Levetiracetam Versus Phenobarbital for Neonatal Seizures: A Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: There are no US Food and Drug Administration-approved therapies for neonatal seizures. Phenobarbital and phenytoin frequently fail to control seizures. There are concerns about the safety of seizure medications in the developing brain. Levetiracetam has proven efficacy and an excellent safety profile in older patients; therefore, there is great interest in its use in neonates. However, randomized studies have not been performed. Our objectives were to study the efficacy and safety of levetiracetam compared with phenobarbital as a first-line treatment of neonatal seizures. METHODS: The study was a multicenter, randomized, blinded, controlled, phase IIb trial investigating the efficacy and safety of levetiracetam compared with phenobarbital as a first-line treatment for neonatal seizures of any cause. The primary outcome measure was complete seizure freedom for 24 hours, assessed by independent review of the EEGs by 2 neurophysiologists. RESULTS: Eighty percent of patients (24 of 30) randomly assigned to phenobarbital remained seizure free for 24 hours, compared with 28% of patients (15 of 53) randomly assigned to levetiracetam (P < .001; relative risk 0.35 [95% confidence interval: 0.22-0.56]; modified intention-to-treat population). A 7.5% improvement in efficacy was achieved with a dose escalation of levetiracetam from 40 to 60 mg/kg. More adverse effects were seen in subjects randomly assigned to phenobarbital (not statistically significant). CONCLUSIONS: In this phase IIb study, phenobarbital was more effective than levetiracetam for the treatment of neonatal seizures. Higher rates of adverse effects were seen with phenobarbital treatment. Higher-dose studies of levetiracetam are warranted, and definitive studies with long-term outcome measures are needed.

Effect of interictal epileptiform discharges on EEG-based functional connectivity networks.

OBJECTIVE: Functional connectivity networks (FCNs) based on interictal electroencephalography (EEG) can identify pathological brain networks associated with epilepsy. FCNs are altered by interictal epileptiform discharges (IEDs), but it is unknown whether this is due to the morphology of the IED or the underlying pathological activity. Therefore, we characterized the impact of IEDs on the FCN through simulations and EEG analysis. METHODS: We introduced simulated IEDs to sleep EEG recordings of eight healthy controls and analyzed the effect of IED amplitude and rate on the FCN. We then generated FCNs based on epochs with and without IEDs and compared them to the analogous FCNs from eight subjects with infantile spasms (IS), based on 1340 visually marked IEDs. Differences in network structure and strength were assessed. RESULTS: IEDs in IS subjects caused increased connectivity strength but no change in network structure. In controls, simulated IEDs with physiological amplitudes and rates did not alter network strength or structure. CONCLUSIONS: Increases in connectivity strength in IS subjects are not artifacts caused by the interictal spike waveform and may be related to the underlying pathophysiology of IS. SIGNIFICANCE: Dynamic changes in EEG-based FCNs during IEDs may be valuable for identification of pathological networks associated with epilepsy.

Expanding the phenotypic spectrum of GABRG2 variants: a recurrent GABRG2 missense variant associated with a severe phenotype.

Pathogenic missense and truncating variants in the GABRG2 gene cause a spectrum of epilepsies, from Dravet syndrome to milder simple febrile seizures. In most cases, pathogenic missense variants in the GABRG2 gene segregate with a febrile seizure phenotype. In this case series, we report a recurrent, de novo missense variant (c0.316 G > A; p.A106T) in the GABRG2 gene that was identified in five unrelated individuals. These patients were described to have a more severe phenotype than previously reported for GABRG2 missense variants. Common features include variable early-onset seizures, significant motor and speech delays, intellectual disability, hypotonia, movement disorder, dysmorphic features and vision/ocular issues. Our report further explores a recurrent pathogenic missense variant within the GABRG2 variant family and broadens the spectrum of associated phenotypes for GABRG2-associated disorders.

Neurological Outcomes After Presumed Childhood Encephalitis.

