Traumatic brain injury (TBI) results from external force to the head, causing anatomical or functional impairment of cranial or brain structures. TBI is a leading cause of morbidity and mortality, particularly in adults under 45 (1). It significantly impacts functional capacity and quality of life (2). In the USA, TBI leads to 2.8 million emergency visits and 124,000 severe cases annually (3). In Europe, TBI accounts for 37% of injury-related deaths and costs an estimated 22.9 billion euros annually (4, 5). In Brazil, TBI hospitalizations cost approximately $70.96 million annually (6); however, estimates may not accurately reflect reality due to underreporting of cases and limited epidemiological studies in developing countries.

Epileptic seizures are a major challenge for TBI survivors (7). Post-traumatic epilepsy (PTE) complicates rehabilitation, impacting quality of life and incurring costs for tests, medical visits, medications, and lost workdays, alongside emotional and social impacts (8). After TBI, seizures can be classified as acute symptomatic seizures (ASS), which include both hyperacute post-traumatic seizures (within 24 h of TBI) and early post-traumatic seizures (within 7 days of TBI) (9–11). Seizures occurring beyond 7 days of TBI are classified as late post-traumatic seizures or PTE, indicating ongoing epileptogenesis (12). The incidence of PTE ranges from 0.4 to 26.7%, depending on the study population, TBI severity, and the presence, number, and location of injuries (13, 14). Late post-traumatic seizure (LPTS) or PTE requires early diagnosis and treatment. While no definitive biomarkers exist for predicting PTE, research is ongoing (15). Most cases develop within the first 2 years post-injury. Though an EEG cannot rule out epilepsy, it can identify interictal abnormalities and electrographic seizures (16). Few studies use EEG prospectively after TBI to evaluate epileptogenesis or identify PTE risk factors (15, 17–20). Additionally, longitudinal evaluations of EEG findings in TBI patients are scarce.

The objective of this study was to prospectively evaluate electroencephalographic data from patients who suffered moderate and severe TBI, from the initial acute phase for a two-year follow-up period. We aimed to assess electrographic evolution and identify potential electrographic findings that could predict the occurrence of PTE in these patients.

This study was carried out at the Clinic Hospital of the Faculty of Medicine of the University of São Paulo, Brazil, with approval from the ethics and research committee (CAAEs: 08533513.6.2002.0068 and 08533513.6.1001.5505). Participants were recruited between February 2018 and March 2020.

Inclusion criteria were patients of both sexes, aged between 18 and 75 years, with signed informed consent (by patient or guardian), diagnosed with acute TBI, with acute intracranial hemorrhage and/or contusion confirmed by head computed tomography (CT), and/or with Glasgow Coma Scale (GCS) ≥ 6 and ≤ 12 on admission or GCS < 6 if sedated. Exclusion criteria included a history of epilepsy, use of antiseizure medication, perinatal injuries, meningitis, encephalitis, neoplasia, neurodegenerative diseases, stroke, cognitive dysfunction (dementia), and pregnancy.

Seizure occurrences were classified as hyperacute post-traumatic seizures (within 24 h of TBI), early post-traumatic seizures (within 7 days of TBI), and late post-traumatic seizures (beyond 7 days of TBI), also defined as PTE. Latency for PTE onset, clinical ictal manifestations, and seizure count were noted. Epileptic seizures were classified per International League Against Epilepsy guidelines (21).

Patients underwent an electroencephalogram (EEG) as early as possible during hospitalization, with recordings lasting 1 h each. Clinical conditions and procedures sometimes prevented early recordings in the acute phase. All EEGs were conducted using a 32-channel digital electroencephalograph (Nihon Kohden system, software EEG-1200), with electrodes placed according to the international 10–20 system and fixed with Elefix paste. The recordings used a 1,000 Hz sampling rate, a 0.3 s time constant, and a 70 Hz high-filter. Two experienced board-certified neurophysiologists analyzed the recordings. Cohen’s kappa coefficient was used to evaluate inter-rater agreement, and any discrepancies were resolved by a third board-certified examiner to reach a consensus.

