First-line Antiepileptic Drug Research Articles

Pharmacokinetic profile of phenytoin in dried blood spot with high-performance liquid chromatography-photodiode array.

Phenytoin is a first-line antiepileptic drug with narrow therapeutic range and follows non-linear pharmacokinetics. Pharmacokinetics of phenytoin have been studied in plasma matrix before, however, there were several disadvantages. This study aimed to obtain partial validation data of the analytical method and the pharmacokinetic profile of phenytoin in Dried Blood Spot (DBS) of six healthy subjects. DBS has the advantage of only requiring small sample volumes and could be transported more efficiently. Phenytoin along with carbamazepine as the chosen internal standard was analyzed with a reversed-phase high performance-liquid chromatography system and a photodiode array detector at 205nm. The results of partial validation, which evaluated the linearity, within-run accuracy, and precision, were within the criteria acceptance range. The pharmacokinetic profile showed that average AUC0-t was 83.81 ± 37.32μg.h/mL and AUC0-∞ was 83.65 ± 38.89μg.h/mL with an average ratio of 93%. Previous study quantifying phenytoin in the plasma matrix found the average AUC0-t was 39.41 ± 8.57µg.h/mL and AUC0-∞ was 42.94 ± 9.55µg.h/mL. Despite the difference between parameters of phenytoin analyzed in DBS and plasma matrices, the pharmacokinetic profiles obtained from both matrices were similar indicated by comparable concentration-time curves, thus, proving that DBS matrix can be used interchangeably with the plasma matrix as a more comfortable and effective alternative to phenytoin quantification in blood.

Association of Valproic Acid and Its Main Metabolites' Plasma Concentrations with Clinical Outcomes among Epilepsy Patients: A 10-Year Retrospective Study Based on Therapeutic Drug Monitoring.

Valproic acid (VPA) is a first-line antiepileptic drug with broad efficacy. Due to significant individual differences in its metabolism, therapeutic drug monitoring is commonly used. However, the recommended therapeutic range (50-100 μg/mL) is inadequate for predicting clinical outcomes. Additionally, the relationship between VPA metabolites and clinical outcomes remains unclear. In this retrospective study, 485 Chinese Southern Han epilepsy patients receiving VPA monotherapy were analyzed after reaching steady-state levels. Plasma concentrations of VPA and its five main metabolites were determined by liquid chromatography-mass spectrometry (LC-MS). We assessed the relevance of the recommended therapeutic VPA range for clinical outcomes and explored the association between VPA/metabolites levels and treatment efficacy/adverse effects. Vitro experiments were conducted to assess 4-ene-VPA hepatotoxicity. The therapeutic range of VPA exhibited no significant correlation with clinical outcomes, and plasma concentrations of VPA failed to serve as predictive indicators for treatment response/adverse effects. Treatment responders had higher 2-PGA concentrations (median, 26.39 ng/mL versus 13.68 ng/mL), with a threshold of 36.5 ng/mL for optimal epilepsy treatment. Patients with abnormal liver function had a higher 4-ene-VPA median concentration (6.41 μg/mL versus 4.83 μg/mL), and the ratio of 4-ene-VPA to VPA better predicted VPA-induced hepatotoxicity (area under the curve, 0.718) than 4-ene-VPA concentration. Vitro experiments revealed that 4-ene-VPA was more hepatotoxic than VPA in HepaRG and L02 cell lines. Total plasma VPA concentration does not serve as a predictor of clinical outcomes. 2-PGA concentrations may be associated with efficacy, whereas the ratio of 4-ene-VPA to VPA may be considered a better biomarker (threshold 10.03%) for VPA-induced hepatotoxicity. SIGNIFICANCE STATEMENT: This was the first and largest observational cohort in China to explore the relationship between patients' parent and metabolites concentrations of VPA and clinical outcomes during the maintenance of VPA monotherapy in epileptic patients. This study provided feasible references of VPA for epilepsy clinical treatment with a larger sample of patients compared with previous studies for a more definitive conclusion based on real-world situations. We found two potential biomarkers in predicting efficacy and liver injury, respectively. This breakthrough has the potential to assist in the rational use of VPA.

Melatonin alleviates valproic acid-induced neural tube defects by modulating Src/PI3K/ERK signaling and oxidative stress.