OBJECTIVE: To evaluate factors during acute presumed childhood encephalitis that are associated with development of long-term neurological sequelae. METHODS: A total of 217 patients from Rady Children's Hospital San Diego with suspected encephalitis who met criteria for the California Encephalitis Project were identified. A cohort of 99 patients (40 females, 59 males, age 2 months-17 years) without preexisting neurological conditions, including prior seizures or abnormal brain magnetic resonance imaging scans was studied. Mean duration of follow-up was 29 months. Factors that had a relationship with the development of neurological sequelae (defined as developmental delay, learning difficulties, behavioral problems, or focal neurological findings) after acute encephalitis were identified. RESULTS: Neurological sequelae at follow-up was associated with younger age (6.56 versus 9.22 years) at presentation (P = 0.04) as well as an initial presenting sign of seizure (P = 0.03). Duration of hospital stay (median of 7 versus 15.5 days; P = 0.02) was associated with neurological sequelae. Of the patients with neurological sequelae, a longer hospital stay was associated with patients of an older age (P = 0.04). Abnormalities on neuroimaging (P = 1.00) or spinal fluid analysis (P = 1.00) were not uniquely associated with neurological sequelae. Children who were readmitted after their acute illness (P = 0.04) were more likely to develop neurological sequelae. There was a strong relationship between the patients who later developed epilepsy and those who developed neurological sequelae (P = 0.02). SIGNIFICANCE: Limited data are available on the long-term neurological outcomes of childhood encephalitis. Almost half of our patients were found to have neurological sequelae at follow-up, indicating the importance of earlier therapies to improve neurological outcome.

Epilepsy After Resolution of Presumed Childhood Encephalitis.

OBJECTIVE: To evaluate factors associated with the development of epilepsy after resolution of presumed childhood encephalitis. METHODS: A total of 217 patients with suspected encephalitis who met criteria for the California Encephalitis Project were identified. Evaluable outcome information was available for 99 patients (40 girls, 59 boys, ages 2 months to 17 years) without preexisting neurological conditions, including prior seizures or abnormal brain magnetic resonance imaging scans. We identified factors correlated with the development of epilepsy after resolution of the acute illness. RESULTS: Development of epilepsy was correlated with the initial presenting sign of seizure (P < 0.001). With each additional antiepileptic drug used to control seizures, the odds ratio of developing epilepsy was increased twofold (P < 0.001). An abnormal electroencephalograph (P < 0.05) and longer hospital duration (median of 8 versus 21 days) also correlated with development of epilepsy (P < 0.01). The need for medically induced coma was associated with epilepsy (P < 0.001). Seizures in those patients were particularly refractory, often requiring longer than 24 hours to obtain seizure control. Individuals who required antiepileptic drugs at discharge (P < 0.001) or were readmitted after their acute illness (P < 0.001) were more likely to develop epilepsy. Of our patients who were able to wean antiepileptic drugs after being started during hospitalization, 42% were successfully tapered off within 6 months. CONCLUSIONS: Limited data are available on the risk of developing epilepsy after childhood encephalitis. This is the first study that not only identifies risk factors for the development of epilepsy, but also provides data regarding the success rate of discontinuing antiepileptic medication after resolution of encephalitis.

A seven-day study of the pharmacokinetics of intravenous levetiracetam in neonates: marked changes in pharmacokinetics occur during the first week of life.

INTRODUCTION: Levetiracetam (LEV) is increasingly used in the treatment of neonatal seizures. The aim of this study was to determine pharmacokinetics in neonates with seizures and to obtain preliminary safety and efficacy data. METHODS: Eighteen term neonates with seizures persisting after 20 mg/kg of phenobarbital received intravenous LEV for 1 wk. LEV was administered as a 20 or 40 mg/kg bolus followed by 5-10 mg/kg/d. Pharmacokinetic data were analyzed using a nonlinear mixed-effects population approach. Continuous electroencephalogram monitoring allowed preliminary assessment of the efficacy of LEV in this population. RESULTS: LEV clearance (CL) increased from a mean of 0.7 ml/min/kg (SD 0.27 ml/min/kg) on day 1 to 1.33 ml/min/kg (SD 0.35 ml/min/kg) by day 7. Mean half-life was 18.5 h (SD 7.1 h) on day 1 of the study and decreased to 9.1 h (SD 2.0 h) by day 7. The mean volume of distribution was 1.01 l/kg (SD 0.13 l/kg). No study-related serious adverse events were observed. DISCUSSION: CL of LEV in neonates was higher than expected on the basis of immature renal function in term infants and increased significantly during the first week of life. More frequent dosing of LEV is needed in term infants to maintain serum concentrations in the range seen in children and adults.