Posttraumatic Epilepsy: Understanding Risk, Severity, and Outcomes

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Posttraumatic epilepsy is characterized by a pattern of spontaneous, recurrent, and chronic seizures.
Posttraumatic epilepsy is characterized by a pattern of spontaneous, recurrent, and chronic seizures.

Traumatic brain injury (TBI) is a common cause of epilepsy, particularly in children and young adults, accounting for 5% of all epilepsy cases.1-3 In a 2009 review, Lowenstein and colleagues3 estimated a risk for posttraumatic epilepsy (PTE) of 40% to 50% "in some settings." Risk for mortality in PTE is high, and negative outcomes affecting cognitive, affective, and physical function are common.4-6

PTE, characterized by a pattern of spontaneous, recurrent, and chronic seizures, is broadly classified into 2 types (early and late seizures), suggesting differences in etiology and pathophysiology after the trauma and leading up to the first seizure event.7,8

Early PTE occurs during the recovery period of the original traumatic brain injury, typically within the first 7 days postinjury.7,9 In a 2016 review, Arndt et al7 suggested that early seizures be further subclassified as occurring immediately, at the time of impact or within minutes of injury; within 24 hours of injury; and from day 2 to day 7 postinjury, although many practitioners treat these all as "early PTE." Alternately, late PTE is classified as seizures that occur more than 7 days after the initial injury.

PTE-Associated Outcomes

The majority of early posttraumatic seizures (50%-75%) have long been recognized to fall into "immediate" subclasses 1 and 2, occurring within the first 3 hours of injury.10 Arndt and colleagues reported 7 that early PTE resulting from a concussion (concussive convulsion), "is an entity that is not felt to be associated with significant intracranial pathology or poor long-term outcome. These seizures are typically brief and generalized, followed by rapid clearing of mentation, and the neurologic examination is nonfocal." At the same time, Zimmerman and colleagues9 point out that in general, "early posttraumatic seizures are not benign," and further, that they cause secondary brain injury "by eliciting a pathophysiologic response at a time when the brain is most vulnerable, and are associated with worse outcomes." A third subclass of PTEs that have delayed occurrence between days 2 and 7 are generally associated with rare, but more significant, traumatic brain injuries, such as intracranial hemorrhage.7

Epileptogenesis

Inflammation is a central mechanism to secondary injury to brain tissue after TBI, which may involve dysfunction of the blood-brain barrier, edema, and microglial and astrocytic activation and migration. In a 2017 review, Webster and colleagues11 explained that within minutes after the initial TBI, inflammatory cytokines are released, and blood-derived leukocytes are recruited into surrounding brain tissues. Neutrophil activity becomes enhanced, leading to oxidative stress and edema, and further promoting production of damaging cytokines and proteases to establish a recurrent, self-perpetuating cycle of seizure activity.12 The particular consequences of TBI differ by individual factors including patient age and circumstances, type, and severity of injury.

The epileptogenic process is believed to develop over time in 3 distinct stages11:

  1. Initiation by a triggering event,
  2. Latency, when the initial seizures transform brain activity toward recurrent epilepsy, and
  3. Chronicity, in which the seizure pattern becomes established.

Posttraumatic epilepsy is often difficult to treat, as commonly used antiepileptic drugs often have limited or no disease-modifying effects against PTEs once they have been initiated, and have shown no benefits in preventing future seizures or reducing their frequency.13,14 At this point, polypharmacy becomes the preferred approach to manage seizure activity; however, these patients are at high risk for the development of drug resistance.11 For these reasons, research has turned its sights on the narrow post-TBI window for interventional opportunities before conversion to PTE occurs.

Risk Factors for PTE

The strongest risk factor for the development of PTE is the severity of the initial trauma. A 2002 study15 found that risk for PTE had a positive correlation with TBI severity, such that mild, moderate, and severe TBI were associated with a 1.4-fold, 4-fold, and 29-fold increased risk for epilepsy, respectively.