Neural tube defects (NTDs) represent a developmental disorder of the nervous system that can lead to significant disability in children and impose substantial social burdens. Valproic acid (VPA), a widely prescribed first-line antiepileptic drug for epilepsy and various neurological conditions, has been associated with a 4-fold increase in the risk of NTDs when used during pregnancy. Consequently, urgent efforts are required to identify innovative prevention and treatment approaches for VPA-induced NTDs. Studies have demonstrated that the disruption in the delicate balance between cell proliferation and apoptosis is a crucial factor contributing to NTDs induced by VPA. Encouragingly, our current data reveal that melatonin (MT) significantly inhibits apoptosis while promoting the restoration of neuroepithelial cell proliferation impaired by VPA. Moreover, further investigations demonstrate that MT substantially reduces the incidence of neural tube malformations resulted from VPA exposure, primarily by suppressing apoptosis through the modulation of intracellular reactive oxygen species levels. In addition, the Src/PI3K/ERK signaling pathway appears to play a pivotal role in VPA-induced NTDs, with significant inhibition observed in the affected samples. Notably, MT treatment successfully reinstates Src/PI3K/ERK signaling, thereby offering a potential underlying mechanism for the protective effects of MT against VPA-induced NTDs. In summary, our current study substantiates the considerable protective potential of MT in mitigating VPA-triggered NTDs, thereby offering valuable strategies for the clinical management of VPA-related birth defects.

Pharmaceutical and Clinical Assessment of Multi-source Tegretol Sold in Egypt

across generic Narrow therapeutic index (NTI) medications compared to brands. However, little attention has been given to possible inequality within the same brand due to transportation and storage conditions, production site, manufacturing condition, and product specification requested by different countries. Market surveys has shown that Egypt is one of the countries suffering from this problem, which consequently augments the need for comparing and evaluating brand products marketed under the same brand name, manufactured in different countries under its own licensing trademark™ and sold in Egypt. This work studies the drug carbamazepine (CBZ) available in Egypt as Tegretol® tablets used as an oral first-line anti-epileptic drug (AED). Objectives: The present work investigate and evaluate the pharmaceutical quality and clinical efficacy of Tegretol®, obtained from Egypt and Saudi Arabia and being marketed and sold in Egypt from 2020 to 21. Methods: In-vitro quality testing included potency and uniformity of content tests performed according to USP 2019 monograph. Dissolution rates were also carried by adopting USP dissolution test for the drug. Studies of stability were adjusted at 25°C/65% RH, 45°C/75% RH and 10°C/15% RH. The clinical efficacy was studied by evaluating the pharmacokinetics parameters and blood sodium level during six months of therapy. Results: Variability between multisource Tegretol® brand products were ensured. Potency results and uniformity of content revealed statistically significant difference between Tegretol® sources. Also, variations in dissolution rates were recognized in both Tegretol® sources when dissolved in HCL/KCL, Acetate and Phosphate Buffer dissolution media. Dissimilarities were obtained for hardness and friability testing. Furthermore, a pharmacokinetically and pharmacodynamically inequivalence was ensured. Hence, hyponatremia was more prominent in patients receiving Saudi Arabian Tegretol® compared to patients taking Egyptian Tegretol®. Conclusion: Interchangeability between multi-source Tegretol brand products should be limited.

Calcium Phosphate-Based Nanoformulation Selectively Abolishes Phenytoin Resistance in Epileptic Neurons for Ceasing Seizures.

Phenytoin (PHT) is a first-line antiepileptic drug in clinics, which could decrease neuronal bioelectric activity by blocking the voltage-operated sodium channels. However, the intrinsically low blood-brain-barrier (BBB)-crossing capability of PHT and upregulated expression level of the efflux transporter p-glycoprotein (P-gp) coded by the gene Abcb1 in epileptic neurons limit its efficacy in vivo. Herein, a nanointegrated strategy to overcome PHT resistance mechanisms for enhanced antiepileptic efficacy is reported. Specifically, PHT is first incorporated into calcium phosphate (CaP) nanoparticles through biomineralization, followed by the surface modification of the PEGylated BBB-penetrating TAT peptide. The CaP@PHT-PEG-TAT nanoformulation could effectively cross the BBB to be taken in by epileptic neurons. Afterward, the acidic lysosomal environment would trigger their complete degradation to release Ca2+ and PHT into the cytosol. Ca2+ ions would inhibit mitochondrial oxidative phosphorylation to reverse cellular hypoxia to block hypoxia-inducible factor-1α (Hif1α)-Abcb1-axis, as well as disrupt adenosine triphosphate generation, leading to simultaneous suppression of the expression and drug efflux capacity of P-gp to enhance PHT retention. This study offers an approach for effective therapeutic intervention against drug-resistant epilepsy.

