Antiseizure medication ≤48 hours portends better prognosis in new-onset epilepsy.

BACKGROUND: Several studies found that patients with new-onset epilepsy (NOE) have higher seizure recurrence rates if they presented already prior seizures. These observations suggest that timing of antiseizure medication (ASM) is crucial and should be offered immediately after the first seizure. Here, we wanted to assess whether immediate ASM is associated with improved outcome. METHODS: Single-center study of 1010 patients (≥16 years) who presented with a possible first seizure in the emergency department between 1 March 2010 and 1 March 2017. A comprehensive workup was launched upon arrival, including routine electroencephalography (EEG), brain computed tomography/magnetic resonance imaging, long-term overnight EEG and specialized consultations. We followed patients for 5 years comparing the relapse rate in patients treated within 48 h to those with treatment >48 h. RESULTS: A total of 487 patients were diagnosed with NOE. Of the 416 patients (162 female, age: 54.6 ± 21.1 years) for whom the treatment start could be retrieved, 80% (333/416) were treated within 48 h. The recurrence rate after immediate treatment (32%; 107/333) was significantly lower than in patients treated later (56.6%; 47/83; p < 0.001). For patients for whom a complete 5-year-follow-up was available (N = 297, 123 female), those treated ≤48 h (N = 228; 76.8%) had a significantly higher chance of remaining seizure-free compared with patients treated later (N = 69; 23.2%; p < 0.001). CONCLUSIONS: In this retrospective study, immediate ASM therapy (i.e., within 48 h) was associated with better prognosis up to 5 years after the index event. Prospective studies are required to determine the value of immediate workup and drug therapy in NOE patients.

Primary vs. pre-emptive anti-seizure medication prophylaxis in anti-CD19 CAR T-cell therapy.

INTRODUCTION: Seizures may occur in up to 30% of non-Hodgkin lymphoma patients who received anti-CD19 CAR T-cell therapy, yet the optimal anti-seizure medication (ASM) prevention strategy has not been thoroughly investigated. METHODS: Consecutive patients affected by refractory non-Hodgkin lymphoma who received anti-CD19 CAR T-cells were included. Patients were selected and assessed using similar internal protocols. ASM was started either as a primary prophylaxis (PP-group) before CAR T-cells infusion or as a pre-emptive therapy (PET-group) only upon the onset of neurotoxicity development. RESULTS: One hundred fifty-six patients were included (PP-group = 88, PET-group = 66). Overall, neurotoxicity and severe neurotoxicity occurred in 45 (29%) and 20 (13%) patients, respectively, equally distributed between the two groups. Five patients experienced epileptic events (PET-group = 3 [4%]; PP-group = 2 [2%]). For all the PET-group patients, seizure/status epilepticus occurred in the absence of overt CAR-T-related neurotoxicity, whereas patients in the PP-group experienced brief seizures only in the context of critical neurotoxicity with progressive severe encephalopathy. ASMs were well-tolerated by all patients, even without titration. No patients developed epilepsy or required long-term ASMs. CONCLUSION: Our data suggest that both primary and pre-emptive anti-seizure prophylaxis are safe and effective in anti-CD19 CAR T-cell recipients. Clinical rationale suggests a possible more favourable profile of primary prophylaxis, yet no definitive conclusion of superiority between the two ASM strategies can be drawn from our study.

Characterizing drug-induced epidermal necrolysis in a pediatric cohort.

This study aims to characterize the timeline and clinical features of onset, progression, and management of drug-induced epidermal necrolysis in pediatric patients. Sixteen pediatric patients were retrospectively identified and selected if under age 18 years at admission with one identified culprit drug exposure. Culprit drugs were antiepileptics (12/16, 75%) and antibiotics (4/16, 25%). Notably, anti-epileptic drugs (AED) had delayed onset and reported dose escalations that precipitated symptom onset; thus, patients prescribed AED with or without planned dose escalations should be monitored for prodromal symptoms longer than the typical onset window.

The North American Antiepileptic Drug Pregnancy Registry: A Canadian Subgroup Analysis.

