Posttraumatic seizures and epilepsy

INTRODUCTION — Seizures and epilepsy are long-recognized complications of traumatic brain injury (TBI).

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 POSTTRAUMATIC SEIZURES

Definition — 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 [1,2]; others include them in the category of early seizures because they may have a similar associated risk for posttraumatic epilepsy [3]. (See 'Prognosis of early seizures' below.)

Epidemiology and risk factors — Overall, the incidence of early posttraumatic seizures ranges from 0.4 to 10 percent but may be as high as 20 to 25 percent in some high-risk groups with severe types of head injury [4-9]. However, early seizures may occur even in patients with mild traumatic brain injury (TBI) and normal head computed tomography (CT). 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 [10,11].

Risk factors for early posttraumatic seizures identified in various studies include the following [4-8,12-15]:

●Greater severity of head injury (as defined by the Glasgow Coma Scale [GCS]) and overall injury

●Depressed skull fracture

●Penetrating head injury

●Intracerebral hematoma requiring evacuation

●Subdural hemorrhage

●Subarachnoid hemorrhage

●History of alcohol abuse

●Higher pre-injury medical comorbidities

●TBI sustained after a low fall

●Young age

Younger children are at higher risk for early posttraumatic seizures than adolescents and adults [13]. 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 [14]. In a larger series of more than 2000 children with severe TBI, the overall risk of early posttraumatic seizures was 25 percent [15]. 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 of early posttraumatic seizures — Approximately one-half of early posttraumatic seizures occur during the first 24 hours, and one-quarter occur within the first hour [16].

Most reported clinical seizures (72 to 84 percent) presenting within the first day are generalized tonic-clonic type [12,17]. 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 focal aware (pure motor) seizures or focal to bilateral tonic-clonic seizures (secondary generalization) [3,17]. Focal seizures with impaired awareness (complex partial seizures) are rare in this setting. However, with continuous EEG monitoring, exclusively nonconvulsive seizures may account for one-half or more of early seizures among patients with moderate to severe TBI [18].

Status epilepticus has been reported in 6.5 to 18 percent of patients with early seizures after acute head injury but occurs in just 0.2 percent of all cases of moderate to severe brain injury [3,8,19]. 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. (See "Convulsive status epilepticus in adults: Classification, clinical features, and diagnosis", section on 'Complications and outcome'.)

Evaluation for TBI and early seizures

●Determining the severity of TBI – The immediate evaluation of patients with TBI is directed by the severity of the injury. The GCS is commonly used to assess and communicate neurologic status in this setting (table 1).

•Adults – Mild TBI is defined by a GCS score of 14 or 15. Moderate TBI is defined by a GCS score 9 through 13. Severe TBI is defined by a GCS score <9. (See "Management of acute moderate and severe traumatic brain injury".)

•Children ≥2 years of age – Minor head trauma is defined by a GCS score of ≥13 or ≥14, no abnormalities on neurologic examination, and no evidence of skull fracture. Moderate TBI is defined by a GCS of 9 through 12 and severe TBI by a GCS score <9. (See "Minor head trauma in infants and children: Management", section on 'Definitions' and "Severe traumatic brain injury (TBI) in children: Initial evaluation and management", section on 'Severity classification'.)

●Concussion or mild TBI – Patients with suspected concussion or mild TBI should be medically evaluated by a trained licensed health professional, whether in a doctor's office, in an emergency department, or on an athletic field sideline. Patients with loss of consciousness or persistent symptoms should be evaluated in an emergency department. Imaging, usually head CT without contrast as the first study, should be obtained for all patients with a seizure, altered mental status, or other neurologic deficit. (See "Acute mild traumatic brain injury (concussion) in adults", section on 'Evaluation' and "Minor head trauma in infants and children: Management".)

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.

●Moderate and severe TBI – Patients with moderate or severe TBI require an imaging study, typically a head CT, as part of their injury evaluation. The early management of moderate and severe TBI is reviewed separately. (See "Management of acute moderate and severe traumatic brain injury" and "Severe traumatic brain injury (TBI) in children: Initial evaluation and management".)