A prospective study of thyroid profile in children aged 1 month to 12 years of age with newly diagnosed seizure disorder started on first line antiepileptic drugs

Background: The study's primary aim was to determine the variation in the thyroid profile status in children with newly diagnosed seizure disorders started on first-line antiepileptic drugs. In addition, this study compares the incidence of hypothyroidism secondary to phenytoin, phenobarbitone, valproate and carbamazepine. Methods: A total of 60 children with newly diagnosed seizure disorders belonging to the age group of 1 month to 12 years were enrolled in the study. The children were subjected to a detailed history and neurological examination, and serum levels of T3, T4, and thyroid-stimulating hormone (TSH) were tested. Results: In this study, out of 60 children, the clinical signs and symptoms of hypothyroidism were present only in one subject (1.7%), and the remaining 59 had no signs and symptoms of hypothyroidism. The mean TSH value increased from baseline 1.62±1.17 to 3 months 2.2±1.38 and 6 months 2.78±149 (p value<0.05%). The incidence of subclinical hypothyroidism among the phenytoin group (n=33) was 6.06%. Among the sodium valproate group (n=23), the incidence was 8.6%, and among the carbamazepine group (n=4), the incidence was 25%. Conclusions: Antiepileptic drugs can alter thyroid function tests. In this study, there was no overt hypothyroidism noted. But subclinical hypothyroidism was reported in subjects using phenytoin, valproate and carbamazepine.

P02.09.B Valproic acid changes total DNA methylation level and influences temozolomide effect in glioblastoma cell lines

Abstract Background Valproic acid (VPA) is a first-line antiepileptic drug for glioblastoma (GBM) patients. There is also some evidence it improves the clinical outcome in those patients. However, the exact mechanism of VPA action is vague. Temozolomide (TMZ) is a first-line chemotherapeutic in GBM. Epigenetics offers a connection between genetic and environmental factors that influence the development of the disease. The best-characterized epigenetic mark is 5-methylcytosine (m5C) in DNA. The aim of that project is to show the effects of VPA administration on the total DNA methylation level. Material and Methods Using the nucleotide post-labeling method, we analyzed the total amount of m5C in DNA of GBM (T98G, U118, U138), cancer (HeLa) and normal (HaCaT) cell lines treated with VPA, and a combination of VPA and with TMZ. Results We adjusted the VPA doses to the ones achieved in the central nervous system during treatment. We observed dose-dependent changes in the total DNA methylation in neoplastic cell lines and the lack of such effect in a normal cell line. VPA alone produced a clear dose-dependent increase in total DNA methylation in GBM cell lines and scarce in the non-neoplastic cell line. In GBM cell lines, TMZ decreased the level of m5C. However, the exposition of GBM cells to the combination of VPA and TMZ caused an adverse synergistic effect resulting in DNA demethylation. The highest loss of m5C was observed at the highest concentration of TMZ (100 μM) and VPA (350 μM), after 3 h of incubation in the T98G cell line. Conclusion Total DNA methylation changes in glioma cell lines under VPA treatment suggest the new mechanism of that drug action and promote clinical implications for adjusting VPA and TMZ therapy in GBM patients. Our results show the potential and possible obstacles of the combined therapy of TMZ with VPA. Our experiments show that combined therapy with both drugs leads to total DNA hypomethylation. Therefore the conclusion would be to stop VPA administration during TMZ chemotherapy temporarily.

A Two-Sequence, Four-Period, Crossover, Full-Replicate Study to Demonstrate Bioequivalence of Carbamazepine Extended-Release Tablets in Healthy Subjects under Fasting and Fed Conditions