BACKGROUND: The North American AED Pregnancy Registry (NAAPR) provides crucial data for understanding the risks of antiepileptic drug (AED) exposure in pregnancy. This study aims to quantify the Canadian contribution to NAAPR and compare AED usage in pregnancy in Canada and the USA. METHODS: Enrollment rate ratios (ERR) to NAAPR, adjusted for the populations of women of childbearing age, were calculated for the USA, Canada, and for the different Canadian provinces. Methods of enrollment to NAAPR and AED usage were compared between the two countries using chi-squared tests. RESULTS: Between 1997 and 2019, 10,215 pregnant women enrolled into NAAPR: 4.1% were Canadian (n = 432, ERR = 0.39, CI95% = 0.35-0.43). Within Canada, no patients were enrolled from the three northern territories or from Prince Edward Island. While fewer patients than expected enrolled from Quebec (ERR = 0.35, CI95% = 0.19-0.58), Nova Scotia had the highest enrollment rate (ERR = 1.55; CI95% = 0.66-3.11). Compared with their American peers, Canadians were less likely to have been enrolled by their healthcare provider and more likely to have been enrolled via social media (p < 0.01). Canadian women were more likely to be taking carbamazepine (24% vs. 15%; p < 0.01) or valproic acid (8% vs. 4%; p < 0.01). CONCLUSION: The proportion of Canadian enrollees into NAAPR was less than expected based on the relative population size of Canadian women of reproductive age. Greater Canadian enrollment to NAAPR would contribute to ongoing worldwide efforts in assessing the risks of AEDs use in pregnant women and help quantify rates of AED usage, major congenital malformations, and access to subspecialized epilepsy care within Canada.

Understanding Lamotrigine's Role in the CNS and Possible Future Evolution.

The anti-epileptic drug lamotrigine (LTG) has been widely used to treat various neurological disorders, including epilepsy and bipolar disorder. However, its precise mechanism of action in the central nervous system (CNS) still needs to be determined. Recent studies have highlighted the involvement of LTG in modulating the activity of voltage-gated ion channels, particularly those related to the inhibition of neuronal excitability. Additionally, LTG has been found to have neuroprotective effects, potentially through the inhibition of glutamate release and the enhancement of GABAergic neurotransmission. LTG's unique mechanism of action compared to other anti-epileptic drugs has led to the investigation of its use in treating other CNS disorders, such as neuropathic pain, PTSD, and major depressive disorder. Furthermore, the drug has been combined with other anti-epileptic drugs and mood stabilizers, which may enhance its therapeutic effects. In conclusion, LTG's potential to modulate multiple neurotransmitters and ion channels in the CNS makes it a promising drug for treating various neurological disorders. As our understanding of its mechanism of action in the CNS continues to evolve, the potential for the drug to be used in new indications will also be explored.

Herbal extracts: the future treatment option for drug-resistant epilepsy.

Epilepsy is a neurological disorder characterised by two or more unprovoked seizures. The high prevalence and incidence of epilepsy globally, especially in Asia, has remained a big concern over the course of centuries. Patients are usually prescribed the already known anti-epileptic drugs, but even after going through three different generations of anti-epileptic drugs, some people still suffer from drug-resistant form of epilepsy. These patients are usually prescribed a higher dose of anti-epileptic drugs, which results in more adverse effects. That is why new treatment options, like herbal extracts, should be explored for patients who do not respond to the classic anti-epileptic drugs. The current narrative review was planned to explore if herbal extracts can be the future for the treatment of drug-resistant epilepsy.

Evaluating the bioequivalence of levetiracetam brand and generic oral tablets available in the Saudi market in vivo.

Background: Epilepsy is a common global neurological disorder. About 30% of epileptic patients are managed with anti-epileptic Drugs (AEDs). Since 2000, Levetiracetam (LEV) has been marketed around the world as an AED under the brand name Keppra, and recently more generics are found in the Saudi market as cheaper alternatives. The objective of this study is to evaluate the bioequivalence of LEV brand and generics available in the Saudi market in mice. Methods: Pharmacokinetics (PK), liver function test, and behavioral studies were conducted for LEV brand and generic in different groups of Blab/c mice. Results: PK results show a significance difference in PK parameters mostly evidenced with generic 3, then generic 2. The only significant different between Keppra and generic 1 was in T1/2. In addition, Keppra did not significantly increase liver enzymes in comparison to other generics. On the other hand, other generics showed less favorable results in increasing liver enzymes. Keppra reduced the number and intensity of epileptic attacks, had no mortality rate due to epilepsy, and was associated with less sever seizures attacks. Conclusion: Keppra, the brand form of LEV, has better safety and efficacy profiles in mice compared to 3 generics found in the Saudi market. Therefore, we recommend evaluating the same parameters tested in this study in patients utilizing similar generics and brand to establish the existence of bioequivalence between LEV brand and generics.

Analgesic utilization in people with knee osteoarthritis: A population-based study using primary care data.

