PTE is one of the most common and serious complications of TBI, leading to poor functional outcomes and a medical burden for survivors of TBI [19, 20]. There is a lack of investigations on the clinical characteristics and latency of PTE, especially with a large sample size of patients with PTE. The current study enrolled 2862 participants diagnosed with PTE, summarized the clinical characteristics of PTE, and found that age at TBI, severity of TBI, post-TBI treatments, acute seizures, and residual disability were independent factors affecting the latency of PTE, thereby providing a reference point for survivors of TBI when making therapeutic decisions.
Clinical characteristics of PTE
Comparing the gender composition of the study participants, we found that males are significantly more likely than females to be diagnosed with TBI, as has been reported [4, 21]. Males and females have different personality traits and gender roles: males are more aggressive, are involved in a wider range of social activities, and are more susceptible to TBI, especially young adult males [2]. Several studies have also indicated that being male was an independent risk factor for PTE after TBI [8, 10]. This might be related to the hormonal differences between the sexes [22]. Higher rates of alcohol abuse among males might also play a role [10]. However, we lacked the data on alcohol use for further analysis. The age range with the most cases of TBI peaked in the 0 to 12 and 15 to 27 year-old groups, consistent with previous studies on PTE in children [5] and adults [8]. The aggregation of patients in the 0 to 12 year-old group might be related to the strong sense of curiosity and lack of discernment amongst children.
Generalized onset seizures were the most common seizure type, accounting for 72.8% of seizures, which is consistent with the previously reported rate of 79.0% [4]. This might be attributed to the altered brain microenvironment after TBI because of decreased cerebral blood flow, altered metabolism, increased neuronal excitability, and large amounts of hemosiderin deposited in the neural fiber network. One the contrary, Tubi et al. reported that continuous EEG monitoring indicated more than half of seizures after TBI were focal onset, and 20 to 30% of what we think of as generalized tonic-clonic seizures were actually focal to bilateral tonic-clonic seizures [20, 23]. Unfortunately, EEG during epileptic seizures was not collected in all participants, thus we were not able to verify the seizure type based on EEG. We also observed that demographic characteristics and TBI details might be factors that impact the development of generalized onset or focal onset seizures.
PTE latency and factors affecting the latency
The latency of PTE
We found that the proportion of patients who had a PTE latency period shorter than 1 year was lower than what Zhao and Englander reported [4, 7], but was consistent with other studies which included a larger number of participants and had longer follow-up periods [3, 5, 15]. In addition, a study of PTE in adults indicated that the median PTE latency period was 1 year after 10 years of follow-up [8], and in this study we found the median PTE latency period was 2 years. Considering that previous studies might miss patients who developed first-time seizure after the follow-up period due to limited follow-up time, we believe that our results on the latency are relatively reliable, as this study was not limited by the follow-up time and no PTE patients would be missing.
Factors affecting the latency of PTE
In this study, participants who suffered TBI at age ≥ 18 years old had shorter latency than those who suffered TBI at age < 18 years old. Christensen et al. [5] also reported that TBI at age ≥ 15 years old was an independent risk factor for PTE. Similar observations of older age on PTE has been reported by Annegers [3] and Zhao [7]. Those studies suggested that epilepsy susceptibility after TBI increases with age, and might be associated with neuroinflammation, decreased neuronal metabolism, neuronal degeneration, and abnormal cerebral hemodynamics [24]. Interestingly, epileptic discharges in juveniles were more frequent than in adults during the acute phase of TBI. A multicenter study reported that epileptic discharges were observed in 42.5% of TBI cases in children, and younger age was a significant risk factor for post-traumatic seizure (PTE) and status epilepticus during the acute phase [25]. The differences in the risk of epileptic seizures between adult and juvenile patients at different periods after TBI are related to the characteristics of brain development of patients of different ages: the cerebral cortex of juvenile patients is immature, the function of inhibiting nerve reflex is not established yet, and they are more sensitive to external injury stimuli. Therefore, abnormal discharges of cerebral neurons are more likely to occur in the acute phase of TBI for juvenile patients, which presents as sub-clinical epileptic discharge or acute symptomatic seizures. At the same time, the young brain of juvenile patients is more malleable and adaptable than the aging brain, so it is less likely to form a chronic epileptic brain network after the acute phase of TBI.