Carbamazepine is a first-line antiepileptic drug (AED) used for the treatment of partial and tonic-clonic seizures. We conducted an open label, balanced, randomized, two-treatment, two-sequence, four-period, single oral dose, full-replicate crossover study to assess and compare the bioequivalence of test product Carbamazepine extended release tablets USP 400 mg with reference product Tegretol®-XR 400 mg (Carbamazepine extended release tablets), respectively in healthy subjects under fasting and fed conditions. Blood samples were collected pre-dose and at regular intervals post-dose up to 240.00 hours. The plasma concentration was analyzed by a validated LC-MS/MS method and the reference-scaled and the unscaled procedure was used to determine bioequivalence for the pharmacokinetics parameters, Cmax, AUC0–t, AUC0-inf, Tmax, T½, Kel and AUC extrapolated was calculated. The results showed that the geometric mean ratios of Cmax, AUC0–t and AUC0-inf were 113.04%, 108.33% and 108.15% respectively, in the fasting conditions and 113.99%, 110.13% and 111.41%, respectively, in the fed conditions and the 90% confidence intervals were all within the range of 80.00% to 125.00%. It can be concluded from the result that the test product Carbamazepine extended release tablets based on osmotic release system (OROS) are bioequivalent to the reference product Tegretol®-XR tablets.
 Keywords: Bioequivalence, Carbamazepine, Sodium Channel Modulators and Epilepsy

Comparison of HPLC-DAD and UPLC-MS/MS in Monitoring Serum Concentration of Lamotrigine

Background: Lamotrigine (LTG) is a broad-spectrum and first-line anti-epileptic drug. To monitor the serum levels of LTG in epileptic seizures patients, high-performance liquid chromatography with diode-array detection (HPLC-DAD) and ultra-performance liquid chromatography-- tandem mass spectrometry (UPLC-MS/MS) methods were established and compared. Methods: Imatinib was used as the internal standard (IS) for both methods. LTG and IS were detected at 246 nm by HPLC-DAD. In UPLC-MS/MS, LTG and IS positive ion were detected by multiple reaction monitoring (MRM), with m/z of 256/210.9 and 494/394.02, respectively. A total of 37 blood samples from epileptic patients were determined and studied by these two methods. Results: There was an acceptable linearity for the two methods. The concentration range of LTG was 0.59 ~ 22.20 mg/L by HPLC, and 0.28 ~ 23.97 mg/L by UPLC-MS/MS. The Pearson regression coefficient of Deming regression was 0.9653 (95% CI: 0.9332 to 0.9821). Bland–Altman method demonstrated that the concentration of LTG determined by UPLC-MS/MS was 8.3% higher than that determined by HPLC (limits of agreement, -32.0% to +48.6%). Conclusion: There was a significant correlation between the two methods. Both HPLC and UPLC- MS/MS can be used for routine clinical monitoring of LTG.

Efficacy and Safety of Levetiracetam vs. Phenobarbital for Neonatal Seizures: A Systematic Review and Meta-Analysis

Background: Neonatal seizures are a common neurological emergency in newborns. Phenobarbital (PB) is the first-line antiepileptic drug (AED). However, PB has some side effects, such as hypotension and respiratory depression, and it can accelerate neuronal apoptosis in the immature brain. Levetiracetam (LEV), a new antiepileptic drug, has been used as a second-line drug for the treatment of neonatal seizures. Compared with PB, LEV has many advantages, including a low incidence of side effects and better neurodevelopmental outcomes. However, there are only a few systematic reviews of LEV for the treatment of neonatal seizures.Objective: To evaluate the efficacy and safety of LEV for neonatal seizures and to compare the efficacy, side effects, and neurological outcomes between LEV and PB in the treatment of neonatal seizures.Methods: The keywords LEV, PB, and neonatal seizure were searched in the MEDLINE, Cochrane Library, Web of Science, EMBASE, clinicaltrials.gov, and China National Knowledge Internet (CNKI) databases with a last update in July 2021 to collect high-quality studies. We collected studies studying the efficacy or safety of LEV and PB in the treatment of neonatal seizures applying strict inclusion and exclusion criteria. The data were extracted and outcome measures, including efficacy, side effect rate, neurological score, and mortality rate, were analyzed with RevMan 5.3 software.Results: Ten articles were finally included in the meta-analysis. The meta-analysis showed that there was no difference in efficacy between LEV and PB in the treatment of neonatal seizures. Compared with PB, the incidence of side effects of LEV was lower. The incidence of hypotension and respiratory depression in the LEV group was significantly lower than that in the PB group. In terms of long-term neurodevelopmental outcomes, there was no significant difference in the Bayley Scales of Infant Development (BSID) scores between LEV and PB.Conclusion: PB is still the first-line AED recommended by the WHO for the treatment of neonatal seizures. The new AEDs LEV may not have better efficacy than PB. At the same time, LEV is associated with better neurodevelopment outcomes and a lower risk of adverse effects. In addition, continuous EEG monitoring should be used to diagnose neonatal seizures to evaluate the severity of the seizures, remission, and drug efficacy.Systematic Review Registration: PROSPERO, identifier: CRD42021279029.

