INTRODUCTION — Seizures are a long-recognized complication of traumatic brain injury (TBI). Seizures that occur early versus late after TBI have different implications for prognosis and management. Early seizures are felt to be acute symptomatic events with a low likelihood of recurrence, whereas late seizures represent epilepsy.

While only 4 percent of all epilepsy cases are attributed to trauma, 13 percent of those cases that are of known cause are posttraumatic [1]. TBI is also the most important cause of symptomatic epilepsy in persons aged 15 to 24 years. Posttraumatic epilepsy contributes significantly to the functional disability in a TBI survivor.

This topic will discuss epidemiologic, clinical, management and prognostic issues that are specific to posttraumatic seizures. More general issues related to seizures and epilepsy are discussed elsewhere. (See "Overview of the management of epilepsy in adults".)

EARLY SEIZURES — Early posttraumatic seizures are defined by their occurrence within one week of head trauma. These are acute symptomatic events and are not felt to represent epilepsy.

A distinct category of immediate seizures, those occurring upon or within seconds of impact, is controversial. Some feel that these are "convulsive concussions" and not epileptic events [2,3]; others include them in the category of early seizures because of their similar associated risk for posttraumatic epilepsy [4,5]. (See 'Prognosis' below.)

Risk factors — Overall, the incidence of early posttraumatic seizures is about 6 to 10 percent but may be as high as 20 to 25 percent in some groups, such as those with depressed skull fracture and intracerebral hematoma requiring evacuation [6-8]. Early seizure rates are also higher in patients with more severe head injuries, subdural hematomas, and penetrating head injury, but they do occur in patients with mild traumatic brain injury (TBI) and normal head computed tomography (CT) [6,7,9].

Younger children are at higher risk for early posttraumatic seizures than adolescents and adults [10]. In one series of patients, 31 percent of children younger than seven years had early seizures compared with 20 percent of children aged 8 to 16 years and 8.4 percent of children over 16 years [11]. In a larger series of more than 2000 children with severe TBI, the overall risk of early posttraumatic seizures was 25 percent [12]. The most important risk factors for early seizure were age less than two years, injury by abuse or assault, and subdural hemorrhage. In the presence of all three of these characteristics, the estimated probability of seizure was 60 percent.

Clinical features — About one-half of early posttraumatic seizures occur during the first 24 hours, and one-quarter occur within the first hour [13].

Most seizures (72 to 84 percent) presenting within the first day are generalized tonic clonic type [9,14]. The later a seizure begins in relationship to the head injury, the more likely it will be focal in onset; after the first day, more than half are either simple partial (pure motor) seizures or focal with secondary generalization [4,14]. Complex partial seizures are rare in this setting.

About 10 percent of patients with acute head injury develop status epilepticus [4,13]. This is more common in children and usually accompanies other underlying complications such as ischemia or metabolic imbalance. Focal motor status epilepticus is most common with subdural hematoma or depressed skull fracture and may be refractory to treatment. Mortality with generalized status epilepticus is high even when associated with mild TBI.

Evaluation — Patients with moderate and severe TBI routinely have a head CT as part of their injury evaluation. Head CT is also required in patients with early posttraumatic seizures after a mild TBI; early seizures are associated with a higher incidence of intracranial bleeding, which may in turn increase the risk of short and long-term complications [15] (see "Acute mild traumatic brain injury (concussion) in adults"). While brain magnetic resonance imaging (MRI) is more sensitive for posttraumatic intracranial abnormalities, the implications of this added information for prognosis and management are less clear.

Electroencephalography (EEG) patterns are often nonspecifically altered during the acute phase of head injury. However, early epileptiform abnormalities on EEG may be associated with an increased risk of posttraumatic epilepsy. (See 'Posttraumatic epilepsy' below.)

Management — Although early posttraumatic seizures may not recur, patients with early seizures are often treated with antiseizure medications because of the risk of status epilepticus or aggravation of a systemic injury. In addition, recurrent seizures may increase cerebral blood flow and could theoretically increase intracranial pressure.

There is no ideal antiseizure medication for the management of early seizures. In practice, phenytoin or fosphenytoin is often used because they do not cause significant sedation and can be loaded intravenously; levetiracetam is a reasonable alternative. The optimal duration of therapy is not clear and depends in part upon the severity of injury. In the absence of seizure recurrence, antiseizure medications are generally continued throughout the hospital stay and are gradually withdrawn within the first few weeks [16,17].

