Update: Posttraumatic epilepsy

Traumatic brain injury (TBI) is one of the most common causes of acquired epilepsy, and posttraumatic epilepsy (PTE) results in significant somatic and psychosocial morbidity.

The incidence of early post-traumatic seizures after civilian traumatic brain injury ranges 4-25%.

The true incidence of PTE in children is still uncertain, because most research has been based primarily on adults.

PTE in a pediatric population with mild traumatic brain injury (MTBI), was found to confer increased risk for the development of PTE and intractable PTE, of 4.5 and 8 times higher, respectively. As has been established in adults, these findings confirm that MTBI increases the risk for PTE in the pediatric population 1).

Risk

The risk of developing PTE relates directly to TBI severity, but the latency to first seizure can be decades after the inciting trauma. Given this “silent period,” much work has focused on identification of molecular and radiographic biomarkers for risk stratification and on development of therapies to prevent epileptogenesis.

Research suggests that there are reciprocal relationships between mental health (MH) disorders and epilepsy risk.

Data suggest that PTE is associated with mental health (MH) outcomes 2years after TBI, findings whose significance may reflect reciprocal, biological, psychological, and/or experiential factors contributing to and resulting from both PTE and MH status post-TBI. Future work should consider temporal and reciprocal relationships between PTE and MH as well as if/how treatment of each condition influences biosusceptibility to the other condition 2).

Treatment

The control of early post-traumatic seizure is mandatory because these acute insults may add secondary damage to the already damaged brain with poor outcome. Prophylactic use of antiepileptic drugs have been found to be have variable efficacy against early post-traumatic seizures.

Based on current studies, however, anticonvulsants have been shown to reduce early PTE occurring within the first 7 days, but little to no benefits have been shown in late PTS occurring after 7 days 3).

Clinical management requires vigilant neurologic surveillance and recognition of the heterogeneous endophenotypes associated with PTE.

Appropriate treatment of patients who have or are at risk for seizures varies as a function of time after TBI, and the clinician’s armamentarium includes an ever-expanding diversity of pharmacological and surgical options.


The lack of evidence on which antiepileptic drug to use in PTE is surprising given the number of patients prescribed an antiepileptic drug therapy for TBI. On the basis of currently available Level III evidence, patients treated with either levetiracetam or phenytoin have similar incidences of early seizures after TBI 4).

There is no statistically significant difference in the efficacy of Phenytoin and Levetiracetam in prophylaxis of early posttraumatic seizures in cases of moderate to severe traumatic brain injury 5).


Most recently, neuromodulation with implantable devices has emerged as a promising therapeutic strategy for some patients with refractory PTE 6).

Systematic review

During June and July 2015, a systematic literature search was performed that identified 6097 articles. Of these, 7 met inclusion criteria. A random-effects meta-analysis was performed. A total of 1186 patients were included. The rate of seizure was 35 of 654 (5.4%) in the levetiracetam cohort and 18 of 532 (3.4%) in the phenytoin cohort. The meta-analysis revealed no change in the rate of early PTS with levetiracetam compared with phenytoin (relative risk, 1.02; 95% confidence interval, 0.53-1.95; P = .96).

The lack of evidence on which antiepileptic drug to use in PTS is surprising given the number of patients prescribed an antiepileptic drug therapy for TBI. On the basis of currently available Level III evidence, patients treated with either levetiracetam or phenytoin have similar incidences of early seizures after TBI 7)

Case series

2016

In a retrospective multicenter cohort study including 5 regional pediatric trauma centers affiliated with academic medical centers, the authors examined data from 236 children (age < 18 years) with severe traumatic brain injury (TBI) (admission Glasgow Coma Scale score ≤ 8, ICD-9 diagnosis codes of 800.0-801.9, 803.0-804.9, 850.0-854.1, 959.01, 950.1-950.3, 995.55, maximum head Abbreviated Injury Scale score ≥ 3) who received tracheal intubation for ≥ 48 hours in the ICU between 2007 and 2011.