Treatment with the combination of clavulanic acid and valproic acid led to recovery of neuronal and behavioral deficits in an epilepsy rat model.

Epilepsy, which is caused by abnormal neuronal firing in the brain, is a common neurological disease and affects motor and cognitive functions. Excessive levels of glutamate and insufficient levels of inhibitory GABA are involved in its pathophysiology. Valproic acid (Val), a GABAergic agonist, is one of the first-line antiepileptic drugs, but it shows many adverse side effects at the clinical dose. Clavulanic acid (CA), a β-lactamase inhibitor, has been demonstrated to increase glutamate transporter-1 expression. This study evaluated the effects of CA and Val in an epilepsy rat model. Male Wistar rats received intraperitoneal injections of pentylenetetrazol (PTZ, 35 mg/kg, every other day, IP, for 13 days) to induce kindling epilepsy. After four times of PTZ injection, rats received daily treatment with CA (1 or 10 mg/kg, IP), Val (50 or 100 mg/kg, IP), or the combination of CA (1 mg/kg) and Val (50 mg/kg) for 7 consecutive days. Motor, learning, and memory functions were measured. Rats with PTZ-induced kindling exhibited seizures, motor dysfunction, cognitive impairment, and cell loss and reduction of neurogenesis in the hippocampus. Neither 1 mg/kg CA nor 50 mg/kg Val treatment was effective in alleviating behavioral and neuronal deficits. However, treatment with 10 mg/kg CA, 100 mg/kg Val, and the combination of 1 mg/kg CA and 50 mg/kg Val improved these behavioral and neuronal deficits. Particularly, the combination of CA and Val showed synergistic effects on seizure suppression, suggesting the potential for treating epilepsy and related neuronal damage and motor and cognitive deficits.

Comparative efficacy of anti-epileptic drugs for neonatal seizures: A network meta-analysis

Anti-epileptic drugs have different effects on neonatal seizures, and new agents have been widely used in recent years. Meanwhile, significant differences still exist in the treatment for neonatal seizures, whether in choice of drug or in duration of treatment. And with the increase in options for treatment, the best choice of second-line treatment has not been recommended. The MEDLINE, the Cochrane Library, Web of Science, Embase and clinicaltrials.gov databases were searched (January 1, 1960 to October 20, 2020). Randomized controlled trials (RCTs) or observational investigations studying anti-epileptic drugs for neonatal seizures were selected. And then we conducted a network meta-analysis and examined comparative efficacy of the first-line and second-line anti-epileptic drugs for neonatal seizures. Data were extracted from 11 included studies by 2 independent investigators. Random effects models were used to estimate odds ratios (ORs). We performed direct meta-analyses with a random effects model and network meta-analyses for first-line and second-line drugs. Five published RCTs and 6 observational investigations with 1333 patients and 6 interventions contributed to the analysis. We recommend phenobarbital as the first-line drug for neonatal seizures. In addition, there is a tendency for levetiracetam to be an effective second-line treatment for neonatal seizures after failure of first-line drugs.

Compliance with status epilepticus management protocol and effect on clinical outcomes in children with status epilepticus

BackgroundGuidelines for the management of status epilepticus (SE) aid in rationalising the treatment for a better clinical outcome; however, published literature regarding the use of antiepileptics and compliance is limited,...

Treatment effects of the combination of ceftriaxone and valproic acid on neuronal and behavioural functions in a rat model of epilepsy.

