Efficacy and safety of levetiracetam in the off-label treatment of neonatal seizures.

Background: Treatment of neonatal seizures includes etiotropic and anticonvulsant treatments. However, anticonvulsant use in neonates is off-label and requires ethical review.Objective: To investigate the efficacy and safety of levetiracetam for neonatal seizures and to establish a predictive model.Methods: We retrospectively analyzed 125 neonatal seizure cases (phenobarbital 66 cases, levetiracetam 59 cases). The efficacy, safety and tolerability of levetiracetam were evaluated by cox regression survival analysis and a regression tree prediction model for the 16-week time point.Results: There was no significant difference between phenobarbital and levetiracetam treatment group in short-term efficacy (p > 0.05). But the cumulative survival function suggested that levetiracetam treatment group was better than phenobarbital (p = 0.026) in long-term efficacy evaluation. Neurodevelopmental assessments at 16 weeks showed that levetiracetam had better effect on the neurodevelopmental level (Gesell scores in response) than phenobarbital (p = 0.011). The main adverse events with levetiracetam were irritability and anorexia. According to the regression tree prediction model, the top three factors influencing the therapeutic effect were pre-treatment seizure frequency, age of onset and etiological classification.Conclusion: Levetiracetam shows good efficacy, safety and tolerability for the long-term neonatal seizure treatment.

Clinical and genetic characteristics of epilepsy of infancy with migrating focal seizures in Chinese children.

OBJECTIVE: Epilepsy of infancy with migrating focal seizures (EIMFS) is a rare and severe developmental epileptic encephalopathy. The aim of this study was to improve our understanding of EIMFS by using phenotype-genotype correlation. METHODS: We recruited, performed clinical genetic testing, and summarized the clinical features and genetic characteristics in five patients with EIMFS in China. RESULTS: The five recruited patients included 2 males and 3 females. The median age of seizure onset was 2 months (range, day 3 to 3 months). All patients exhibited the characteristics of clinically migrating focal motor (tonic or clonic) seizures. Typical migrating ictal electrical patterns were found in 1 patient; the remaining four patients presented with overlapping seizures with different areas of ictal onset in differing hemispheres. All the patients had the associated variants, including KCNT1, SCN1A, SCN2A, TBC1D24 and ALG1. All patients received two or more antiseizure medications, and 1 patient became seizure-free, 1 reported >75 % seizure reduction, 2 reported >50 % seizure reduction, and 1 patient showed no improvement. Varying degrees of psychomotor developmental delays were observed in all patients. CONCLUSIONS: The course of EIMFS could be related to the type of gene variant present, and different genes may have specific clinical features. Larger cohorts are required to elucidate such potential phenotype-genotype correlations.

Effects of gap junctions blockers on fast ripples and connexin in rat hippocampi after status epilepticus.

OBJECTIVE: To assess the dynamic changes in the average and peak spectral power of fast ripples (FRs) in the hippocampi after interventions with valproate sodium (VPA), carbenoxolone (CBX) and quinine (QUIN). METHOD: Adult rats were used to establish a lithium-pilocarpine (pilo) epileptic model, and were assigned to a lithium-pilocarpine (PILO), VPA + PILO, QUIN + PILO or CBX + PILO group. Intracranial electroencephalography was performed before and after status epilepticus (SE). The hippocampal connexin (CX) 43, CX32 and CX36 expressions were analyzed via western blotting. RESULTS: The time required for the disappearance of SE after chloral hydrate injection was lower in the intervention groups than in the PILO group (p < 0.05). Seizures induced CX43 expression, but had no significant effects on CX36 or CX32 expressions. Pretreatment with VPA, QUIN and CBX inhibited CX43, CX36 and CX32 expression after SE. The average spectral power of the FRs was significantly lower in the VPA + PILO and QUIN + PILO groups than in the PILO group at 10 min after SE, 10 min before chloral hydrate injection, and 10 min after chloral hydrate injection (p < 0.05). The average spectral power of FRs was lower in the CBX + PILO group than in the PILO group at 10 min after SE (p < 0.05). The average spectral power of FRs in the 3 intervention groups recovered to the baseline level at 10 min after chloral hydrate injection and persisted for 3 days after SE. The dynamic changes in the average and peak spectral power of FRs were similar. SIGNIFICANCE: After SE, CX may participate in pathological FR generation by establishing abnormal electrical synaptic transmission. Gap junction blockers can inhibit various CX expressions, and thus decrease FR energy and alleviate the degree of seizure. These findings could contribute to the development of new anti-epileptic drugs with novel mechanistic targets.

Dynamic Changes in Spectral and Spatial Signatures of High Frequency Oscillations in Rat Hippocampi during Epileptogenesis in Acute and Chronic Stages.

OBJECTIVE: To analyze spectral and spatial signatures of high frequency oscillations (HFOs), which include ripples and fast ripples (FRs, >200 Hz) by quantitatively assessing average and peak spectral power in a rat model of different stages of epileptogenesis. METHODS: The lithium-pilocarpine model of temporal lobe epilepsy was used. The acute phase of epilepsy was assessed by recording intracranial electroencephalography (EEG) activity for 1 day after status epilepticus (SE). The chronic phase of epilepsy, including spontaneous recurrent seizures (SRSs), was assessed by recording EEG activity for 28 days after SE. Average and peak spectral power of five frequency bands of EEG signals in CA1, CA3, and DG regions of the hippocampus were analyzed with wavelet and digital filter. RESULTS: FRs occurred in the hippocampus in the animal model. Significant dynamic changes in the spectral power of FRS were identified in CA1 and CA3. The average spectral power of ripples increased at 20 min before SE (p < 0.05), peaked at 10 min before diazepam injection. It decreased at 10 min after diazepam (p < 0.05) and returned to baseline after 1 h. The average spectral power of FRs increased at 30 min before SE (p < 0.05) and peaked at 10 min before diazepam. It decreased at 10 min after diazepam (p < 0.05) and returned to baseline at 2 h after injection. The dynamic changes were similar between average and peak spectral power of FRs. Average and peak spectral power of both ripples and FRs in the chronic phase showed a gradual downward trend compared with normal rats 14 days after SE. SIGNIFICANCE: The spectral power of HFOs may be utilized to distinguish between normal and pathologic HFOs. Ictal average and peak spectral power of FRs were two parameters for predicting acute epileptic seizures, which could be used as a new quantitative biomarker and early warning marker of seizure. Changes in interictal HFOs power in the hippocampus at the chronic stage may be not related to seizure occurrence.