●Role of EEG – Continuous EEG monitoring is indicated in the setting of TBI for all patients with clinical suspicion of seizures, as suggested by paroxysmal events of uncertain cause or altered mental status, and for patients with conditions that may mask seizures, including sedation, anesthesia, or paralysis [20]. Patients should be transferred (if possible) to a center with continuous EEG and epilepsy expertise if these are not available at the local center. Additional proposed indications for children include the presence of intra-axial blood on brain imaging, evidence of abusive head trauma, and younger age [19]. Routine EEG is not sufficient to exclude seizures in these settings but may be helpful in the setting of abnormal mental status.

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 of early seizures

●Treatment of early seizures – Although early posttraumatic seizures may not recur, antiseizure medications are used to reduce the risk of seizure recurrence, status epilepticus, aggravation of a systemic injury, and other complications of seizures. As an example, recurrent seizures may increase cerebral blood flow and could theoretically increase intracranial pressure.

●Choice and duration of antiseizure medication treatment – 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 [21,22].

●Prophylaxis for early seizures – Selected patients with moderate or severe TBI may be treated with short-term prophylactic antiseizure medication. Patients with less severe TBI generally do not require prophylactic treatment. This is discussed separately. (See "Management of acute moderate and severe traumatic brain injury", section on 'Antiseizure medications and electroencephalography monitoring'.)

In patients who have not had a seizure but appear to be at increased risk for early seizures (see 'Epidemiology and risk factors' above), antiseizure medication treatment reduces the incidence of early seizures [21,23].

The use of antiseizure medications after head injury does not reduce the risk of late seizures or posttraumatic epilepsy and has been associated with worse rehabilitation outcomes [24]. (See 'Prophylaxis against epilepsy' below.)

Prognosis of early seizures

●Early outcomes – Early posttraumatic seizures are associated with worse in-hospital outcomes, including longer length of stay, increased intensive care unit admission, need for mechanical ventilation, and discharge to a facility rather than home; data regarding risk of mortality are inconsistent [7,8].

●Risk for development of epilepsy – 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 relatively low likelihood of recurrence, whereas late seizures represent epilepsy. Nevertheless, patients with early seizures are at higher risk for the development of posttraumatic epilepsy compared with those who do not have early seizures [6].

Some investigators believe that immediate seizures or "concussive convulsions" occurring upon or within seconds of impact 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 [1]. Others have found a more similar prognosis for immediate seizures and all early seizures [3,25,26].

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 [10]. 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 [4].

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.

Pathophysiology — Posttraumatic seizures may be associated with the typical pathologic 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 [27-29].

Selective damage to the hilar region of the hippocampus is produced in animal models after fluid-percussion traumatic brain injury (TBI) [30]. 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 [31].

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 [32]. Brain injury due to mechanical trauma induces delayed secondary injury from inflammation, which influences the progression of epileptogenesis in addition to the effect of genetic susceptibilities [33-35]. These findings suggest a possible future role for neuroprotective treatment [17,34].

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) [36]. 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 [37]. 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 [38].

Epidemiology and risk factors — While only 4 percent of all epilepsy cases are attributed to trauma, 13 percent of those cases that are of known cause are posttraumatic [39]. TBI is also the most important cause of symptomatic epilepsy in persons aged 15 to 24 years.

The estimated incidence of epilepsy after TBI is as high as 15 percent in adults [40] and 10 percent in children [41].