Of 236 patients, 187 (79%) received seizure prophylaxis. In 2 of the 5 centers, 100% of the patients received seizure prophylaxis medication. Use of seizure prophylaxis was associated with younger patient age (p < 0.001), inflicted TBI (p < 0.001), subdural hematoma (p = 0.02), cerebral infarction (p < 0.001), and use of electroencephalography (p = 0.023), but not higher Injury Severity Score. In 63% cases in which seizure prophylaxis was used, the patients were given the first medication within 24 hours of injury, and 50% of the patients received the first dose in the prehospital or emergency department setting. Initial seizure prophylaxis was most commonly with fosphenytoin (47%), followed by phenytoin (40%).

While fosphenytoin was the most commonly used medication for seizure prophylaxis, there was large variation within and between trauma centers with respect to timing and choice of seizure prophylaxis in severe pediatric TBI. The heterogeneity in seizure prophylaxis use may explain the previously observed lack of relationship between seizure prophylaxis and outcomes 8).

1)

Keret A, Bennett-Back O, Rosenthal G, Gilboa T, Shweiki M, Shoshan Y, Benifla M. Posttraumatic epilepsy: long-term follow-up of children with mild traumatic brain injury. J Neurosurg Pediatr. 2017 Jul;20(1):64-70. doi: 10.3171/2017.2.PEDS16585. Epub 2017 May 5. PubMed PMID: 28474982.

2)

Juengst SB, Wagner AK, Ritter AC, Szaflarski JP, Walker WC, Zafonte RD, Brown AW, Hammond FM, Pugh MJ, Shea T, Krellman JW, Bushnik T, Arenth PM. Post-traumatic epilepsy associations with mental health outcomes in the first two years after moderate to severe TBI: A TBI Model Systems analysis. Epilepsy Behav. 2017 Jun 25;73:240-246. doi: 10.1016/j.yebeh.2017.06.001. [Epub ahead of print] PubMed PMID: 28658654.

3)

Kirmani BF, Robinson DM, Fonkem E, Graf K, Huang JH. Role of Anticonvulsants in the Management of Posttraumatic Epilepsy. Front Neurol. 2016 Mar 22;7:32. eCollection 2016. Review. PubMed PMID: 27047441.

4)

Khan NR, VanLandingham MA, Fierst TM, Hymel C, Hoes K, Evans LT, Mayer R, Barker F, Klimo P Jr. Should Levetiracetam or Phenytoin Be Used for Posttraumatic Seizure Prophylaxis? A Systematic Review of the Literature and Meta-analysis. Neurosurgery. 2016 Sep 30. PubMed PMID: 27749510.

5)

Khan SA, Bhatti SN, Khan AA, Khan Afridi EA, Muhammad G, Gul N, Zadran KK, Alam S, Aurangzeb A. Comparison Of Efficacy Of Phenytoin And Levetiracetam For Prevention Of Early Post Traumatic Seizures. J Ayub Med Coll Abbottabad. 2016 Jul-Sep;28(3):455-460. PubMed PMID: 28712212.

6)

Rao VR, Parko KL. Clinical Approach to Posttraumatic Epilepsy. Semin Neurol. 2015 Feb;35(1):57-63. Epub 2015 Feb 25. PubMed PMID: 25714868.

7)

Khan NR, VanLandingham MA, Fierst TM, Hymel C, Hoes K, Evans LT, Mayer R, Barker F, Klimo P Jr. Should Levetiracetam or Phenytoin Be Used for Posttraumatic Seizure Prophylaxis? A Systematic Review of the Literature and Meta-analysis. Neurosurgery. 2016 Dec;79(6):775-782. PubMed PMID: 27749510.

8)

Ostahowski PJ, Kannan N, Wainwright MS, Qiu Q, Mink RB, Groner JI, Bell MJ, Giza CC, Zatzick DF, Ellenbogen RG, Boyle LN, Mitchell PH, Vavilala MS; PEGASUS (Pediatric Guideline Adherence and Outcomes) Study.. Variation in seizure prophylaxis in severe pediatric traumatic brain injury. J Neurosurg Pediatr. 2016 Oct;18(4):499-506. PubMed PMID: 27258588.

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