PURPOSE: Osteoarthritis (OA) is a chronic painful condition that often affects large joints such as the knee. Treatment guidelines recommend paracetamol, nonsteroidal anti-inflammatory drugs (NSAIDs), and opioids. Antidepressants and anti-epileptic drugs (AEDs) are commonly prescribed for chronic noncancer pain conditions including OA, as an off-label use. This study describes analgesic utilization in patients with knee OA at population level using standard pharmaco-epidemiological methods. METHOD: This was a cross-sectional study between 2000 and 2014 using data from the U.K. Clinical Practice Research Datalink (CPRD). The use of antidepressants, AEDs, opioids, NSAIDs, and paracetamol was studied in adults with knee OA using the following measures: annual number of prescriptions, defined daily doses (DDD), oral morphine equivalent dose (OMEQ), and days' supply. RESULTS: In total, there were 8,944,381 prescriptions prescribed for 117,637 patients with knee OA during the 15-year period. There was a steady increase in the prescribing of all drug classes, except for NSAIDs, over the study period. Opioids were the most prevalent class prescribed in every study year. Tramadol was the most commonly prescribed opioid, with the number of DDD increasing from 0.11 to 0.71 DDDs per 1000 registrants in 2000 and 2014, respectively. The largest increase in prescribing was for AEDs, where the number of prescriptions increased from 2 to 11 per 1000 CPRD registrants. CONCLUSION: There was an overall increase in the prescribing of analgesics apart from NSAIDs. Opioids were the most frequently prescribed class; however, the greatest increase in prescribing between 2000 and 2014 was observed in AEDs.

Management of status epilepticus: a narrative review.

Status epilepticus causes prolonged or repetitive seizures that, if left untreated, can lead to neuronal injury, severe disability, coma and death in paediatric and adult populations. While convulsive status epilepticus can be diagnosed using clinical features alone, non-convulsive status epilepticus requires confirmation by electroencephalogram. Early seizure control remains key in preventing the complications of status epilepticus. This is especially true for convulsive status epilepticus, which has stronger evidence supporting the benefit of treatment on outcomes. When status epilepticus becomes refractory, often due to gamma-aminobutyric acid and N-methyl-D-aspartate receptor modulation, anaesthetic drugs are needed to suppress seizure activity, of which there is limited evidence regarding the selection, dose or duration of their use. Seizure monitoring with electroencephalogram is often needed when patients do not return to baseline or during anaesthetic wean; however, it is resource-intensive, costly, only available in highly specialised centres and has not been shown to improve functional outcomes. Thus, the treatment goals and aggressiveness of therapy remain under debate, especially for non-convulsive status epilepticus, where prolonged therapeutic coma can lead to severe complications. This review presents an evidence-based, clinically-oriented and comprehensive review of status epilepticus and its definitions, aetiologies, treatments, outcomes and prognosis at different stages of the patient's journey.

Seizure outcomes after meningioma resection.

Meningiomas are one of the most common primary brain tumours, and seizures are a common presenting symptom. Complete tumour resection results in seizure freedom in up to 90% patients. The use of AEDs in these patients is inconsistent, and current evidence shows that they do not have any benefit in long-term seizure prevention after resection. Tumour histology, location, surrounding oedema, recurrence and post-operative complications are important risk factors for having post-operative seizures.

Possible interplay between the theories of pharmacoresistant epilepsy.

Epilepsy is one of the oldest known neurological disorders and is characterized by recurrent seizure activity. It has a high incidence rate, affecting a broad demographic in both developed and developing countries. Comorbid conditions are frequent in patients with epilepsy and have detrimental effects on their quality of life. Current management options for epilepsy include the use of anti-epileptic drugs, surgery, or a ketogenic diet. However, more than 30% of patients diagnosed with epilepsy exhibit drug resistance to anti-epileptic drugs. Further, surgery and ketogenic diets do little to alleviate the symptoms of patients with pharmacoresistant epilepsy. Thus, there is an urgent need to understand the underlying mechanisms of pharmacoresistant epilepsy to design newer and more effective anti-epileptic drugs. Several theories of pharmacoresistant epilepsy have been suggested over the years, the most common being the gene variant hypothesis, network hypothesis, multidrug transporter hypothesis, and target hypothesis. In our review, we discuss the main theories of pharmacoresistant epilepsy and highlight a possible interconnection between their mechanisms that could lead to the development of novel therapies for pharmacoresistant epilepsy.

Prevalence of Medically Resistant Epilepsy in Saudi Arabia.

