[145]. Complications following cranial trauma, such as hypoxia, increased intracra­nial pressure, hypotension, ischemia, brain edema, intracranial hemorrhage, elec­trolyte imbalances, or infections, can precipitate symptomatic seizures, mostly occurring within weeks after trauma [137, 140]. Additionally, alterations in inam­matory markers, blood–brain barrier integrity, astrocytes, glucose metabolism, and metabolic dysregulation have been implicated in the pathogenesis of posttraumatic seizures [147–150]. For example, posttraumatic inammation triggers toll-like receptor-1 (TLR-1) expression elevation in the hippocampi of rodent models, lead­ing to protein kinase B (Akt) phosphorylation and activation of the nuclear factor κB (NF-κB) and mammalian target of rapamycin (mTOR) pathways [151]; HMBP-1 protein expression activates the MAPK/ERK 1/2 pathway [152]; and NMDA recep­tor activation increases neuronal excitability [153], among others.

Research has suggested that an increased risk of delayed-onset seizures is associ­ated with early-onset seizures; however, an increased risk of PTE is not a direct consequence of early seizure activity [137, 140, 154]. Population-based studies ana- lyzing large samples have shown that the increased risk of PTE following TBI may be attributed to various factors, including the occurrence of cerebral contusion or hematoma, particularly subdural hematomas and skull fractures, or age [140]. Cerebral contusions, lacerations resulting from direct or indirect traumatic brain injury, and compression-induced brain trauma can evolve into epilepsy after a period of asymptomatic latency, which can range from months to years and is dependent on the individual [128]. Studies have indicated that following TBI, injured brain tissue undergoes cellular apoptosis and long-term remodeling of neu­ral circuits over time, including inhibition and apoptosis of GABAergic neurons and enhanced excitability of glutamatergic neurons. Ultimately, these changes lead to an imbalance between excitatory and inhibitory neurotransmitters, increasing the risk of spontaneous epileptic seizures [155–157]. There is also evidence suggesting that the deposition of iron-containing hemosiderin, the formation of iron-free radicals, and iron-related necrosis are involved in epileptogenesis [158]. Following the advancement of genetic testing technologies, the role of genetics in PTE is gradu­ally gaining attention, especially with the discovery of certain genes that serve as biomarkers for predicting the occurrence of PTE following TBI.Genes such as SLC1A3, SLC1A1, ADK, NT5E, IL1B, GAD1, MTHFR, ADORA1, and APOE have been extensively reported to inuence various pathological and physiological processes, including stress response, regulation of biomass, metabolic processes, signaling pathways, responses to external stimuli and their regulation, and cellular localization, among others, thus facilitating the onset of epilepsy [159]. The rela­tionship between the gamma-aminobutyric acid (GABA) signaling pathway and PTE is signicant. Changes of decreased GABAergic activity and increased gluta­mate content may be associated with microRNA regulation, indicating the involve­ment of epigenetic regulation in PTE [160]. Currently, mechanistic studies on

epilepsy are primarily based on animal experiments rather than specically target­ing traumatic epilepsy. Animal models for studying PTE mainly include uid per­cussion models, controlled cortical impact models, liquid impact models, cortical undercut models, impact acceleration models, penetrating brain injury models, and canine models of PTE [157, 161–164]. Based on uid percussion model studies, selective apoptosis of interneurons in the dentate gyrus and partial survival of mossy bers may lead to sustained granule cell hyperexcitability [165]. Recent studies have increasingly shown that a severe uid impact leading to focal TBI can trigger spontaneous epileptic seizures [157, 166]. Seizures originate from the lesion site and progress over time with worsening clinical and electrophysiological symptoms [167, 168]. Controlled cortical impact models involve creating a focal brain contu­sion using an impactor controller, allowing for sustained or reproducible outcomes without diffuse brain injury. Studies have shown that damage to the dentate gyrus leads to mossy ber sprouting and structural reorganization, resulting in increased spontaneous excitability [169, 170]. Rat models of penetrating brain injury better simulate the conditions of TBI, but whether this model can produce delayed-onset epileptic seizures remains uncertain [157]. The cortical undercut model involves transverse transection of the white matter with a needle, resulting in isolation of a small portion of the cortex, and monitoring seizure-like activity in brain slices. Increased axonal sprouting adjacent to pyramidal cells is associated with increased excitatory connections [171]. Recent studies have shown reduced GABA output from fast-spiking neurons in the cortex [172]. Early application of tetrodotoxin after trauma delays action potentials and prevents induced or noninduced epileptoid activity in brain slices, suggesting that posttraumatic epilepsy can be an event­dependent process [173]. Administration of tetrodotoxin within 3days of trauma can prevent delayed epilepsy in PTE animal models [174]. The occurrence of epi­leptogenesis overlaps with the recovery process after injury, suggesting common underlying mechanisms, including neuroregeneration, axonal sprouting, and event dependence [155]. Therefore, disease-modifying agents and anti-seizure drugs may have both positive and negative effects on recovery and epileptogenicity. Limited research suggests that anti-seizure drugs, including ramacemide, topiramate, pirace­tam, and levetiracetam, have no benecial or harmful effects on recovery following TBI [155].

Risk Factors forPosttraumatic Seizures

consciousness loss or amnesia and structural brain damage [137]. Mild TBI refers to a lack of skull fractures or consciousness loss, or amnesia lasting ≤5minutes; moderate TBI involves skull fractures or other injuries, conscious­ness loss, or amnesia lasting 30min to 24 h without meeting the criteria for severe TBI; severe TBI indicates evidence of cerebral contusion, intracerebral hematoma, or consciousness loss or amnesia lasting more than 24h [137]. The risks of developing PTE after mild, moderate, and severe TBI increase by 1.5,

myoclonus, with over 50% of patients having only EEG-detected electrical sei­zures [127].

months later, rats treated with brivaracetam starting 30minutes, 4h, and 8h after traumatic brain injury showed a 38% reduction in the overall seizure occurrence rate, a 59% reduction in seizure frequency, a 67% reduction in seizure duration, and a 45% reduction in the proportion of spreading seizures, demonstrating good anti­seizure properties and providing support for clinical trials of brivaracetam and other SV2A-targeting drugs for the prevention of posttraumatic epilepsy in humans [197].

from 56–83%, with only 12.5% of patients discontinuing medication due to adverse events [127]. Studies with larger sample sizes should be conducted for the same tumor pathologies while evaluating the effects of PER on tumor progression, overall survival, and progression-free survival.