern California
Alexander A. Bruckhaus, Student – University of Southern California
Tuba Asifriyaz, MS – University of Southern California
Terence J. O'Brien, MBBS, MD – Alfred Health
Denes V. Agoston, MD, PhD – Uniformed Services University
Richard Staba, PhD – University of California, Los Angeles
Nigel Jones, Professor – Monash University
Solomon L. Moshé, MD – Albert Einstein College of Medicine and Montefiore Medical Center
Aristea S. Galanopoulou, MD, PhD – Albert Einstein College of Medicine
Dominique Duncan, PhD – University of Southern California
Rationale:
Post-traumatic epilepsy (PTE) is a severe long-term complication of traumatic brain injury (TBI), affecting between 2% and 53% of TBI patients. Despite its prevalence, there are no validated biomarkers for predicting the development of PTE, which is critical to design preventive clinical trials. This review systematically analyzes potential biomarker candidates for PTE in humans who have experienced moderate to severe TBI, focusing on biofluid-based protein, genetic, neuroimaging, and neurophysiological biomarkers. The goal is to distinguish between TBI patients who develop PTE and those who do not, thereby improving predictability and treatment strategies.
Methods:
The review adheres to established methodologies outlined in the Cochrane Handbook for Systematic Reviews of Interventions. It follows the Meta-analyses of Observational Studies and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A systematic search was conducted in Medline, Embase, and Web of Science, yielding 7,538 records. Of these, 18 studies met the inclusion criteria: moderate-severe TBI in humans, a follow-up period of at least six months, and no prior history of epilepsy. The review includes 15 cohort studies and 3 case-control studies, with the risk of bias assessed using the Newcastle-Ottawa Scale. The study's protocol is registered in the International Prospective Register of Systematic Reviews PROSPERO (Registration ID: CRD42023470245).
Results:
We identified 2 biofluid-based protein, 11 genetic, 16 neuroimaging, and 7 neurophysiological biomarkers significantly associated with late seizures.
Proteomics: IL-6 levels were significantly higher in seizure patients (121.36 pg/mL vs. 65.30 pg/mL). Elevated IL-1β ratios(PTE=3.79±2.27; p=0.02) were also linked to PTE.
Genetics: SNPs in genes like SLC1A1, SLC1A3, and GAD1 showed significant associations with late seizures. Notably, SLC1A3’s rs4869682 increased late PTS risk by 2.06 times.
Neuroimaging: Significant biomarkers included FA in the ALIC-R, lesion volumes, and temporal lobe atrophy. Lower FA in ALIC-R and larger lesion volumes correlated with PTE.
Neurophysiology: Elevated delta power and epileptiform discharges were significant EEG biomarkers. Higher delta power and variability were strongly associated with PTE development. Only two studies were eligible for meta-analysis, which showed heterogeneity in biomarker associations with PTE, indicating variable predictive value across populations. Theta power variance was the most significant contributor to the overall effect.
There was a significantly smaller number of neurophysiological studies available; however, neurophysiological biomarkers showed the strongest effect size in a meta-analysis of two studies.
Conclusions:
A multimodal approach, integrating biofluid-based protein, genetic, neuroimaging, and neurophysiological data, offers a promising strategy to enhance the predictability of PTE development and, potentially, its treatment. The identification of reliable biomarkers is critical to forecast PTE and design preventive clinical trials, which could ultimately improve outcomes for individuals with TBI.Funding:
Grants U54 NS100064 (EpiBioS4Rx), R01NS111744, and R01NS127524