●Risk factors – Risk factors for posttraumatic epilepsy identified in various studies include the following [4,5,14,40-45]:

•Severity of TBI as defined by the Glasgow Coma Scale (GCS)

•Penetrating brain injury

•Depressed skull fracture

•Alcohol-related head injury

•Early seizures (see 'Prognosis of early seizures' above)

•Intracranial hemorrhage

•Intracranial infection

•Surgical procedures including hemorrhage evacuation and ventriculostomy

•Older age

•Epileptiform abnormalities on EEG

•Focal neurologic signs

●Severity of TBI – The severity of TBI correlates with risk of posttraumatic epilepsy [10,11,42,43,46-49]. 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) [10]. In another study of 647 hospitalized patients that categorized TBI severity more traditionally with the GCS, the two-year incidence of epilepsy was 8.0 percent for GCS 13 to 15 and 16.8 percent for GCS 3 to 8 [47].

Simple concussion may not be a risk factor for epilepsy, although most studies have found that TBI is associated with a slightly elevated risk. One retrospective cohort study of 330 patients with a history of concussion or mild TBI found no increased risk of epilepsy; exclusion criteria were abnormal brain imaging on CT or MRI, a GCS <13 more than one hour postinjury, or hospitalization >48 hours [50].

●Other markers of increased risk – Other subsets of patients at higher risk have been identified and include those with early seizures, intracranial hemorrhage or cerebral contusion, depressed skull fracture, penetrating head injury, decompressive hemicraniectomy, and intracranial infection [4,5,14,42-44]. Any alcohol-related head injury, even when classified as mild, is a significant predictor of new-onset seizures [11]. TBI associated with intracranial lesions on CT was associated with an 18 percent risk of late seizures in one series [17]. In penetrating missile combat injuries, the incidence is more than 50 percent [17,51]. The requirement for neurosurgical procedure (hemorrhage evacuation, ventriculostomy) increased the risk, and multiple surgeries increased the risk over single surgeries [47].

●EEG findings – Epileptiform abnormalities on EEG that are apparent within five days after TBI may be a marker of increased risk for the development of first-year posttraumatic epilepsy [49]. However, in those with early epileptiform abnormalities, the benefit of starting antiseizure medication before the onset of the first seizure is uncertain.

●Age and sex – In contrast to early seizures, older age (>65 years) is a risk factor for posttraumatic epilepsy [10]. Posttraumatic epilepsy is less common in the pediatric population [10,46]. In one large, population-based study, the risk of posttraumatic epilepsy was slightly higher in women than men [46]; in another, men were at higher risk [43].

●Genetics – 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 [52,53]. 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 [46].

Prophylaxis against epilepsy — We do not treat patients with antiseizure medications for prophylaxis because of the absence of proven benefit for the prevention of posttraumatic epilepsy and the known risk of the adverse effects of these medications.

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 preventive interventions. 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 [23]. 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 [54]. However, the failure to reduce the incidence of posttraumatic epilepsy is similar to the results of efforts to limit epileptogenesis in other conditions [55].

Clinical features of posttraumatic epilepsy

●Onset – Approximately 40 percent of individuals with posttraumatic epilepsy have onset within six months, 50 percent within one year, and approximately 80 percent within two years of head injury [6,17,56]. Posttraumatic epilepsy may begin more than 15 years later [10,16,42,46]. The more severe the head injury, the longer the patient is at risk for late seizures; in a population-based study, patients remained at risk for epilepsy after mild TBI for up to five years, after moderate TBI for up to 10 years, and after severe TBI for 20 years or more [10].

●Seizure types in posttraumatic epilepsy – 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 focal to bilateral (secondarily generalized) with or without apparent focal onset in 60 to 80 percent [47,57]. Focal aware (simple) and focal impaired awareness (complex partial) seizures each account for 10 to 20 percent. Primary generalized epilepsy has not been documented after head injury.

●Alcohol withdrawal seizures – Not all posttraumatic seizures are unprovoked. Alcohol use confounds seizure diagnosis in many patients with head injury. 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 [10]. In another cohort study, nearly half of all new-onset seizures following head trauma were alcohol related [11].

●Paroxysmal nonepileptic seizures (PNES) – In addition to posttraumatic epilepsy, TBI is associated with PNES in adult and pediatric populations [58]. (See "Psychogenic nonepileptic seizures: Etiology, clinical features, and diagnosis", section on 'Common comorbidities'.)

