As pediatricians who work with little children who has little to express in their early days, we tend to overlook the long-term effect of out treatment of their condition and often focus on the condition itself. With the adaptation of the patient-center approach in medical practice, as well as from an ethical point of view, we are urged to weight our treatment of acute condition against the long-term effect that might affect the patient well-being in life later on. This lecture, which is a journal club review, aims at shedding light at this aspect of medical practice, reminding physicians that chemical drugs are both an antidote as well as a poison, and the decision to treat should be always made judicially.

1. Comparison of the
Neurocognitive Outcome in
Term Infants Treated with LEV
and PB Monotherapy for
Neonatal Clinical Seizures
Prepared by: Hasan Arafat, MD
Supervised by: Aysha Al-Masri, MD

2. Background
• Treatment of neonatal seizure can be quite challenging
• There are a few evidence-based guidelines for the evaluation &
management of neonatal seizures
• Available guidelines indicate that phenobarbital (PB) remains the first-
line treatment for neonatal seizure (Booth D, Enans DK.
Anticonvulsants for neonates with seizures. A Cochrane systematic
review).
• There is no consensus regarding the second-line antiepileptic drug

3. Background
• Levetiracetam (LEV), benzodiazepines (BZD), fosphenytoin and
lidocaine are all available options
• LEV has gained a widespread popularity in the last decade as a first-
line antiepileptic drug in neonatal seizure
• But potential neurotoxicity is still an issue

4. Background
• Animal model studies proposed that PB & phenytoin seem to have an
effect of accelerating neuronal apoptosis when administered to the
immature brain
• On the contrary, animal models showed that LEV does not lead to
that effect
• The neurodevelopmental effects of antiepileptics are a major
concern, but human studies are still laking

5. Objective
• The aim of this cross-sectional study is to evaluate the
neurodevelopmental outcome of the term infant with neonatal
clinical seizures who were treated with PB & LEV monotherapy using
the Bayley Scales of Infant Development, 3rd ed.

6. Methods
• Inclusion criteria:
• Term infants
• Treated with PB OR LEV for neonatal seizures
• Followed-up in the pediatric neurology outpatient clinic
• Exclusion criteria:
• Infants who received a second-line antiepileptic drug in the NICU or during
follow-up

7. Methods: Study Group & Data Collection
• Neurodevelopmental assessment was carried out using the BSID-III
• Neurodevelopmental impairment was defined as BSID-III scale score
<7 or a composite score <85
• Subgroup analysis was carried out to explore the effects of
antiepileptic drugs on neurodevelopmental outcomes in infants
• Infants with impairment were excluded from subgroup analysis

8. Bailey Scale for Infant Development-III
• Five developmental domains
• Adaptive behavior
• Cognitive
• Language
• Motor
• Socio-emotional

9. Seizure Treatment Protocols
• In case of PB, initial dose was 20 mg/kg intravenously, increased
gradually by 10 mg/kg up to 40 mg/kg in case of persistent seizures
• When LEV was used as treatment, initial dose was 20 mg/kg, and the
dose was increased by 10 mg/kg up to 40-60 mg/kg in the case of
persistent seizure

10. Seizure Treatment Protocol
• Indications for discontinuation in NICU
• Cessation of seizure
• Normal neurological exam
• EEG normal
• Indications for discontinuation in the follow-up period
• Normal EEG (performed every 3 months)
• No recorded seizures

11. Statistical Analysis
• Performed using Statistical Package for the Social Sciences software
program, version 21.0
• Categorical variables were summarized using percentages
• Continuous variables were summarized using means and standard
deviations (SD)
• Chi-square & Fischer’s exact test were used for comparison of
categorical variables between independent groups
• P < 0.05 (two-tailed) values were considered statistically significant

15. Discussion
• Neurodevelopmental adverse effects of antiepileptic drugs are of
major concern in the developing brain
• In this study, exposure to a PB and LEV monotherapy was associated
with similar neurodevelopmental outcomes at 18-24 months of age
• Risk factors for neurodevelopmental oucomes:
• Underlying etiology
• Younger age at seizure onset
• Polytherapy
• Side effects of each antiepileptic drug

16. Discussion
• In our study, there were no significant difference in sex, age, seizure
etiology (specific etiology vs. unknown etiology), cranial MRI findings,
EEG findings, EEG improvement rate, and duration of treatment
between LEV and PB monotherapy groups.
• No adverse hematological, biochemical, or vital sign parameters
changes were reported in any child
• No patient discontinued the drug because of treatment-related side
effects

17. Discussion
• Phenobarbital is the most frequently used antiepileptic drug for
neonatal seizures
• Levetiracetam is proposed as an alternative, efficacy vs phenobarbital
is promising but a concrete conclusion needs further studies and
clinical trials
• Data is limited regarding the adverse effects of PB compared to LEV

18. Study Limitations
• A cross-sectional study
• Small sample size
• No control group
• The assessment tool, BSID-III, is only limited to infants 1-42 months of
age
• Only clinical seizures were included, electrographic neonatal seizures
were not included due to lack of required hardware

19. Study Strengths
• Two study groups for comparison
• Homogenous structure

20. Conclusion
• Our findings suggest that both LEV and PB therapy were equally safe
as monotherapy for neonatal seizures treatment regarding
neurodevelopmental outcomes assessment with BSID-III
• Double-blind prospective controlled studies, including efficacy and
long-term evaluation of cognitive outcome, are warranted to establish
a reasonable alteration of LEV to PB as first-line antiepileptic
treatment