Traumatic brain injury (TBI) is one of the leading causes of death and disability worldwide (1, 2), and there are approximately one million new cases of TBI annually in China alone (3). Previous large-scale studies have concluded that only about 40–50% of individuals achieve a favorable outcome 6 months after moderate-to-severe TBI (4, 5), and within 10 years after TBI, the long-term outcome may tend either to deteriorate or improve (6, 7). Pre-injury employment, white-collar work, and shorter post-trauma amnesia duration have been reported as prognostic factors for better long-term outcomes (7), while male gender, younger age, less severe TBI have shown good prognostic effects on long-term outcomes in several studies (7, 8), but no such prognostic effects were observed in other studies (6, 9). Crucially, however, the importance of rehabilitation programs for certain TBI patients has been highlighted for favorable outcomes (6).

Post-traumatic seizure (PTS) is one of the most common sequelae of TBI and is classified as immediate PTS (within 24 h postinjury), early PTS (between 1 and 7 days postinjury), or late PTS (more than 7 days postinjury) according to the time of occurrence, and recurrent unprovoked late PTS is referred to as PTE (10). The presence of PTE in particular has been found to develop in 4.2–53% of patients who suffer moderate-to-severe TBI (10–13). Since TBI most commonly occurs in young adults (3), who may survive for decades after their injury (14), TBI might in fact become a chronic health condition rather than an acute event (15), especially for those who develop PTE after TBI. Some authors have reported that the development of PTE following TBI is independently associated with unfavorable functional outcomes (16–19). Hence, predicting the long-term outcomes of patients with PTE may help clinicians to provide more personalized medical care and rehabilitation programs that can better improve these patients' quality of life.

During clinical admission of PTE patients, clinicians may pay more attention to the seizure outcome rather than the global functional outcome. Although many studies have focused on the global functional outcome of patients with TBI (5, 7, 20), few studies have systematically investigated the global functional outcome of patients with PTE as well. This lack of study prevents clinicians from effectively identifying patients whose global function prognoses were likely to deteriorate and from further developing clearer treatment strategies for them. Briefly, clinical management of PTE requires recognition of the heterogeneous endophenotypes associated with functional outcomes. Identifying the risk factors for functional decline in patients with PTE and establishing a simplified prognostic model for predicting the long-term functional outcome may therefore become quite useful in improving the therapy of PTE.

This study sought to describe global function changes up to 5 years after the first late PTS onset, identify predictors that significantly relate to 5-year global functional outcomes, and to develop a prognostic model that can be used at the clinic for predicting unfavorable functional outcomes among patients with PTE after moderate-to-severe TBI.

This is one of the first studies to focus on the long-term global functional outcomes over 5 years and to investigate the predictors of global functional outcomes in a sample of patients with PTE after moderate-to-severe TBI, and this study now presents the following findings. First, the global function of PTE patients assessed based on GOSE score showed dynamic changes overtime: with a favorable global function at the onset of first late PTS, 13.59% of patients experienced deterioration in their conditions and had an unfavorable global functional outcome 5 years later. Second, it was found that gender, age at TBI, lesion location, multiple injuries, the severity of TBI, and latency of PTE were predictors for 5-year global functional outcomes. Finally, a prognostic model for global function prediction by using the above variables was developed and it was presented as a graphical score chart. This model achieved significant potential to be used in clinics based on our above analysis and may help to screen patients at high risk of unfavorable global functional outcomes and to develop more effective strategies for rehabilitation.

As previously mentioned, GOSE is the recommended measurement for measuring the global function following TBI, and it outlines the overall impact of TBI on function, independence, and participation (29). To date, several studies have used GOSE for functional outcome assessment in TBI patients (5, 7, 20, 30, 31) and have suggested that there is a dynamic process of change in global functional outcomes over time, which we also found in this study.

Although the method by which gender affects the global functional outcomes remains poorly understood (32), this study found that female PTE patients were less likely to experience deterioration in a global function, and it was consistent with several previous long-term studies (20, 31) yet contrary to others (7, 33). Due to a different profession and hobbies characteristics, the TBI mechanism is different between males and females (34). Previous animal studies have shown female rodents have better outcomes after TBI than males because of the neuroprotective effect of sexual hormones (estrogen and progesterone) (35, 36); while several clinical studies also have found differences in TBI outcomes between genders, but suggesting that sexual hormones do not provide a neuroprotective effect on clinical outcomes (37, 38). Therefore, the difference in global functional outcomes between genders is still controversial, that may need to be explored in further large-sample, age-stratified, prospective studies. In addition, we realized that the influence of gender on epileptic seizure may also play a role in global functional outcomes since a larger proportion of patients were males in this present study than in previous studies (88.5% vs. 72.0–78.4%) (7, 20, 31). One other demographic characteristic, age, however, has been shown in the literature to have a clear effect on long-term functional outcomes (older patients were more likely to experience deterioration) (8, 20, 31, 39), and the findings of this present study are consistent with these earlier works. We hypothesize that the better functional outcomes of younger patients might be related not only to their physical status but also to social factors such as better medical care and better return-to-work characteristics (39).