Due to the COVID-19 pandemic starting March 2020, our TBI follow-up protocol, including clinical visits and EEG recordings at specified intervals (1, 3, 6, 12, 18, and 24 months post-injury), was disrupted. New patient recruitment ceased temporarily, and in-person visits and EEGs were suspended. From September 2020 onwards, follow-up activities partially resumed via teleconsultation, with EEG recordings gradually reintroduced under safety protocols. These interruptions caused delays of 1–3 months in data collection, resulting in EEG recordings being classified within pm 3 months of the scheduled intervals. Consequently, some patients were followed for up to 32 months to compensate for overlapping delays caused by the pandemic. For consistency, EEG recording intervals were grouped as follows: acute phase < 7 days (0–7 days); 1 month (7 days–1 month); 3 months (2–4 months); 6 months (5–8 months); 12 months (9–15 months); 18 months (16–22 months) and 24 months (23–32 months).

EEG analysis was performed by visual examination, and the frequencies that constituted the background activity were analyzed and semi-quantified (delta < 4 Hz; theta 4–7.9 Hz; alpha 8–13 Hz; and beta >13 Hz). Delta frequency presence was categorized as absent, rare (<1%), occasional (1–9%), frequent (10–49%), abundant (50–89%), or continuous (>90%). Other parameters included asymmetries, predominant background frequency when awake or after stimulation (beta, alpha, theta, and delta), occurrence of theta or delta in bursts, presence of posterior dominant rhythm and sleep spindle, epileptiform discharges, and electrographic or electroclinical seizures. Electrographic findings adhered to American Clinical Neurophysiology Society guidelines (22).

All patients underwent an initial head CT scan, which served as the primary imaging modality for correlation with other data. Intraparenchymal injuries (contusions and hematomas) were categorized as none, single, dual, or multiple. Lesions were classified by laterality (unilateral or bilateral) and location (frontal, parietal, temporal, occipital). Additional classifications included skull fractures, subdural hematoma (SDH), subarachnoid hemorrhage (SAH), epidural hematoma (EDH), and presence of midline shift (≥ 5 mm). We primarily utilized computed tomography (CT) for evaluations due to the emergency nature of brain trauma care; patients often present with hemodynamic instability or decreased consciousness, necessitating a rapid and readily accessible imaging modality. Thus, the use of magnetic resonance imaging (MRI) for these evaluations was not feasible due given these technical constraints.

This study aimed to prospectively evaluate the electroencephalographic data of patients with acute TBI to assess electrographic evolution and identify potential routine EEG findings that could predict PTE. Despite the SARS-CoV-19 pandemic interruptions, we initially recruited 123 patients and prospectively followed 73 of them. Both PTE and NO-PTE patients showed improved background activity over 2 years. EEG recordings revealing delta background indicated a higher risk of PTE development. Additionally, multiple and bilateral lesions are also indicative of a greater probability of developing PTE.

The findings align with existing literature on early seizure incidence and risk factors following severe TBI. The observed ASS incidence (21.9%) falls within the reported range (2–30%) for severe TBI patients (23–26). Notably, a substantial proportion of ASS occurred within the first 24 h post-TBI. Although no statistically significant correlation was found between ASS and PTE development, the higher ASS proportion in the PTE group suggests a potential association, consistent with literature indicating ASS as predictors of later epilepsy development (26, 27). This highlights the complex interplay of injury severity, neuronal circuit disruptions, and genetic predisposition in PTE pathogenesis, beyond the immediate occurrence of ASS.

The PTE incidence in our series was 12.4%, consistent with literature data but lower than expected. PTE represents 20% of all structural causes and 5% of all acquired epilepsies (28). Known risk factors include advanced age, injury severity, intracranial hemorrhage, focal contusion, multiple injuries, coma for over 24 h, loss of consciousness for over 24 h, and prolonged amnesia (7, 13, 29). The PTE incidence varies based on trauma severity and the number of injuries, with cumulative risk ranging from 2 to 50% depending on injury location and severity (7, 24, 25). Following a single late seizure post-TBI, the likelihood of subsequent seizures increases by 80%, typically occurring within 2 years of the first spontaneous late seizure (7). In this study, 22.2% of PTE cases were mild and 77.7% were severe TBI. Among the 9 PTE patients, 6 had more than 2 seizures, with all experiencing only one seizure type.

The mortality rate in TBI is variable, depending on age, trauma severity, and presence of polytrauma, with literature reporting rates from 3.5 to 38.5% (6, 30). In this study, focusing on a small sample of mostly young adults with severe TBI, and mild cases with intraparenchymal injury, the mortality rate was 22.5%. Notably, patients with a GCS ≤ 6 at the scene were not enrolled, potentially excluding those with an even higher likelihood of death.

