A clinical trial of enteral Levetiracetam for acute seizures in pediatric cerebral malaria

Abstract

BackgroundAcute seizures are common in pediatric cerebral malaria (CM), but usual care with phenobarbital risks respiratory suppression. We undertook studies of enteral levetiracetam (eLVT) to evaluate pharmacokinetics (PK), safety and efficacy including an open-label, randomized controlled trial (RCT) comparing eLVT to phenobarbital.MethodsChildren 24–83 months old with CM were enrolled in an eLVT dose-finding study starting with standard dose (40 mg/kg load, then 30 mg/kg Q12 hours) titrated upward until seizure freedom was attained in 75% of subjects.The RCT that followed randomized children to eLVT vs. phenobarbital for acute seizures and compared the groups on minutes with seizures based upon continuous electroencephalogram. Due to safety concerns, midway through the study children allocated to phenobarbital received the drug only if they continued to have seizures (either clinically or electrographically) after benzodiazepine treatment. Secondary outcomes were treatment failure requiring cross over, coma duration and neurologic sequelae at discharge. PK and safety assessments were also undertaken.ResultsAmong 30 comatose CM children, eLVT was rapidly absorbed and well-tolerated. eLVT clearance was lower in patients with higher admission serum creatinine (SCr), but overall PK parameters were similar to prior pediatric PK studies. Within 4 h of the first dose, 90% reached therapeutic levels (> 20 μg/mL) and all were above 6 μg/mL. 7/7 children achieved seizure freedom on the initial eLVT dose.Comparing 23 eLVT to 21 phenobarbital patients among whom 15/21 received phenobarbital, no differences were seen for minutes with seizure, seizure freedom, coma duration, neurologic sequelae or death, but eLVT was safer (p = 0.019). Phenobarbital was discontinued in 3/15 due to respiratory side effects.ConclusionEnteral LVT offers an affordable option for seizure control in pediatric CM and is safer than phenobarbital.Trial registrationNCT01660672.NCT01982812.

Pathogenicity and virulence of malaria: Sticky problems and tricky solutions

“…Fluid bolus resuscitation was shown to increase mortality compared to use of maintenance fluids alone [ 381 ]. Similarly, routine treatment of seizures in children with cerebral malaria with the anticonvulsant drug, phenobarbitone, was associated with increased mortality in a clinical trial meta-analysis [ 382 ], although a recent small study suggested levetiracetam may be a safer alternative [ 383 ], and management of brain swelling with mannitol was associated with increased length of coma [ 384 ]. A deeper understanding of the molecular mechanisms of cerebral malaria may lead to more effective adjunctive therapies.…”

Severe malaria

“…In a large randomized trial, conducted in a centre without access to artificial ventilation, seizure prevention by full dose prophylactic phenobarbitone increased mortality because of respiratory depression [ 16 ]. In a small trial levetiracetam proved safer [ 124 ], and may well become the anticonvulsant of choice, as it is in other settings, although more evidence is needed. Fosphenytoin was ineffective [ 125 ].…”

Parasitic Infections of the Nervous System

“…15 Seizures are usually managed with phenobarbital and benzodiazepines, with respiratory suppression a common complication. Enteral levetiracetam may provide an effective and safe alternative, 21 although availability is limited in endemic areas. Otherwise, treatment is supportive, with patients often requiring intensive care unit-level care.…”