Evaluation of late seizures — 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 (see 'Epidemiology and risk factors' above), then the diagnostic evaluation for underlying etiology may be curtailed. As an example, if a patient has a seizure with focal 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 (generally a CT, which should reveal the trauma-related brain injury) 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, 45 percent of patients with confirmed psychogenic nonepileptic seizures had a history of traumatic brain injury [59].

Management of late seizures — For patients with a history of moderate to severe TBI, we recommend long-term treatment with antiseizure medication after an initial late seizure. Recurrence of seizures without treatment is likely for these patients, as high as 86 percent in the first two years [57]. In contrast to patients with moderate or severe TBI, patients with a history of mild TBI may have late seizures or epilepsy due to other reasons, and recurrence risk and treatment decisions should be based upon brain imaging and EEG findings.

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. Some experts consider lamotrigine, carbamazepine, oxcarbazepine, and lacosamide as first-line choices for patients with TBI, particularly if there are comorbid behavioral or mood issues [58]. Levetiracetam is also an option, although behavioral problems and irritability are potential adverse effects. (See "Initial treatment of epilepsy in adults".)

Prognosis of posttraumatic epilepsy — Posttraumatic epilepsy contributes significantly to the functional disability in a survivor of TBI [9]. The remission rate for posttraumatic epilepsy is approximately 25 to 40 percent with initial treatment [5]. 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 [51].

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 [5,60]. Surgical therapies may be an option for some of these patients. (See "Evaluation and management of drug-resistant epilepsy" and "Surgical treatment of epilepsy in adults".)

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

●Implications of early versus late seizures – Early and late seizures following traumatic brain injury (TBI) are distinct entities; early seizures occur within one week of TBI and are acute events with a relatively low risk of recurrence. Late seizures occur more than one week after TBI and usually represent the onset of posttraumatic epilepsy. (See 'Early posttraumatic seizures' above and 'Posttraumatic epilepsy' above.)

●Risk factors for early seizures – Early seizures are more common with greater severity of head injury, intracranial hemorrhage, penetrating head injury, depressed skull fracture, and other factors discussed above. (See 'Epidemiology and risk factors' above.)

●Evaluation of TBI and early seizures – Patients with mild TBI who have loss of consciousness or persistent symptoms should be evaluated in an emergency department. Imaging, usually head CT without contrast, should be obtained for all patients with a seizure, altered mental status, or other neurologic deficit. Patients with moderate or severe TBI require an imaging study, typically a head CT, as part of their injury evaluation. Continuous EEG monitoring (where available) is indicated in the setting of TBI for patients with clinical suspicion of seizures. (See 'Evaluation for TBI and early seizures' above.)

●Prophylaxis for early seizures – Selected patients with moderate or severe TBI may be treated with short-term prophylactic antiseizure medication. Patients with less severe TBI generally do not require prophylactic treatment. This is discussed separately. (See "Management of acute moderate and severe traumatic brain injury", section on 'Antiseizure medications and electroencephalography monitoring'.)

●Treatment of early seizures – Antiseizure medication is used to treat early seizures to prevent seizure recurrence and to reduce the risk of status epilepticus or other complications of seizures. In the absence of seizure recurrence, antiseizure medication may be gradually withdrawn over a few weeks after hospital discharge. (See 'Management of early seizures' above.)

●Posttraumatic epilepsy – 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.)

●Prophylaxis for late seizures – In patients who have not had a late posttraumatic seizure, we suggest against 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 against epilepsy' above.)

●Evaluation and management of late seizures

•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".)

•For patients with a history of moderate to severe TBI who have a first late posttraumatic seizure, we recommend long-term treatment with antiseizure medication (Grade 1B). Recurrence of seizures without treatment is likely for these patients. Patients with a history of mild TBI may have late seizures or epilepsy due to other reasons, and recurrence risk should be based on brain imaging and EEG findings. (See 'Management of late seizures' above.)