In patients who have not had a seizure but appear to be at increased risk for early seizures (see 'Risk factors' above), antiseizure medication treatment reduces the incidence of early seizures and may be used because of similar concerns for secondary complications [16,18]. Pooled analysis of two randomized trials found that phenytoin prophylaxis reduced the risk of early posttraumatic seizures compared with placebo (relative risk 0.37, 95% CI 0.18-0.74) [16]. Another randomized trial found that prophylactic treatment with either phenytoin or levetiracetam was associated with similarly low rates of early posttraumatic seizures (1.5 percent) and adverse drug reactions (8 to 10 percent) [19]. In unselected patients, the risk of early posttraumatic seizures is low and is not substantially reduced by treatment [20].

The use of antiseizure medications after head injury does not reduce the risk of late seizures or posttraumatic epilepsy. (See 'Prophylaxis' below.)

Prognosis — Patients with early seizures are at higher risk for the development of posttraumatic epilepsy compared with those who do not have early seizures [8].

Some investigators believe that immediate seizures or "concussive convulsions" are more benign in terms of their risk for long-term seizures. In one study of 22 Australian rugby players with this phenomenon, none developed epilepsy over a mean follow-up of 3.5 years [2]. Others have found a more similar prognosis for immediate seizures and all early seizures [4,21,22].

It is possible that the association between early and late seizures reflects the shared risk factors for early and late seizures or that early seizures represent an independent risk factor for epilepsy. Multivariate analysis has given somewhat conflicting results. One population-based cohort study of 4541 adults and children with head injury followed for >20 years did not find early seizures to be an independent risk factor [23]. In a pooled analysis of a selected group of 783 high-risk trauma patients followed for two years as part of a clinical trial, early seizures remained in the multivariate analysis as an independent risk factor for epilepsy [6].

Alcohol withdrawal is a common cause of both early and late-onset seizures in patients with head trauma, regardless of the severity of head injury [23,24].

POSTTRAUMATIC EPILEPSY — Seizures occurring more than one week after head injury reflect more permanent structural and physiologic changes within the brain and usually represent the onset of posttraumatic epilepsy.

Epidemiology and risk factors — The 10-year incidence of epilepsy after traumatic brain injury (TBI) is estimated at about 2 percent [25]. However, mild TBI/concussion may not be a risk factor for epilepsy; one retrospective cohort study of 330 patients postconcussion found no increased risk of epilepsy; abnormal brain imaging on computed tomography (CT)/magnetic resonance imaging (MRI) or a Glasgow coma scale (GCS) <13 more than one hour post-injury were exclusion criteria [26]. Other studies have found that the severity of TBI correlates with risk [23,27-31]. In one population-based cohort, the cumulative five-year probability of seizures was 0.5 percent in patients with mild injury (those with loss of consciousness or amnesia <30 minutes); 1.2 percent for those with moderate injuries (loss of consciousness for 30 minutes to 24 hours or skull fracture); and 10.0 percent in those with severe injuries (loss of consciousness or amnesia for more than 24 hours or subdural hematoma or cerebral contusion) [23]. Another study of 647 hospitalized patients categorized TBI severity more traditionally with the GCS [28]. The two-year incidence of epilepsy was 8.0 percent for GCS 13 to 15 and 16.8 percent for GCS 3 to 8.

Other subsets of patients at much higher risk have been identified and include those with early seizures, intracranial hemorrhage or cerebral contusion, depressed skull fracture, and penetrating head injury [6,7,11,30,31]. Any alcohol-related head injury, even when classified as mild, is a significant predictor of new-onset seizures [24]. TBI associated with intracranial lesions on CT was associated with an 18 percent risk of late seizures in one series [14]. In penetrating missile combat injuries, the incidence is more than 50 percent [14,32]. The requirement for neurosurgical procedure (hemorrhage evacuation, ventriculostomy) increased the risk, and multiple surgeries increased the risk over single surgeries [28].

Epileptiform abnormalities on electroencephalography (EEG) that are apparent within five days after traumatic brain injury may be a marker of increased risk for the development of first-year posttraumatic epilepsy [33]. However, in those with early epileptiform abnormalities, the benefit of starting antiseizure medication before the onset of the first seizure is uncertain.