Electrographic biomarkers may predict seizure onset and epileptogenesis, allowing for the development of targeted preventative therapies. Currently, no validated electrophysiological biomarkers for PTE exist. However, potential markers include pathological high-frequency oscillations (HFOs), reduced sleep spindle duration, changes in theta oscillations, and slower transition from slow wave N3 to REM (31, 32).

Our study aimed to identify electrographic patterns indicative of PTE development through prospective EEG evaluations over 2 years. Initially, many recordings showed delta slow waves, which progressively decreased, reflecting improved EEG frequencies and background activity over time. In the PTE group, one patient showed background activity slowing after 16 months, preceding their first epileptic seizure. Although not statistically significant, these findings suggest that slow waves may indicate dysfunction in epileptogenesis-related circuitry or result from frequent epileptiform discharges or unrecognized seizures. Overall, our EEG data reveal abnormal patterns characterized by background activity replaced by slow waves, loss of physiological sleep patterns, and loss of anteroposterior differentiation while awake.

In clinical practice, epileptiform activities are crucial in evaluating epilepsy or suspected epilepsy, while background rhythms analysis is often undervalued and not correlated with clinical aspects. For instance, a patient with frequent seizures may show slowing or attenuation of physiological rhythms, which can be lateralizing or localizing. Conversely, a patient with controlled seizures may show normal baseline rhythms more frequently. These findings highlight the potential utility of EEG abnormalities as predictors of PTE.

The data found in this study associate epileptiform paroxysms with the risk of progression to PTE. This finding is surprising, given that many patients with refractory epilepsy do not have epileptiform elements during their routine EEG recordings. Often during long-term video-EEG tentative recording of those seizures, several hours or even days may pass without showing any epileptiform elements. The location and depth of the epileptogenic and irritative zone may also not favor surface recordings, and finally, it may be that pathological action potentials are the last phase of the epileptogenic process, with the beginning of epileptic seizures being the completion of the installation of epileptogenesis, which may even continue to evolve after the onset of seizures.

Kim et al. (18) performed a retrospective case–control study of risk factors for post-traumatic epilepsy, in which 25 consecutive cases developed epilepsy within 1 year of a head trauma. They found that EEG epileptiform abnormalities during the acute period post-injury and sporadic epileptiform discharges were associated with PTE.

Regarding the presence of structural injuries, it is already known that the cumulative probability of PTE is higher according to the number of lesions, reaching 25% for multiple lesions (7). In our study, for each brain lesion, individuals are approximately 5.05 times more likely to develop PTE. Individuals with lesions predominantly located on one side of the brain are approximately 0.13 times (or 86% less likely) to develop PTE as compared to those with bilateral lesions.

The data found in this study reinforce the importance of performing routine EEG in the acute phase and in the follow-up of TBI patients. In addition to EEG being the best test for recording epileptic seizures, it is a low-cost test that can be carried out at the bedside without having to transport the patient, who is often unstable, immediately after severe TBI.

Unfortunately, our series was small due to the SARS-CoV-19 pandemic. We acknowledge that the small number of PTE cases (n = 9) constitutes a substantial limitation, which may reduce the power to detect true associations and limit the generalizability of our findings. Furthermore, given the number of predictors included in our model, there is an inherent risk of overfitting, which can result in unstable estimates and reduced applicability of the results to other populations. We are currently enrolling a new series of patients, with continuous EEG being performed in the acute phase of TBI. Several issues complicated the multi-visit prospective study of TBI patients. Patients often do not feel the need to return for visits, especially if they have no new complaints. The challenge is ongoing, with difficulties increasing proportionally to the number of recruited patients. Another factor is that brain injury patients need a family member to attend medical visits, particularly to report potential epileptic seizures, ideally someone who witnessed the seizure. Despite these challenges and visit delays of 2–3 months, the study was completed, providing important data on the epidemiology and incidence of PTE in a developing country.

PTE affects a significant proportion of TBI patients, with no efficient preventative treatments available. Developing predictive biomarkers is crucial to guide patients and families. Understanding epileptogenesis is key to prevention. Routine EEG, a low-cost, accessible, and non-invasive test, is valuable not only for detecting epileptiform elements but also for identifying abnormalities in underlying activity.