What is the central question of this study? Imbalance of activities between GABAergic and glutamatergic systems is involved in epilepsy. It is not known whether simultaneously increasing GABAergic and decreasing glutamatergic activity using valproic acid and ceftriaxone, respectively, leads to better seizure control. What is the central question of this study? Ceftriaxone suppressed seizure and cognitive deficits and restored neuronal density and the number of newborn cells in the hippocampus in a rat model of epilepsy. Combined treatment with ceftriaxone and valproic acid showed additive effects in seizure suppression. The pathophysiology of epilepsy is typically considered as an imbalance between inhibitory GABA and excitatory glutamate neurotransmission. Valproic acid (Val), a GABA agonist, is one of the first-line antiepileptic drugs in the treatment of epilepsy, but it exhibits adverse effects. Ceftriaxone (CEF) elevates expression of glutamate transporter-1, enhances the reuptake of synaptic glutamate, increases the number of newborn cells and exhibits neuroprotective effects in animal studies. In this study, we evaluated effects of the combination of CEF and Val on behavioural and neuronal measures in a rat epilepsy model. Male Wistar rats were injected i.p. with pentylenetetrazol (35mg/kg, every other day for 13days) to induce the epilepsy model. Ceftriaxone (10 or 50mg/kg), Val (50 or 100mg/kg) or the combination of CEF and Val were injected daily after the fourth pentylenetetrazol injection for seven consecutive days. Epileptic rats exhibited seizure and impairments in motor and cognitive functions. Treatment with CEF and Val reduced the seizure and enhanced motor and cognitive functions in a dose-dependent manner. The combination of CEF (10mg/kg) and Val (50mg/kg) improved behaviours considerably. Histologically, compared with control animals, epileptic rats exhibited lower neuronal density and a reduction in hippocampal newborn cells but higher apoptosis in the basolateral amygdala, all of which were restored by the treatment with CEF, Val or the combination of CEF and Val. The study findings demonstrated that the combination of low doses of CEF and Val has beneficial effects on seizure suppression, neuroprotection and improvement in motor and cognitive functions in epilepsy.

First-line antiepileptic drug treatment in glioma patients with epilepsy: Levetiracetam vs valproic acid.

ObjectiveThis study aimed at estimating the cumulative incidence of antiepileptic drug (AED) treatment failure of first‐line monotherapy levetiracetam vs valproic acid in glioma patients with epilepsy.MethodsIn this retrospective observational study, a competing risks model was used to estimate the cumulative incidence of treatment failure, from AED treatment initiation, for the two AEDs with death as a competing event. Patients were matched on baseline covariates potentially related to treatment assignment and outcomes of interest according to the nearest neighbor propensity score matching technique. Maximum duration of follow‐up was 36 months.ResultsIn total, 776 patients using levetiracetam and 659 using valproic acid were identified. Matching resulted in two equal groups of 429 patients, with similar covariate distribution. The cumulative incidence of treatment failure for any reason was significantly lower for levetiracetam compared to valproic acid (12 months: 33% [95% confidence interval (CI) 29%–38%] vs 50% [95% CI 45%–55%]; P < .001). When looking at specific reasons of treatment failure, treatment failure due to uncontrolled seizures was significantly lower for levetiracetam compared to valproic acid (12 months: 16% [95% CI 12%–19%] vs 28% [95% CI 23%–32%]; P < 0.001), but no differences were found for treatment failure due to adverse effects (12 months: 14% [95% CI 11%–18%] vs 15% [95% CI 11%–18%]; P = .636).SignificanceOur results suggest that levetiracetam may have favorable efficacy compared to valproic acid, whereas level of toxicity seems similar. Therefore, levetiracetam seems to be the preferred choice for first‐line AED treatment in patients with glioma.

Effect of Phenobarbitone on Amplitude-Integrated Electroencephalography in Neonates with Hypoxic-Ischemic Encephalopathy during Hypothermia

Background: Phenobarbitone induces suppression of cerebral electrical activity on amplitude-integrated electroencephalography (aEEG) in neonates with hypoxic-ischemic encephalopathy (HIE); however, its effect during therapeutic hypothermia (TH) has not been well characterized. Objective: To evaluate the effect of phenobarbitone on aEEG in neonates with HIE undergoing TH. Methods: Thirty-five neonates born at ≥35⁰ weeks gestational age (GA), who received phenobarbitone as first-line antiepileptic drug during TH for ≥ Sarnat stage II HIE with aEEG recordings were retrospectively studied. Background pattern, upper and lower margin voltages were characterized for a 30-min period before and 30–60 min after phenobarbitone administration. Primary outcome was presence of severely abnormal aEEG pattern after phenobarbitone administration. Results: Mean (±SD) GA and median birth weight were 38.2 ± 1.9 weeks and 3.1 (2.5–3.9) kg, respectively. Phenobarbitone (10–20 mg/kg), administered at median age 16.8 h, was associated with background pattern worsening in 19/29 (65.5%) cases. Severe background patterns were more prevalent in post- versus pre-phenobarbitone tracings (21/29 [72%] vs. 11/29 [38%]; p = 0.01). Presence of severe pattern versus either continuous normal voltage or discontinuous normal voltage pattern post-phenobarbitone, (20/25 [80%] vs. 3/8 [38%]; p = 0.036) was associated with death or moderate-to-severe injury on MRI brain. Median time to trace recovery, when measurable, was 4 h (45 min–72 h). Conclusions: Phenobarbitone induces significant suppression on aEEG in infants with HIE undergoing TH. Development of severe aEEG background patterns after phenobarbitone may unmask a population at greater risk of abnormal outcome.

