Grants

This FDA approved research project will focus on 1) determining efficacy of synthetic (1,24) ACTH compared to vigabatrin in children with new onset infantile spasms; 2)determine the efficacy of combination therapy of synthetic (1,24) ACTH and vigabatrin to monotherapy synthetic (1,24) ACTH; 3) determine outcome of development in children with infantile spasms at 18 months of age; and 4) determine seizure outcomes in children with infantile spasms at 18 months of age. There are 15 participating sites that are active in PERC. PERC has 43 centers and has successfully collaborated to develop a National Infantile Spasms Database (NISD). Participation in NISD has led to the development of an infrastructure at each of these centers to rapidly identify children presenting with new onset IS, use of standardized treatment protocols and the ability to enter data into a common database. As of May 2017, IRB approval at the lead site (University of Colorado) is pending.

We propose to study how treatments for infantile spasms compare to one another. First we will perform a rigorous, modern, comparative effectiveness analysis of an existing data set called National Infantile Spasms Consortium (NISC), which includes the largest prospective cohort of newly diagnosed infantile spasms at 26 US hospitals (nearly 500 cases). Second, we will perform a cost analysis of different treatments using US Medicaid claims data over three years. To do so, we must develop and validate an algorithm to correctly identify children with infantile spasms in the claims dataset. The case finding algorithm is the core innovation of the grant, and will lay the foundation for several new domains of pediatric epilepsy research, including research in comparative effectiveness, health services, quality of care, epilepsy informatics, and surveillance and epidemiology. The investigators expect to apply the study findings directly to policy and practice through their leadership positions in the AAN, CNS and PERC.

Infantile epileptic encephalopathies (IEEs) are a groups of disorders that start with intractable epilepsy within the first few weeks to months of life (infantile), are marked by recurrent unprovoked seizures (epilepsy), and result in devastating global developmental delay and intellectual disability (encephalopathy). IEE represents a final common pathway that results from a heterogeneous group of underlying metabolic, structural or genetic conditions. Although previously thought to be acquired, due to recent advances in genetics an increasing number of individual genetic disorders are now recognized to cause IEEs. The identification of new causative genes therefore offers opportunities to elucidate the pathogenic role of genetic mutations and shed light on mechanistic-based drug design and screen. Little is known about the function of these newly identified genes, particularly regarding how the gene mutations disrupt neurodevelopment and lead to hyperexcitability. Therefore, new platforms and assays are urgently required to study the function of individual IEE genes and develop higher throughput drug screening to identify novel treatments. We propose to use CRISPR-mediated genome editing methods and patients derived iPSCs to model IEEs in vivo and in vitro. With a better understanding of the role that IEE related genes play in neurodevelopment and epileptogenesis, MMEA drug screening assays will be performed to develop mechanistic-based therapies. In vivo strategy using CRISPR-mediated genome editing methods has the potential to generate rodent models of epileptic encephalopathy. The iPSC and the MMEA approaches used will advance the field of iPSC-based neurological disease modeling and lead to new therapies for IEEs and other epilepsies. Completion of these studies should put us in a strong position to successfully compete for future NIH funding. We will test our hypothesis with three specific aims: 1) to examine how mutations in IEE genes alter neural development using an in vivo rodent model; 2) to examine how mutations in IEE genes alter neural development and excitability using patient-derived neurons generated via iPSCs; 3) to screen for novel modulators of excitability in mutant neurons. As of May 2017 they have completed Year 1.

The abstract "Models and Mechanisms of SPTAN1 Epileptic Encephalopathy" was presented at the American Epilepsy Society meeting, 2016.

This ongoing multicenter research network intends to evaluate different treatment alternatives for children and adolescents with one of the most severe manifestations of pediatric epilepsy: refractory convulsive status epilepticus (SE). The "Pediatric Status Epilepticus Group" (pSERG) was founded in 2010. The group has now grown to 11 centers. The results of this research network aim to identify best treatment options for SE using a comparative effectiveness approach. By identifying and ultimately implementing improved treatment options these results will enhance the quality of life of children with epilepsy. The network aims to identify variability of care in the treatment of both convulsive pediatric SE and refractory convulsive pediatric (rSE) at different reference Children’s Hospitals across the US by means of a registry to learn from this variability. Analysis of clinical presentation, EEG, neuroimaging and genetic biomarkers, as well as longitudinal follow-up between SE and rSE patients may provide the basis for specific future clinical and basic science hypotheses related to pediatric SE.

