Abstracts

Rationale: Traumatic brain injury (TBI) causes 5% of all epilepsy. Attempts at preventing post-traumatic epilepsy (PTE) with older AEDs have failed. Levetiracetam (LEV)has potent anti-epileptogenic effects in animal models and a favorable side-effect and pharmacokinetic(PK)profile that make it a good candidate for PTE prevention.However,it has not been previously administered to patients with acute TBI.In this pilot study, we evaluate safety, tolerability, feasibility and pharmacokinetics of LEV administration to TBI subjects with high PTE risk. Methods: Subjects aged ≥6 years with TBI with high PTE risk (TBI with intracranial hemorrhage, penetrating injury, depressed skull fracture or early post-traumatic seizure)were enrolled in an open label study of LEV 55 mg/kg/day by mouth,n.g. tube or i.v. Treatment started within 8 hours of TBI and lasted 30 days, with two months’ post-TBI follow up. LEV levels were checked on study days 2, 3, 4, 7,14 and 30.PK profile of oral, n.g. and i.v. formulations was done on study days 3 and 30 in 26 adults and 16 children. AEs were evaluated on days 3,7,14,30 and 60. Additional 40 eligible adults and 20 children who presented 8-24 hours after TBI served as an “observational arm” for comparison of infection, psychiatric AEs and mortality (only), potential AEs of greatest concern. Results: 66 treatment (46 adults, 20 children) and 60 “observational” subjects (40 adults, 20 children) were enrolled. The 8 hour injury-treatment interval was not a barrier to enrollment. 81% (54/66) treated subjects completed the full protocol (78% adults, 90% children). 5% (3/66) subject were lost to follow up (4% adults, 5% children). LEV was safe and well tolerated. 4% subjects died, all adults, all of LEV-unrelated causes, with no difference between treated and observation groups. There were no medication-related SAEs. 12% (8/66) subjects discontinued LEV prematurely (15% adults, 5% children):3% (2) due to LEV-related toxicity (somnolence),both adults,9% for LEV-unrelated reasons. The elderly (>75)discontinued LEV more than other age groups (p<0.001). AES were mainly mild-moderate and transient. The commonest were fatigue, headache, somnolence, memory impairment, irritability, dizziness, depression and ataxia. Severity of symptoms did not correlate with trough LEV levels. Infections and behavioral scores did not differ between treated and observational groups. PK was similar to PKs in healthy and epileptic subjects. LEV was rapidly absorbed, with treatment day 3 mean T Max 2.5 h,Cmax 54 μg /ml, and area under curve of 380 h/μg/ml. Mean serum trough levels on days 2-30 ranged from 21-30 µg/ml, comparable to levels in kindling studies with antiepileptogenic effect.