Efficacy of Levetiracetam as Add-On Therapy in the Treatment of Seizures in Neonates

Abstract

Introduction: There is no consensus regarding the efficacy of add-on therapy with levetiracetam (LEV) in the treatment of seizures in neonates. The aim of this study was to evaluate the efficacy of add-on therapy with LEV for achieving >80% seizure reduction after phenobarbital (PB) treatment.

Methods: Retrospective cohort study of near term neonates admitted to the neonatal intensive care unit with EEG-confirmed seizures despite treatment with PB as first-line therapy and using LEV as 2nd-, 3rd- or 4th-line treatment. Antiseizure medication was administered according to national guidelines. All neonates were monitored with 2-channel amplitude-integrated electroencephalography. The total seizure burden in minutes, 2 h before and 4 h after administration of LEV, was calculated using raw EEG. Primary outcome was the efficacy of LEV in achieving >80% seizure reduction. The efficacy of additional midazolam (MDZ) and lidocaine (LDC) was also calculated.

Results: A total of 47 full-term neonates were included. The mean total loading dose of LEV was 40 mg/kg (36-44 mg/kg). Seizure etiology consisted of hypoxic-ischemic encephalopathy (n = 11), hemorrhagic or ischemic stroke (n = 16), central nervous system infection (n = 8), genetic (n = 8), metabolic disorders (n = 3), and unknown (n = 1). Following LEV administration, >80% seizure reduction was observed in 17% (8/47) of neonates, whereas it was 23% (6/26) after MDZ and 92% (23/25) after LDC administration.

Discussion: Although the cumulative loading dose of LEV was low and the group of infants studied was heterogeneous, the efficacy of LEV as add-on therapy for the treatment of seizures in neonates was limited. The highest seizure reduction rate was seen after LDC administration.

Keywords: Amplitude-integrated electroencephalography; Antiseizure medication; Levetiracetam; Lidocaine; Midazolam; Seizure reduction; Seizures in neonates.

Fig. 1.

Flow diagram of study population.

Fig. 2.

Example of aEEG tracings in neonates after the administration of LEV, MDZ, and LDC. a Full-term neonate with perinatal asphyxia based on fetomaternal transfusion shows repetitive seizures at 5.30 u. After midazolam (MDZ), a temporary resolution of the seizures is visible, but repetitive seizures start from 07:00 h onward. An example of the seizure on the raw EEG is shown at the blue arrows (a1/a2). First administration of levetiracetam (LEV) did not result in seizure reduction. A second dose of LEV did not result in seizure reduction either (a2). Only after administration of lidocaine (LDC), a 100% seizure reduction with 72 h of complete seizure freedom was achieved (a3). b Full-term neonate with a meningitis had repetitive seizures, with a burst suppression pattern on the aEEG. LEV (up to 40 mg/kg) and MIDA (up to 0.3 mg/kg/h) were administered with no seizure control (b1). After LDC (b2), the seizures were successively controlled, the aEEG background pattern changed to discontinuous normal voltage pattern (b3). Afterward, no seizures were seen for at least 72 h.

Fig. 3.

Overview of the efficacy of levetiracetam (LEV), midazolam (MDZ), and lidocaine (LDC). The efficacy of LEV (n = 47), MDZ (n = 26), and LDC (n = 25) in achieving >80% seizure reduction (a) and >50% seizure reduction (b). The need for another ASM after initial administration of LEV (n = 47), MDZ (n = 25), and LDC (n = 25): within 4 h (c) and within 12 h (d). The figure presents the percentages of patients experiencing seizure freedom at 24 h (e) and 72 h (f) after the administration of LEV (24 h: n = 47; 72 h: n = 44), MDZ (n = 26), and LDC (n = 25) (online suppl. Fig. 1). Local protocol for seizures in neonates.