Effects of Long-term Antiepileptic Therapy on Carotid Artery Intima- Media Thickness.

ABSTRACTBackground:Common first-line antiepileptic drugs (AEDs) used in children are valproate, phenytoin, and levetiracetam. Many side effects for these AEDs are reported including obesity, atherosclerosis, and metabolic syndrome. The aim of our study was to evaluate changes in carotid artery intima-media thickness (CIMT) in epileptic children and to correlate with lipid profile of those who are on long-term antiepileptic therapy.Materials and Methods:This case–control study was done over 18 months in department of pediatrics. Sample size was 84 with equal number of cases and controls. Epileptic children between 1 and 18 years of age receiving monotherapy with valproate, phenytoin, or levetiracetam for at least 6 months were included in the study. Measurement of CIMT was done by B mode ultrasonography. Lipid profile was analyzed. Statistical analysis was performed using one-way analysis of variance (ANOVA) test and Pearson correlation.Results:Among 42 cases of epilepsy, 30 were on valproate, 9 on phenytoin, and 3 on levetiracetam monotherapy. No significant difference was noted in body mass index (BMI) among children receiving AED compared with that of controls (P = 0.82). Mean value for CIMT was significantly higher among valproate (0.43 ± 0.04, P ≤ 0.001), phenytoin (0.44 ± 0.04, P ≤ 0.001), and levetiracetam group (0.43 ± 0.03, P = 0.01) compared to controls (0.39 ± 0.01). Significant correlation was noted between CIMT and total cholesterol (P = 0.034), triglyceride (P = 0.011), low-density lipoprotein (P = 0.008), and very low-density lipoprotein (P = 0.011).Conclusion:Children on long-term monotherapy with valproate, phenytoin, and levetiracetam have significantly abnormal CIMT. This might be associated with atherosclerotic changes, and these children may require close follow-up to prevent cardiovascular and cerebrovascular risks.

Epilepsy management in pregnant HIV+ women in sub-Saharan Africa, clinical aspects to consider: a scoping review

BackgroundSince the introduction of highly active antiretroviral therapy (HAART), acquired immune deficiency syndrome (AIDS) related mortality has markedly declined. As HAART is becoming increasingly available, the infection with human immunodeficiency virus (HIV+) in sub-Saharan Africa (SSA) is becoming a chronic condition. While pregnancy in HIV+ women in SSA has always been considered a challenging event for the mother and the fetus, for pregnant HIV+ women also diagnosed with epilepsy (WWE), there are additional risks as HIV increases the odds of developing seizures due to the vulnerability of the central nervous system to other infections, immune dysfunction, and overall metabolic disturbances. In light of a growing proportion of HIV+ WWE on HAART and an increasing number of pregnant women accessing mother-to-child transmission of HIV programs through provision of HAART in SSA, there is a need to develop contextualized and evidenced-based clinical strategies for the management of epilepsy in this population. In this study, we conduct a literature scoping review to identify issues that warrant consideration for clinical management.ResultTwenty-three articles were retained after screening, which covered six overarching clinical aspects: status epilepticus (SE), Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), dyslipidemia, congenital malformation (CM), chronic kidney disease (CKD), and neurological development. No studies for our population of interest were identified, highlighting the need for a cautionary approach to be employed when extrapolating findings.ConclusionHigh risks of CM and drug interactions with first-line antiepileptic drugs (AEDs) warrant measures to increase the accessibility and choices of safer second-line AEDs. To ensure evidence-based management of epilepsy within this population, the potential high prevalence of SE, CKD, dyslipidemia, and SJS/TEN and the cumulative effect of drug-drug interactions should be considered. Further understanding of the intersections between pregnancy and drug-drug interactions in SSA is needed to ensure evidenced-based management of epilepsy in pregnant HIV+ WWE. To prevent SE, the barriers for AED treatment adherence in pregnant HIV+ women should be explored. Our review underscores the need to conduct cohort studies of HIV+ WWE in reproductive age over time and across pregnancies to capture the cumulative effect of HAART and AED to inform clinical management.