In contrast to early seizures, older age, >65 years, is a risk factor for posttraumatic epilepsy [23]. Posttraumatic epilepsy is less common in the pediatric population [23,27]. In one large, population-based study, the risk of posttraumatic epilepsy was slightly higher in women than men [27]; in another, men were at higher risk [31].

Genetic factors may influence the risk of developing seizures after epilepsy. Most studies have not found an increased risk of epilepsy among family members of patients with posttraumatic epilepsy [34,35]. However, one large, population-based cohort found that a family history of epilepsy increased the risk of posttraumatic epilepsy, with a relative risk estimate roughly equivalent to what would have been predicted from an additive risk model [27].

Pathophysiology — Posttraumatic seizures may be associated with the typical pathological changes that are seen in brain injuries including reactive gliosis, axon retraction balls, Wallerian degeneration, microglial scar formation, and cystic white matter lesions. There is also evidence suggesting that posttraumatic seizures may be a result of alterations of intrinsic membrane properties of pyramidal neurons together with enhanced N-methyl-D-aspartate synaptic conductances [36-38].

Selective damage to the hilar region of the hippocampus is produced in animal models after fluid-percussion traumatic brain injury [39]. While this pattern of injury appears more restricted than the hippocampal sclerosis associated with temporal lobe epilepsy, some speculate that this mechanism may contribute to the development of posttraumatic epilepsy in some cases. In one pathologic case series, a similar pattern of hippocampal injury was found in all of the 21 patients undergoing epilepsy surgery for posttraumatic epilepsy [40].

When a contusion or cortical laceration is present, the breakdown of hemoglobin releases iron. Based on animal and cell culture studies, iron may increase intracellular calcium oscillation. It may also increase free radical formation through activation of the arachidonic acid cascade thereby producing increased intracellular calcium and resulting in excitotoxic damage, neuronal death, and glial scarring, which lead to epileptiform activity [41]. These findings suggest a possible role for neuroprotective treatment in the future [14].

MRI studies have the potential to add to our understanding of epileptogenesis after head injury. One study of 17 patients with posttraumatic epilepsy found that the presence of gadolinium enhancement was more common than in individuals with head trauma without epilepsy (77 versus 33 percent) [42]. Depending on the timing of the MRI, however, this finding may represent the effect rather than the cause of seizures. Using a specialized technique, diffusion tensor imaging, investigators have demonstrated that MRI characteristics associated with glial proliferation are more pronounced in head-injured patients with, rather than without, epilepsy [43]. In another study, in 135 patients with serial MRI examinations after TBI, hemosiderin deposits in the parenchyma associated with either incomplete or delayed surrounding gliosis were associated with the development of epilepsy compared with early hemosiderin completely surrounded by gliosis [44].

Clinical features — About 40 percent of individuals with posttraumatic epilepsy have onset within six months; 50 percent within one year; and about 80 percent within two years of head injury [8,14,25]. Posttraumatic epilepsy may begin more than 15 years later [13,23,27,30]. The more severe the head injury, the longer the patient is at risk for late seizures; patients with mild TBI remain at risk for about five years, moderate TBI for 10 years, and severe TBI for 20 years or more [23].

The primary site of injury contributes to the symptomatic manifestation of epilepsy. Epilepsy appears earliest after lesions in the motor area followed by temporal lobe lesions and those in the frontal or occipital lobes. These seizures are usually secondarily generalized with or without apparent focal onset in 60 to 80 percent [28,45]. Simple and complex partial seizures each account for 10 to 20 percent. Primary generalized epilepsy has not been documented after head injury.

Not all posttraumatic seizures are unprovoked. In one population-based cohort, there was a higher than expected incidence of alcohol withdrawal seizures, presumably a result of the relationship between alcohol ingestion and the risk of TBI [23]. In another cohort study, nearly half all new-onset seizures following head trauma were alcohol related [24].

Evaluation — The differential diagnosis and diagnostic approach to a patient with first late seizure is similar to the evaluation of any patient with a first seizure (see "Evaluation and management of the first seizure in adults"). If there is a history of TBI within the past two years, particularly one associated with risk factors for epilepsy, then the diagnostic evaluation for underlying etiology may be curtailed. As an example, if a patient has a seizure with partial onset that corresponds to the site of brain injury, and has no fever or unexplained abnormalities on examination, then it may be reasonable to limit the evaluation to a neuroimaging study (CT or MRI) and basic laboratories (chemistries and toxicology screen). If the trauma history is more remote, or the injury mild, then an association between the seizure and trauma may be less clear, and a thorough evaluation should be completed.