The severity of TBI is an established etiological risk factor for PTE [3, 5, 6, 10]. It was reported that patients who had more severe TBI may develop recurrent seizures within a shorter time interval and may have more frequent seizures [23]. In terms of the distribution of PTE latency, we found that there was no difference between participants who had mild TBI and moderate TBI. PTE latency in participants that suffered severe TBI was related to their post-TBI treatments: latency in participants who received conservative treatments was longer than that of participants who had mild to moderate TBI; the latency of participants that underwent a single surgical operation (PD/DC) showed no difference with that of participants that had mild to moderate TBI; and the latency of patients undergoing multiple surgical operation (PD/DC + CP) was shorter than that of participants that had mild to moderate TBI. This observation is not only related to the brain damage caused by TBI, but also to the secondary brain damage caused by the operation itself. As seizures are mainly related to abnormal discharges of the cerebral cortical network, patients with severe TBI are more likely to have damage in the deep brain and even the brain stem rather than the cerebral cortex or subcortical, which might explain why they have a longer latency. However, surgical procedures after TBI can cause significant damage to the cerebral cortex, especially the CP procedure. For patients with TBI complicated with intracranial edema, cerebral hernia, or high cranial pressure, PD/DC surgery helps to expand brain volume, reduce intracranial pressure, and reduce mortality after TBI. Thus, it is recommended that the PD/DC procedure be performed as soon as possible after TBI for those who meet the surgical indication. Although CP might shorten the latency, some reports have shown that it plays an important role in regulating brain blood flow, improving brain metabolism, and reducing the complications caused by PD/DC surgery. Additionally, CP could effectively eliminate the abnormal appearance of bone flap defects, and reduce the psychological burden of patients with TBI [26]. Therefore, we suggest that a multidisciplinary assessment be made to make recommendations regarding the decision and timing of CP operation. While it has been reported that the high incidence of PTE may be related to multiple craniocerebral injuries and lesion location (the temporal lobe) [4, 20], we found that latency was not affected by single or multiple craniocerebral injuries.
Annegers et al. [3] reported that acute seizures were not a risk factor for PTE. Alan et al. [23] also reported that the seizure recurrence rate did not increase in patients with acute seizures. On the contrary, other studies [4, 7] found that acute seizures were a predictor of PTE, and the secondary brain injury caused by acute seizures plays an important role in PTE progression [27, 28]. The results of our study support the latter view as we found that patients with acute seizures had shorter latency. Thus, we recommend that prophylactic AED treatments be administered in the acute phase of TBI. Although the incidence of PTE is not reduced, it might reduce acute seizures, which is expected to prolong PTE latency by reducing secondary brain injury, thus improving the prognosis of PTE [13].
We found that patients who had residual disability after TBI had a significantly shorter PTE latency than those who did not have residual disability, which was not described in previous studies. We believe that short PTE latency and residual disability might be mutually reinforcing, but further investigation is required to confirm this hypothesis.
Continuous EEG monitoring during the acute phase helps to identify subclinical epileptic discharges and non-convulsive epileptic state [25]. While epileptiform abnormalities have been reported to increase the risk of PTE, especially sporadic epileptiform [29], it showed no effect on PTE latency in this study. We observed an abnormal EEG rate of 78.0%, lower than the previous reported rate of 90.0% [7]. The discrepancy in abnormal EEG rate may due to the fact that EEG examination was performed during the interictal stage in most patients in this study, and the EEG monitoring time might have been too short to detect abnormalities.
We found that the neuroimaging abnormalities also did not affect PTE latency, in contrast with its effect on the incidence of PTE [3, 5, 7, 8]. This may be related to the fact that not all the neuroimaging was performed within 24 h after TBI. That is to say, the neuroimaging results might not truly reflect the changes in craniocerebral structure in the acute phase of TBI. Further studies are needed to determine the exact effects of craniocerebral structural damage on PTE latency.
Limitation
As a retrospective study, this study is limited by the inherent to the retrospective nature. Most of the participants in the study were from Beijing and surrounding areas, the results might not be representative of the general situation around China. The results of long-tern EEG monitoring and neuroimaging during the acute phase of TBI were lacking in a part of subjects. Therefore, partial description of the clinical characteristics of PTE lacks of sufficient data support. In addition, this study didn’t analyze all reported risk factors for PTE (e.g., alcoholism, post-traumatic amnesia, focal neurologic signs, et al.), which means possible missing of few factors affecting the latency. Thus, further population-based prospective studies are needed to fully clarify the clinical characteristics of PTE and factors affecting the latency of PTE.