Efficacy of Levetiracetam in neonatal seizures: a systematic review

Background Neonatal seizures represent the most frequent presenting sign of any neurological abnormality secondary to various etiologies in the neonatal period. Phenobarbitone (PB) has been used as first-line anti-epileptic drug in the treatment of seizures but concerns have been raised regarding its neuro-apoptotic effects over the developing brain. Levetiracetam (LEV) is a newer anti-epileptic drug with neuroprotective property and has been used in adults and pediatric patient but its use in neonates have very limited experience. Recently many neonatal studies have sought the role of LEV in the management of neonatal seizures. Aims and objective To evaluate the efficacy of Levetiracetam in the management of neonatal seizures. Search methods The literature search was done for this systematic review by searching the Cochrane Central Register of Controlled Trials (CENTRAL), and other various electronic databases including PubMed and various sites for ongoing trials and abstracts of conferences. Results Two eligible studies were analyzed that fulfilled the inclusion criteria of the systematic review. Fifteen studies were excluded due to the non-fulfillment of inclusion criteria. The primary outcome of both studies was to see the efficiency of LEV in controlling neonatal seizures when compared to PB. Better seizure control after a single loading dose of LEV was seen. Rates of seizure cessation at 24 h was also better in the LEV arm. Neonatal seizures secondary to hypoxic-ischemic encephalopathy (HIE) and receiving therapeutic hypothermia were better controlled with LEV. The side effect of LEV was significantly less when compared to PB. Conclusion Levetiracetam has shown to have promising anti-epileptic properties for the management of neonatal seizure with better efficacy and less or no side effects. There is a need to conduct more randomized controlled trials seeking the role of LEV in the acute management of neonatal seizures and also for assessing its neuroprotective role and neurodevelopmental outcome in these neonates.

NCOG-45. FIRST-LINE ANTIEPILEPTIC DRUG TREATMENT IN GLIOMA PATIENTS WITH EPILEPSY: LEVETIRACETAM VERSUS VALPROIC ACID

Abstract BACKGROUND Levetiracetam and valproic acid are two of the most commonly prescribed antiepileptic drugs (AEDs) in patients with a glioma and epilepsy. This study aimed at estimating the cumulative incidence of treatment failure of first-line monotherapy levetiracetam versus valproic acid in glioma patients with epilepsy. METHODS In this retrospective observational study, a competing risk model was used to estimate the cumulative incidence of treatment failure, from AED treatment initiation, for the two AEDs with death as competing event. Patients were matched on baseline covariates potentially related to treatment assignment and/or outcomes of interest according to the nearest neighbour propensity score matching technique. Secondary outcomes were the cumulative incidence of recurrent seizure, from AED treatment initiation (estimated with a competing risk model), and severity of adverse effects. Maximum duration of follow-up was 36 months. RESULTS In total, 776 patients using levetiracetam and 659 using valproic were identified. Matching resulted in two equal groups of 429 patients, with similar covariate distribution. The cumulative incidence of treatment failure (any reason) at 12 months for levetiracetam and valproic acid was equal to 33% (95%CI=29-38%) versus 50% (95%CI=45-55%), respectively (p&amp;lt; 0.001). The cumulative incidence of treatment failure due to uncontrolled seizures was significantly lower for levetiracetam compared to valproic acid (12 months: 16% [95%CI=12-19%] versus 28% [95%CI=23-32%]; p&amp;lt; 0.001), but no differences were found for treatment failure due to adverse effects (12 months: 14% [95%CI=11-18%] versus 15% [95%CI=11-18%]; p=0.636). The cumulative incidence of recurrent seizure of levetiracetam was significantly lower compared to valproic acid (12 months: 54% [95%CI=49-59%] versus 67% [95%CI=62-71%]; p&amp;lt; 0.001). No significant differences were found for level of toxicity. CONCLUSION Our results suggest that levetiracetam has superior efficacy compared to valproic acid, while showing a similar level of toxicity. Therefore, levetiracetam seems the preferred choice for first-line AED treatment in glioma patients.