Some authors have reported that the severity of TBI was associated with functional outcomes: the more severe the TBI, the worse the functional outcomes (39). Considering that we lacked the Glasgow Coma Scale (GCS) scores of some patients in this retrospective study, this study instead assessed the severity of TBI according to neurological and imaging evaluation (10) and found that patients who suffered severe TBI were more likely to have deterioration of global function. In addition, this study found that among patients with severe TBI, the risk of unfavorable 5-year global functional outcomes was higher in those who received surgery (OR, 2.03) than in those who received conservative treatment (OR, 1.51) compared to patients with moderate TBI. The difference may be related to the TBI condition of those patients who underwent surgery (for example, those who had marked cerebral edema, increased intracranial pressure, etc.) or to the surgical procedure itself, which may have resulted in secondary brain damage.

Multiple injuries and injuries located in the temporal lobe (especially the left temporal lobe) were also associated with unfavorable 5-year global functional outcomes. The specific role of the temporal lobe in the overall brain network may explain our findings. For most people (who are right-handed), left temporal injury is more likely to interfere with dominant-hand-motor pathways, compromise language regions, and affect language function. As language function is extremely important in independence, employment, social and leisure activities, family and friendship, and returning to normal life after TBI, we may expect patients with left temporal lobe injuries to have low long-term functional outcomes. Moreover, previous literature has also reported that epilepsy with temporal lobe damage was more likely to develop into DRE (40, 41).

We were surprised to find that, in addition to the latency of PTE, other characteristics of PTE (such as seizure type, presence of SE, drug responsiveness to ASMs, and EEG findings) were not associated with 5-year global functional outcomes. This suggests that more attention should be paid to the etiology of epilepsy, TBI, rather than to the seizure itself when assessing the functional outcome of patients with PTE. The latency of PTE ranges from 7 days to decades, with 60–80% of patients having a latency of <1 year (11, 14, 27). In this study, patients with a latency of shorter than 12 months were more likely to have deterioration of global function 5 years later, while those with longer latencies tended to have a stable global function. We realize that this result may be related to the design of the present study as it only included patients who had GOSE scores of 5–8 at their first late PTS onset. These patients who had long latencies may have already experienced a dynamic process of change in global function and already reached a stable state of global function at the onset of their first late PTS. Future prospective studies with long-term follow-up of new TBI cases and evaluation of the seizures and global function of TBI patients at different time points may help us better clarify the relationship between latency of PTE and functional prognosis.

Though it is not free from limitations (discussed below), this study has the following strengths. First, this study recorded the 5-year GOSE after the onset of the first late PTS, and the follow-up period was long enough to detect changes since the functional prognosis tends to become stable 5–10 years after TBI (6, 7). Second, this is the first study to identify the factors that affect the long-term functional outcomes among patients with PTE after moderate-to-severe TBI, establish a prognostic model, and construct a graphical score chart for clinical use, and the prognostic model can provide a more individualized prediction of the long-term functional outcomes for a patient with PTE. Specifically, based on gender, age, easily ascertainable TBI details, and latency of PTE, this prognostic model exhibited acceptable predictive capability (with a C-statistic of >0.75), and the prognostic model can be easily integrated into daily clinical practice simply by checking the graphical score chart. Once externally validated, our research may provide a basis for more effective courses of treatment.

There are several limitations to this study that constrain the generalizability of our findings. First, only patients with PTE were included; patients without PTE after TBI were not included as controls. The unfavorable outcomes might be mediated by the presence of PTS, rather than directly and independently correlated with factors analyzed in this study, which means that there might be selection bias that this study did not take into account. Furthermore, as this was a retrospective study, the model was developed based on factors that were recorded in the medical records or supplemented by recollections of patients or their caregivers. However, there could be other risk factors that affect global functional outcomes that need to be considered but were missed due to a lack of reliable data (such as pre-injury employment, education, etc.). This made it difficult to correct for potential confounding of variables. Finally, information bias may also exist. Further external validation is therefore needed to evaluate the prognostic model, and further large-scale prospective studies are needed to clarify fully the factors that affect the long-term functional outcomes of PTE.

The global function of PTE patients assessed based on the GOSE score showed dynamic changes over time. Effective screening of high-risk patients and clearer treatment strategies are therefore essential to help ameliorate unfavorable outcomes. In this study, it was found that suffering TBI at the age of 30.0 years or older, having severe TBI (especially severe TBI with surgery), having multiple injuries, and having temporal lobe lesions were risk factors for an unfavorable 5-year global functional outcome, while being female and long (12.0 months or longer) PTE latency were protective factors. This study developed a prognostic model using these identified predictors to predict 5-year outcomes among patients with PTE after moderate-to-severe TBI, and the model achieved significant potential for clinical use. However, additional prospective studies are still needed to validate and further explore predictors of the functional outcomes of PTE patients.

The data that supports the findings of this study are available from the corresponding author, upon reasonable request.

The studies involving human participants were reviewed and approved by the Ethics Committee of the Beijing Tiantan Hospital affiliated with the Capital Medical University of the People's Republic of China. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

TY, XL, RL, and QW were major contributors to the acquisition of data. TY, LS, JW, and QW analyzed the data. TY drafted and revised the manuscript and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. All authors contributed to the study's conception and design.

The work was supported by the National Key R&D Program of China grant (2017YFC1307500 to QW), the Capital Health Research and Development of Special Grants (2016-1-2011 and 2020-1-2013 to QW), the Beijing-Tianjin-Hebei Cooperative Basic Research Program (H2018206435 to QW), and the Beijing Natural Science Foundation (Z200024 to YGW and QW).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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