Biomarker profiling aims to separate low-risk from high-risk first seizures
A first unprovoked seizure often leaves patients and clinicians with the same immediate problem: the event has happened, but the likelihood of another seizure remains uncertain. In adults, that uncertainty shapes every downstream decision, from counseling about driving and work to whether early epilepsy treatment deserves serious consideration. This BMJ Open protocol sets out a prospective observational cohort study designed to test whether serum biomarkers, quantitative EEG, and quantitative MRI can identify which patients are most likely to experience seizure recurrence after a first unprovoked seizure.
The study is built around a simple but clinically difficult question. Conventional assessment can miss the biological signals that separate a single isolated seizure from the earliest phase of chronic epilepsy. By combining blood-based measures with advanced neurophysiologic and imaging analyses, investigators are trying to move beyond descriptive diagnosis toward risk stratification grounded in measurable disease biology.
A first seizure is not a diagnosis of epilepsy, but it may be the first visible sign of an epileptogenic network already in motion.
A 100-patient cohort with layered imaging and blood-based analysis
The protocol plans to recruit 100 patients with a first unprovoked seizure from a tertiary neuroscience centre. Every participant will undergo baseline structural MRI, EEG, and blood sampling. The design then splits into two imaging pathways: 40 patients will enter a nested pilot study with advanced MRI sequences usually reserved for refractory chronic epilepsy, while the remaining 60 will receive standard clinical MRI sequences.
This structure is more than a technical detail. It allows the investigators to ask whether advanced MRI methods can detect network or microstructural abnormalities at the very start of the disease process, before epilepsy becomes clinically established. The inclusion of standard MRI in the majority of participants also keeps the protocol anchored to routine care, making the findings more likely to inform real-world triage if useful markers emerge.
Patients will be followed every 6 months for 24 months to determine seizure recurrence. That 2-year window is clinically important because recurrence is the outcome that often drives a diagnosis of epilepsy and shapes the threshold for treatment. A longitudinal design also gives the study a chance to capture early divergence between those who recur and those who do not, rather than relying on a single static measurement.
EEG, MRI and serum data are being tested as a single predictive framework
The study’s core scientific ambition is to examine the combined utility of data streams that are usually interpreted separately. Connectivity and network-based analyses of EEG and MRI will be evaluated in relation to seizure recurrence, rather than simply cataloguing whether an abnormality is present. This matters because epilepsy is increasingly understood as a disorder of networks, not just of isolated lesions or single discharges.
Quantitative EEG may reveal alterations in synchrony or connectivity that standard visual interpretation can overlook. Quantitative MRI can similarly capture structural differences that are too subtle for routine reads but still relevant to seizure generation and propagation. If these modalities converge on the same subgroup of patients, the predictive value could exceed any single test used in isolation.
The protocol also includes analysis of high-mobility group box-1 in serum samples. HMGB1 is biologically plausible in this setting because it has been linked to inflammatory signaling pathways, and inflammation has long been implicated in epileptogenesis. A biomarker with that profile would be attractive not only for prediction, but also for helping explain why some patients transition from a first seizure to recurrent events while others do not.
Why this design could matter for early epilepsy trials
The protocol explicitly positions biomarker discovery as a way to improve patient stratification for counseling and for future trials of disease-modifying agents in early epilepsy. That is a practical goal. Early epilepsy studies are vulnerable to heterogeneity: patients enter with different underlying etiologies, different recurrence risks, and different biological signatures, which can dilute treatment effects if enrollment is too broad.
A predictive biomarker set could help define a higher-risk subgroup in whom recurrence is more likely and in whom preventative interventions are more likely to show signal. It could also reduce uncertainty in the clinic. Patients with a lower predicted risk might avoid unnecessary escalation, while those with a higher predicted risk could be monitored more closely and counseled more directly about safety and treatment options.
The research question extends beyond prognosis. If the combined biomarker approach works, it could expose the hidden biology of early epilepsy at a stage when disease-modifying intervention might still be plausible.
Ethical approval, funding and dissemination plans
The study received approval from the North East-Tyne & Wear South Research Ethics Committee, reference 20/NE/0078. Funding came from an Association of British Neurologists and Guarantors of Brain clinical research training fellowship. The trial is registered in the NIHR Clinical Research Network’s Central Portfolio Management System under CPMS-44976.
Planned dissemination is conventional but appropriate: findings will be presented at national and international meetings and published in peer-reviewed journals. That matters because the field still lacks a validated, clinically usable biomarker strategy for predicting recurrence after a first unprovoked seizure in adults. A protocol alone cannot answer the question, but it does establish a framework for testing whether routine clinical assessment can be strengthened by layered biomarker analysis.
The main limitation remains embedded in the design itself. This is a single-centre cohort with 100 patients, and the nested advanced MRI arm includes only 40 participants, so any positive signal will need careful validation before it can be generalized. Even so, the study is aimed at one of the most persistent uncertainties in epilepsy care: identifying, early and reliably, which first seizures are the opening event of a recurrent disorder rather than a one-time episode.