OBJECTIVES: The objective of this study was to evaluate the prevalence of medically resistant epilepsy (MRE) in our hospital and to compare the prevalence with that in other populations. METHODS: We retrospectively analyzed the data of patients who visited the epilepsy clinics at King Fahd University Hospital, Al-Khobar, Saudi Arabia between January 2017 and December 2018. This study included patients aged ≥14 years who had at least 2 unprovoked seizures 24 h apart. Patients who had provoked seizure(s), paroxysmal events, or syncope or had incomplete medical records were excluded. The definition and classification of the International League Against Epilepsy were used. Moreover, we searched the En-glish literature using PubMed and Google Scholar to compare the prevalence of MRE between our population and other populations. RESULTS: In total, 1,151 patients were screened, and 751 patients were included in the final analysis. Of the 751 patients, 229 (male: 56.3%, female: 43.7%; mean age: 32.07 years, and standard deviation, 12.2 years) had MRE, with a cumulative prevalence of 30%. The etiology was as follows: unknown, 63.3% (n = 145); structural, 31.9% (n = 73); genetic, 3.1% (n = 7); and infectious, 1.7% (n = 4). None of the patients had metabolic or immune-related etiologies. CONCLUSION: The prevalence of MRE in our population (30%) is close to that in other populations (30-36.5%). Early identification of such patients is crucial to improve their management.

Effect of valproate and add-on levetiracetam on inflammatory biomarkers in children with epilepsy.

BACKGROUND: Contemporary research indicates the role of neuroinflammation/inflammatory markers in epilepsy. In addition, comorbidities such as anxiety and poor health-related quality of life are vital concerns in clinical care of pediatric patients with epilepsy. This open-label, prospective, observational study evaluated the effect of valproate and add-on levetiracetam on serum levels of C-C motif ligand 2 (CCL2) and Interleukin-1 beta (IL-1ß) in pediatric patients with epilepsy. We also studied effect of valproate and add-on levetiracetam on anxiety and health-related quality of life (HRQoL) in specified age subgroups. METHODS: Children aged 1 to 12 years, diagnosed with epilepsy (generalized or focal seizures), treated with valproate (n = 40) and valproate with add-on levetiracetam (n = 40) were included. All patients were followed up for 16 weeks and assessed for changes in serum CCL2 and IL-1ß levels. Spence Children Anxiety Scale short version (SCAS-S) and QOLCE-16 scales were used to measure anxiety and HRQoL, respectively, in specific age groups. RESULTS: The serum CCL2 level decreased significantly (p < .001) from 327.95 ±â€¯59.07 pg/ml to 207.02 ±â€¯41.50 pg/ml in the valproate group and from 420.65 ±â€¯83.72 pg/ml to 250.06 ±â€¯46.05 pg/ml in the add-on levetiracetam group. Serum IL-1ß level did not change significantly in both groups. Spence Children Anxiety Scale short version scores were decreased and QOLCE-16 scores were increased significantly (p < .001) in both valproate and add-on levetiracetam groups. CONCLUSIONS: The results of our study suggest that valproate and levetiracetam led to decrease serum CCL2 levels without any change in serum IL-1ß levels in children with epilepsy. Anti-inflammatory property of valproate and levetiracetam might underlie their antiepileptic effect and CCL2 could be a potential marker of drug efficacy in epilepsy. Also, valproate and levetiracetam reduced anxiety and improved quality of life in children with epilepsy in the age groups evaluated.

Starting stiripentol in adults with Dravet syndrome? Watch for ammonia and carnitine.

OBJECTIVE: Dravet syndrome (DS) is a rare cause of severe and pharmacoresistant epileptic encephalopathy. Stiripentol (STP) has a significant therapeutic benefit in the pediatric DS population. However, STP effects on adult patients have not been well studied. In our adult STP-naive DS patient population, STP initiation was associated with encephalopathy, despite decreases in valproate and clobazam dosage. Here we explored the cause and treatment of encephalopathic manifestations associated with STP in adults. METHODS: Twenty-eight patients with a confirmed clinical and genetic diagnosis of DS who attended the Adult Epilepsy Genetics Clinic were identified retrospectively. Patients who declined or discontinued STP after fewer than 3 months of use, patients who were deceased before starting STP or seizure-free when the genetic diagnosis was confirmed, and those who started STP before leaving the pediatric system (<18 years) were excluded. Levels of ammonia, carnitine, and other anti-epileptic drugs (AEDs) were observed for patients receiving STP. Patients with high ammonia levels who received carnitine supplementation were reevaluated. They were also offered an increased dosage of stiripentol if treatment with carnitine improved the encephalopathy. RESULTS: We observed hyperammonemic encephalopathy in 77% of patients treated with STP. In seven of nine patients, we observed a rate of improvement in ammonia levels of 35% (95% confidence interval [CI] 21%-49%) at a mean carnitine dose of 991 ± 286 mg/d (range 660-1320 mg/d). Five patients whose ammonia levels normalized were also offered an increase in STP dose and they were able to tolerate higher doses with improvement in side effects. Despite such adjustments, the mean maximum stiripentol dose reached was 14.89 ± 8.72 mg/kg/d, which is lower than what is typically recommended in children (50 mg/kg/d). SIGNIFICANCE: We report hyperammonemia in adult STP-naive patients who were on valproate and clobazam, despite dose reduction of the latter drugs. We also report that treatment with carnitine improved hyperammonemia, allowing the continuation of STP.

