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Keywords:

  • Posttraumatic epilepsy;
  • Levetiracetam;
  • Pediatric

Summary

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References

Posttraumatic seizures develop in up to 20% of children following severe traumatic brain injury (TBI). Children ages 6–17 years with one or more risk factors for the development of posttraumatic epilepsy, including presence of intracranial hemorrhage, depressed skull fracture, penetrating injury, or occurrence of posttraumatic seizure were recruited into this phase II study. Treatment subjects received levetiracetam 55 mg/kg/day, b.i.d., for 30 days, starting within 8 h postinjury. The recruitment goal was 20 treated patients. Twenty patients who presented within 8–24 h post-TBI and otherwise met eligibility criteria were recruited for observation. Follow-up was for 2 years. Forty-five patients screened within 8 h of head injury met eligibility criteria and 20 were recruited into the treatment arm. The most common risk factor present for pediatric inclusion following TBI was an immediate seizure. Medication compliance was 95%. No patients died; 19 of 20 treatment patients were retained and one observation patient was lost to follow-up. The most common severe adverse events in treatment subjects were headache, fatigue, drowsiness, and irritability. There was no higher incidence of infection, mood changes, or behavior problems among treatment subjects compared to observation subjects. Only 1 (2.5%) of 40 subjects developed posttraumatic epilepsy (defined as seizures >7 days after trauma). This study demonstrates the feasibility of a pediatric posttraumatic epilepsy prevention study in an at-risk traumatic brain injury population. Levetiracetam was safe and well tolerated in this population. This study sets the stage for implementation of a prospective study to prevent posttraumatic epilepsy in an at-risk population.

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality in the pediatric age group, causing >50% of childhood deaths (Mazzola & Adelson, 2002). There are 1.4 million TBIs in the United States annually; 626,000 are in children up to age 19 (Aitken et al., 2009). Posttraumatic epilepsy is reported in 10–20% of children following severe TBI (Statler, 2006). Posttraumatic seizures may be immediate (<24 h following injury) or early (<1 week following injury), both of which are referred to as “early posttraumatic seizures” or late (>1 week after injury), referred to as “late posttraumatic seizures or “post-traumatic epilepsy (PTE).” Although phenytoin, valproate, and carbamazepine may prevent early posttraumatic seizures (Temkin, 2009), no medication has been demonstrated to effectively prevent posttraumatic epilepsy.

Levetiracetam (LEV), a broad spectrum antiepileptic, has been shown to have antiepileptogenic and neuroprotective effects in animal models, and a favorable side-effect profile. LEV is used as a first- or second-line therapy in idiopathic generalized epilepsies (generalized and myoclonic seizures) and in partial seizures. We present the pediatric data of a phase II study of LEV to prevent posttraumatic epilepsy. This is the first study to investigate the prevention of PTE in children since a negative phenytoin study in 41 children 30 years ago (Young et al., 1983).

In this pilot study, we evaluated safety, tolerability, retention, compliance, and feasibility of acute and chronic LEV administration to pediatric TBI patients with high risk factors for developing posttraumatic epilepsy. This study was a prerequisite and antecedent to a larger study powered to test efficacy in reducing the incidence of PTE. Results of the combined adult and pediatric cohorts are reported separately (Klein et al., 2012). This report provides separate details on the pediatric population, which was studied at a single site (Children's National Medical Center, Washington, DC, U.S.A.).

Methods

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References

Inclusion criteria were age 6–17 years and TBI with risk factors for the development of posttraumatic epilepsy. Risk factors were intracranial hemorrhage (except isolated subarachnoid hemorrhage) or penetrating wound injury, depressed skull fracture with subdural tear, or early posttraumatic seizure. These criteria identify adult patients with an average 20% risk of PTE (Temkin, 2003).

Exclusion criteria included a best Glasgow Coma Score (GCS) <6 measured within 4 h of injury (to avoid high risk of mortality); serum creatinine levels ≥1.0 for ages 13–17 and ≥0.7 for ages 6–12; history of unprovoked seizures, psychosis, stroke, or prior TBI or encephalitis within the last 3 years; antiepileptic drug use in the previous 3 months; existing unstable medical disease, pregnancy, or moderate to severe intellectual deficiency.

Treatment subjects received LEV 55 mg/kg/day, b.i.d., with the first dose delivered within 8 h of injury, and continuing for 30 days. Children received the tablet form; those children who were unable to swallow tablets received suspension. Children who were nothing by mouth upon admission received nasogastric or intravenous administration until they were able to swallow. Treated subjects were evaluated on days 3, 7, 14, 30, and 60 (1 month posttreatment) with examinations and LEV blood levels measured through day 30.

The recruitment goal was 20 treated patients. An additional 20 patients who presented between 8 and 24 h post-TBI and otherwise met all other eligibility criteria were recruited into a nontreatment group monitored for infection, psychiatric symptoms, and potential medication-related side effects. The Achenbach System of Empirically Based Assessment (ASEBA) and the Center for Epidemiological Studies Depression Scale for Children (CES-DC) were used to monitor psychological symptoms. Subjects were followed for 2 years.