Types of injuries, including skull fracture and intracranial hematoma, are also associated with a higher risk for PTE, as is the occurrence of the first seizure within 7 days of TBI.3 Several studies have also reported a higher risk for seizures occurring after abusive head trauma compared with other injuries caused by falls, bicycle or motor vehicle accidents, or blunt force trauma.16

A particularly interesting risk factor is age, as numerous reviews have consistently reported a higher risk for TBI-associated PTE in young children compared with adults, with reported risks as high as 60%7 Children younger than 5 years appear to be more likely to have a first seizure within 7 days after TBI, which may contribute to the overall increase in this age group compared with those older than 5 years.10 The main mechanism for this may be a higher propensity for inflammation in neonatal nervous systems.

Given these facts, investigators recommend immediate prophylactic treatment postinjury for both children and adults at high risk for PTE with available antiepileptic drugs to reduce the incidence of early seizures, although such therapy has not been shown to prevent future seizures once PTE has started.1,8,9

References

  1. Xu T, Yu X, Ou S, et al. Risk factors for posttraumatic epilepsy: a systematic review and meta-analysis. Epilepsy Behav. 2017;67:1-6.
  2. Englander J, Bushnik T, Wright JM, Jamison L, Duong TT. Mortality in late post-traumatic seizures. J Neurotrauma. 2009;26:1471-1477.
  3. Lowenstein DH. Epilepsy after head injury: an overview. Epilepsia. 2009;50:4-9.
  4. Christensen J. The epidemiology of posttraumatic epilepsy. Semin Neurol. 2015;35:218-222.
  5. Englander J, Bushnik T, Duong TT, et al. Analyzing risk factors for late posttraumatic seizures: a prospective, multicenter investigation. Arch Phys Med Rehabil. 2003;84:365-373.
  6. Mazzini L, Cossa FM, Angelino E, Campini R, Pastore I, Monaco F. Posttraumatic epilepsy: neuroradiologic and neuropsychological assessment of long-term outcome. Epilepsia. 2003;44:569-574.
  7. Arndt DH, Goodkin HP, Giza CC. Early posttraumatic seizures in the pediatric population. J Child Neurol. 2016;31:46-56.
  8. Arndt DH, Giza CC. Post-traumatic seizures and epilepsy. In: Chapman K, Rho JM, eds, Pediatric Epilepsy Case Studies: From Infancy and Childhood Through Adolescence. Boca Raton, FL: CRC Press; 2008.
  9. Zimmerman LL, Diaz-Arrastia R, Vespa PM. Seizures and the role of anticonvulsants after traumatic brain injury. Neurosurg Clin N Am. 2016;27:499-508.
  10. Jennett B. Early traumatic epilepsy. Incidence and significance after nonmissile injuries. Arch Neurol. 1974;30:394-398.
  11. Webster KM, Sun M, Crack P, et al. Inflammation in epileptogenesis after traumatic brain injury. J Neuroinflammation. 2017;14:10.
  12. Morganti-Kossmann MC, Rancan M, Stahel PF, Kossmann T. Inflammatory response in acute traumatic brain injury: a double-edged sword. Curr Opin Crit Care 2002;8:101-105.
  13. Temkin NR. Antiepileptogenesis and seizure prevention trials with antiepileptic drugs: meta-analysis of controlled trials. Epilepsia. 2001;42:515-524.
  14. Beghi E. Overview of studies to prevent posttraumatic epilepsy. Epilepsia. 2003;44:21-26.
  15. Herman ST. Epilepsy after brain insult: targeting epileptogenesis. Neurology. 2002;59:S21-26.
  16. Arndt DH, Lerner JT, Matsumoto JH, et al. Subclinical early posttraumatic seizures detected by continuous EEG monitoring in a consecutive pediatric cohort. Epilepsia. 2013;54:1780-1788.
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