Brain MRI may be useful in ruling out other causes of epilepsy, but like EEG, it has no specific value in predicting either the development or remission of posttraumatic epilepsy. In patients whose seizures seem intractable to treatment or atypical of epilepsy, evaluation with video EEG can be helpful to rule out psychogenic nonepileptic seizures (see "Video and ambulatory EEG monitoring in the diagnosis of seizures and epilepsy" and "Psychogenic nonepileptic seizures: Etiology, clinical features, and diagnosis"). In one center, 24 percent of patients with confirmed nonepileptic seizures had a history of head trauma and a diagnosis of presumed posttraumatic epilepsy [46].

Management and prognosis — Recurrence of seizures without treatment is likely, as high as 86 percent in the first two years [45]. As a result, long-term anticonvulsant treatment is recommended for patients after an initial late seizure. An antiseizure medication active in partial epilepsy should be selected according to the considerations of age and comorbidity that apply to other individuals with new-onset epilepsy. (See "Initial treatment of epilepsy in adults".)

The remission rate for posttraumatic epilepsy is about 25 to 40 percent with initial treatment [7]. The event rate in the first year is predictive of the future course; patients having frequent seizures in the first year are less likely to have seizure remission [32]. Some will be refractory to treatment; over 13 percent of patients in the treatment groups of prophylactic antiseizure medication trials had seizures despite aggressive treatment regimens [7,47]. Surgical therapy may be an option for some of these patients. (See "Surgical treatment of epilepsy in adults".)

Prophylaxis — Because of the high incidence of posttraumatic epilepsy in some identified subgroups of head-injured patients and the potential for significant functional disability related to refractory epilepsy, many investigators have examined the potential of different preventative interventions. Animal models have shown encouraging results using antiseizure medications as well as neuroprotective agents in preventing the development of posttraumatic epilepsy.

In a pooled analysis of nine randomized controlled trials that compared antiseizure medications (carbamazepine, phenytoin, or phenobarbital) with placebo or standard care in patients with acute TBI, there was low-quality evidence that antiseizure medication therapy reduced early seizures but not late seizures [18]. Limitations in study design and execution of these trials, including delayed treatment, low power, primary use of older drugs with anticonvulsant rather than antiseizure properties, and suboptimal dosing, may have contributed to the lack of demonstrated benefit in the prevention of epilepsy [48]. However, the failure to reduce the incidence of posttraumatic epilepsy is similar to the results of efforts to limit epileptogenesis in other conditions [49].

Because of the absence of proven benefit for prophylactic antiseizure medication therapy for the prevention of posttraumatic epilepsy and the known risk of the adverse effects of these medications, they are not recommended for this purpose.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Seizures and epilepsy in adults" and "Society guideline links: Seizures and epilepsy in children".)

SUMMARY AND RECOMMENDATIONS — Early and late seizures following traumatic brain injury (TBI) are distinct entities.

●Early seizures occurring within one week are acute symptomatic events and are more common with intracranial hematoma, depressed skull fracture, severe injury, and in young children. (See 'Risk factors' above.)

●Short-term use of antiseizure medications is recommended for the prevention of early seizures in patients who are at high risk and in whom seizures present a threat because of elevated intracranial pressure, systemic injury, or other reason (Grade 1B). (See 'Management' above.)

●Seizures that occur after one week of TBI are likely to represent epilepsy. Except for age, late seizures share similar risk factors with early seizures. Posttraumatic epilepsy is more common in older adults and relatively unusual in children. (See 'Epidemiology and risk factors' above.)

●A neuroimaging study (computed tomography [CT] or magnetic resonance imaging [MRI]) is indicated for all patients with a new seizure. (See 'Evaluation' above and 'Evaluation' above.)

●Because of the high rate of recurrence, long-term treatment with antiseizure medications is recommended after a first late posttraumatic seizure (Grade 1B). (See 'Management and prognosis' above.)

●In patients who have not had a late posttraumatic seizure, we suggest not using antiseizure medications to prevent late seizures or posttraumatic epilepsy (Grade 2B). There is a lack of demonstrated efficacy in this setting and many potential adverse events with these medications. (See 'Prophylaxis' above.)