Therapeutic drug monitoring of anti-epileptic drugs - a clinical verification of volumetric absorptive micro sampling.

Background Therapeutic drug monitoring (TDM) of antiepileptic drugs (AEDs) can serve as a valuable tool in optimising and individualising epilepsy treatment, especially in vulnerable groups such as pregnant women, the elderly and children. Unfortunately, TDM is often performed suboptimally due to limitations in blood collection. Therefore, we investigated volumetric absorptive micro sampling (VAMS) - a new home-sampling technique. We aimed to evaluate VAMS to determine and quantify the different AEDs and concentrations of 16 different AEDs in whole blood collected by VAMS. Methods Patient blood samples (n = 138) were collected via venepunctures at the Academic Centre for Epileptology Kempenhaeghe. AED concentrations were determined, and these concentrations were used to compare the VAMS method (whole blood) with the conventional method (serum). In addition, the recovery was examined as well as the impact of haematocrit. Finally, AED-spiked blood was used to test the stability of the AEDs inside the micro-sampler devices over a period of time and whether temperature had an effect on the stability. Results VAMS allows for an accurate detection of 16 different AEDs within 2 days after sampling. Deviation in recovery was less than 10% and high correlations were found between VAMS and conventional sampling. Moreover, haematocrit does not have an effect with values between 0.3 and 0.5 (L/L). Finally, although storage temperature of VAMS does affect some AEDs, most are unaffected. Conclusions VAMS enables an accurate detection of a wide variety of AEDs within 2 days after sampling.

Psychiatric Comorbidities in Pediatric Epilepsy.

PURPOSE OF REVIEW: Psychiatric comorbidities are close to 5-times higher in children and youth with epilepsy (CYE) compared to general population. With epilepsy being one of the most common neurological disorders in children, we provide a timely review of psychiatric issues in CYE. RECENT FINDINGS: A meta-analysis found a pooled prevalence of anxiety in 18.9% and depression in 13.5% of CYE. Attention deficit hyperactivity disorder (ADHD) is 2.5 to 5.5 times higher in CYE compared to healthy counterparts. Recent evidence highlights that behavioral adverse effects may lead to discontinuation of anti-epileptic drugs (AEDs) in more than 10% of CYE. Up to 70% CYE shows elevation in baseline psychological symptoms after AED initiation. Identifying psychiatric symptoms can be easily accomplished by the routine use of psychiatric screening instruments in CYE clinics, which is associated with improved health-related quality of life (HRQOL). Psychoeducation is a key component for any visit with CYE. There is some evidence of the effectiveness of behavioral psychological interventions for CYE. There are no therapeutic trials of psychotropics in CYE, but treatment recommendations based on the experience in adults with epilepsy and general population are applicable. Early diagnosis and management of psychiatric comorbidities leads to improvement in HRQOL of CYE. This requires routine screening and a multidisciplinary teamwork.

A Microfluidic System for Stable and Continuous EEG Monitoring from Multiple Larval Zebrafish.