Results

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References

Recruitment of 20 patients each into both the treatment and observation cohorts was achieved in 29 months. There were 45 patients screened within 8 h of head injury, and 20 were recruited into the treatment arm (recruitment rate 44%).

Causes for injury included motor vehicle–related incidents (automobile passengers or struck pedestrians), sports-related, assaults, falls, and recreational vehicles (bicycles, all-terrain vehicles, and skateboards). The most common cause of injury in all pediatric age groups involved motor vehicles, with struck pedestrians occurring most frequently (in six patients ages 6–9 and five patients ages 10–13).

The study population male-to-female ratio was 4:1 and racial distribution was 55% African American, 43% Caucasian, and 2% Latino. The mean GCS score for recruited patients was 12.28, with standard deviation of 3.47 (Table 1).

Table 1. Demographics of subject population, N = 40
DemographicTotalLVT treatedNot LVT treated
n%n%n%
Gender      
Male338314701995
Female71763015
Race      
African American22558401470
Caucasian17431155630
Other121500
Age      
6–914351050420
10–1318458401050
14–18820210630
Glasgow Coma Score      
6–81128105015
9–1241015315
13–1525629451680

No patients died; 19 of 20 treatment patients were retained, and one treatment patient withdrew for reasons unrelated to medication. One observation patient was lost to follow-up. There were no higher incidences of disordered mood or behavior problems among treatment subjects compared to the observation group (adjusted p ≥ 0.547 for mean ASEBA and CES-D scores, by multivariate analysis). In addition, there was no statistically significant difference (p = 0.695, by Fisher's exact test) in the incidence of infections: three patients (15%) in the treatment group and five patients (20%) in the observation group developed infections within 60 days.

The most common symptoms ranked as severe by treatment subjects were headache, fatigue, drowsiness, and irritability. Although 85% of treated subjects reported fatigue, only 5% ranked it severe. Mild to moderate headaches were reported by 55% of treated subjects and mild to moderate drowsiness or somnolence by 45% of treated subjects. One patient in the treatment group experienced psychosis, characterized by transient mild paranoia with spontaneous resolution without LEV discontinuation.

LEV blood levels measured at each visit indicated that 60% of children were 100% compliant, that is, 40% of patients had at least one plasma LEV measurement of <7 μm/ml. Only 1 (2.5%) of 40 children developed posttraumatic epilepsy. This subject was in the treatment group. In contrast, 13 (15%) of 86 adult subjects developed PTE—5 (11%) of 46 treated and 8 (20%) of 40 untreated (Klein et al., 2012). However, patients were not randomized to compare the incidence of PTE in matched cohorts in this phase II study.

Reasons for inclusion in the study differed between the pediatric (age ≤17) and adult (≥18) cohorts. More children were enrolled with early posttraumatic seizures as the sole inclusion criterion when compared to adults (20% of children vs. 1% of adults). This was true even when an early posttraumatic seizure was one of multiple inclusion criteria (30% of children and 8% of adults). In addition, fewer children were enrolled with intracranial hemorrhages: 75% of children, as opposed to 98% of adults (Table 2). Intracranial hemorrhage sizes were small (≤2 cc) in the majority (70%) of enrolled children.

Table 2. Patient breakdown by inclusion criteria
Inclusion criteriaChildren (N = 40)Adults (N = 86)
n%n%
Early seizure123078
Early seizure only82011
Intracranial hemorrhage30758498
Subdural hematoma11283541
Skull fracture8202428
Penetrating wound1345

Discussion

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References

This was the first prospective evaluation of posttraumatic epilepsy in children after head injury with follow-up >18 months. Few pediatric studies of PTE risk factors have been performed, and many of these have been small, heterogeneous, have defined posttraumatic epilepsy to include both late and early seizures, and have included infants—a population in which the most common etiology is nonaccidental trauma (Statler, 2006). A recent study found lesser susceptibility to posttraumatic epilepsy in individuals younger than 15 years compared to older individuals (Christensen et al., 2009). A retrospective study of 275 children older than 4½ years with moderate-to-severe TBI identified impact seizures (beginning in the first moments after injury), as a risk factor for early posttraumatic seizures, that is, those occurring within the first week after injury (Liesemer et al., 2011).

Our study demonstrated feasibility and tolerability of LEV in the context of epilepsy prevention following TBI in a high-risk pediatric population. Risk factors and inclusion criteria followed those indicated for adults (Temkin, 2003). Acute and chronic treatment with LEV (55/kg/day) was safe and well tolerated in children ages 6–17 years with TBI. No children discontinued treatment caused by side effects. Timely pediatric subject recruitment, that is, within 8 h of injury, and retention in an interventional study of TBI subjects is feasible. This study demonstrated successful pediatric involvement in a phase II safety and feasibility study to prevent or modify the development of epilepsy in an at-risk population.

Acknowledgments

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References

The study was supported by the NIH, Grant 1 R01 NS45656, and the GCRC of Children's National Medical Center. Levetiracetam was provided by UCB Pharma, Inc.

Disclosure

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References

None of the authors have conflicts of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

References

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References