Along with the increasing popularity of larval zebrafish as an experimental animal in the fields of drug screening, neuroscience, genetics, and developmental biology, the need for tools to deal with multiple larvae has emerged. Microfluidic channels have been employed to handle multiple larvae simultaneously, even for sensing electroencephalogram (EEG). In this study, we developed a microfluidic chip capable of uniform and continuous drug infusion across all microfluidic channels during EEG recording. Owing to the modular design of the microfluidic channels, the number of animals under investigation can be easily increased. Using the optimized design of the microfluidic chip, liquids could be exchanged uniformly across all channels without physically affecting the larvae contained in the channels, which assured a stable environment maintained all the time during EEG recording, by eliminating environmental artifacts and leaving only biological effects to be seen. To demonstrate the usefulness of the developed system in drug screening, we continuously measured EEG from four larvae without and with pentylenetetrazole application, up to 60 min. In addition, we recorded EEG from valproic acid (VPA)-treated zebrafish and demonstrated the suppression of seizure by VPA. The developed microfluidic system could contribute to the mass screening of EEG for drug development to treat neurological disorders such as epilepsy in a short time, owing to its handy size, cheap fabrication cost, and the guaranteed uniform drug infusion across all channels with no environmentally induced artifacts.

Breakdown of blood brain barrier as a mechanism of post-traumatic epilepsy.

Traumatic brain injury (TBI) accounts for approximately 16% of acute symptomatic seizures which usually occur in the first week after trauma. Children are at higher risk for post-traumatic seizures than adults. Post-traumatic seizures are a risk factor for delayed development of epilepsy. Delayed, chronic post-traumatic epilepsy is preceded by a silent period during which therapeutic interventions may arrest, revert or prevent epileptogenesis. A number of recent review articles summarize the most important features of post-traumatic seizures and epilepsy; this review will instead focus on the link between cerebrovascular permeability, epileptogenesis and ictal events after TBI. The possibility of acting on the blood-brain barrier (BBB) and the neurovascular unit to prevent, disrupt or treat post-traumatic epilepsy is also discussed. Finally, we describe the latest quest for biomarkers of epileptogenesis which may allow for a more targeted intervention.

Evolving dynamic networks: An underlying mechanism of drug resistance in epilepsy?

At least one-third of all people with epilepsy have seizures that remain poorly controlled despite an increasing number of available anti-epileptic drugs (AEDs). Often, there is an initial good response to a newly introduced AED, which may last up to months, eventually followed by the return of seizures thought to be due to the development of tolerance. We introduce a framework within which the interplay between AED response and brain networks can be explored to understand the development of tolerance. We use a computer model for seizure generation in the context of dynamic networks, which allows us to generate an 'in silico' electroencephalogram (EEG). This allows us to study the effect of changes in excitability network structure and intrinsic model properties on the overall seizure likelihood. Within this framework, tolerance to AEDs - return of seizure-like activity - may occur in 3 different scenarios: 1) the efficacy of the drug diminishes while the brain network remains relatively constant; 2) the efficacy of the drug remains constant, but connections between brain regions change; 3) the efficacy of the drug remains constant, but the intrinsic excitability within brain regions varies dynamically. We argue that these latter scenarios may contribute to a deeper understanding of how drug resistance to AEDs may occur.

Practice variation in anti-epileptic drug use for neonatal hypoxic-ischemic encephalopathy among regional NICUs.

BACKGROUND: While intercenter variation (ICV) in anti-epileptic drug (AED) use in neonates with seizures has been previously reported, variation in AED practices across regional NICUs has not been specifically and systematically evaluated. This is important as these centers typically have multidisciplinary neonatal neurocritical care teams and protocolized approaches to treating conditions such as hypoxic ischemic encephalopathy (HIE), a population at high risk for neonatal seizures. To identify opportunities for quality improvement (QI), we evaluated ICV in AED utilization for neonates with HIE treated with therapeutic hypothermia (TH) across regional NICUs in the US. METHODS: Children's Hospital Neonatal Database and Pediatric Health Information Systems data were linked for 1658 neonates ≥36 weeks' gestation, > 1800 g birthweight, with HIE treated with TH, from 20 NICUs, between 2010 and 2016. ICV in AED use was evaluated using a mixed-effect regression model. Rates of AED exposure, duration, prescription at discharge and standardized AED costs per patient were calculated as different measures of utilization. RESULTS: Ninety-five percent (range: 83-100%) of patients with electrographic seizures, and 26% (0-81%) without electrographic seizures, received AEDs. Phenobarbital was most frequently used (97.6%), followed by levetiracetam (16.9%), phenytoin/fosphenytoin (15.6%) and others (2.4%; oxcarbazepine, topiramate and valproate). There was significant ICV in all measures of AED utilization. Median cost of AEDs per patient was $89.90 (IQR $24.52,$258.58). CONCLUSIONS: Amongst Children's Hospitals, there is marked ICV in AED utilization for neonatal HIE. Variation was particularly notable for HIE patients without electrographic seizures, indicating that this population may be an appropriate target for QI processes to harmonize neuromonitoring and AED practices across centers.