The specific aims of the project are 1) expand and optimize the standardized web-based data entry tool within a robust network of 11 collaborating tertiary care centers across the USA in order to facilitate outcome assessment in SE and rSE. 2) develop an outcome registry for both SE and rSE to determine which variables affect patient outcome. 3) conduct a case control study between SE and rSE patients assessing time to first line treatment. 4) determine variability in care of SE and rSE among the 11 institutions. 5) determine if there are genetic biomarkers that predispose patients to SE and rSE and expand the repository for specimens and data of SE and rSE patients.

To date, 4 manuscripts and 8 abstracts (posters) have been generated. Publications include: 1."Refractory Status Epilepticus in Children: intention-to-treat with continuous infusions of midazolam and pentobarbital" Pediatr Crit Care Med. 2016 Oct; 17(10): 968-975. 2."Refractory status epilepticus in children with and without prior epilepsy or status epilepticus" Neurology 2017; 88:386-394. 3."Time to treatment and Outcome in Pediatric Refractory Status Epilepticus" Lancet 2016 Under review. Abstracts include 1."Status epilepticus in children: a relationship between pre-hospital treatment and outcome" Poster American Academy of Neurology meeting 2016. 2."Status epilepticus in children: first line medication and dosing" Poster American Clinical Neurophysiology meeting 2016. The following posters were presented at the 2016 AES meeting: 3."Efficacy and safety of ketogenic diet for management of refractory status epilepticus"; 4."Under-dosing of lorazepam as a first-line anti-epileptic drug is associated with increased seizure duration in pediatric refractory status epilepticus"; 5."EEG reporting in the pediatric intensive care unit" and 6."Treatment of repeated episodes of pediatric status epilepticus".

SIPS II will be conducted as a sub-study of the International Pediatric Stroke Study (IPSS), using its well-established organization and infrastructure. The IPSS originally developed out of the Canadian Pediatric Ischemic Stroke Registry, a population based study of stroke in childhood across Canada from 1992-2002. In 2003, it expanded to include investigators in 11 centers in other countries, forming the foundation of the IPSS. The data from the origins SIPS study (deVeber 2010) provide strong evidence for additional research on seizure after pediatric stroke and drive our current proposal. Building on the success of the first SIPS study and the solid infrastructure of the IPSS, we propose to perform SIPS II, an extended prospective cohort study of seizures after ischemic stroke in neonates and children. They will follow the original 150 infants and children and learn about whether they have developed epilepsy up to five years after the stroke. We will enroll an additional 150 infants and children to provide the statistical power needed to address our new questions. We plan to collect and analyze MRI and EEG studies to find biomarkers that identify children at high risk for acute seizures and epilepsy. We will learn which characteristics of the stroke itself – like location or size seen on MRI – make a child more likely to have seizures to help determine whether acute seizures are only correlated with epilepsy because of stroke severity, size and location, or whether they are part of the causal pathway that leads to epilepsy. Three aims of the project: 1) provide more accurate information for children and their families about the likelihood of seizure or epilepsy in the five years after stroke; 2) early prognostic biomarkers of epilepsy after stroke, which will help clinicians decide the best treatment options; 3) critical evidence to help answer whether acute seizures after stroke harm the brain in a way that ultimately causes a child to develop epilepsy. The evidence is needed to decide whether a research trial of early anti-convulsant medications after pediatric stoke is justified. We hope that the results will ultimately lead to discovering better strategies to treat pediatric stroke and reduce the risk of childhood epilepsy in stroke survivors. As of May 2017, they have completed Year 1 of the project.

This proposal applies quantitative health services research methods to improve care for children with epilepsy. The central hypothesis was to lower emergency department (ED) visits, reduce healthcare costs, and improve clinical outcomes for children with epilepsy by 1) predicting which children will become frequent ED visitors and 2) providing those children with a care management intervention. The three aims of the study were to 1) develop and evaluate a predictive model to identify future frequent ED visitors (> 4/year) among children with epilepsy, via machine learning techniques, using both clinical and administrative data; 2) evaluate the effectiveness of care management to reduce ED visits, reduce costs, and improve clinical outcomes among children with epilepsy, via three analyses: 1) matched pair analysis with historical controls, 2) difference-in-difference analysis comparing those who receive care management vs. those who receive standard of care and 3) comparison between predicted and actual ED visits.

Preliminary data for this project was presented at the American Epilepsy Society and Child Neurology Society meetings in 2014, 2015 and 2016. "Comorbidities Associated with Frequent Emergency Department Visits Among Children with Epilepsy" presented at the American Epilepsy Society (AES) meeting, Columbus, OH 2014. "Identifying Children with Technology Dependence through Use of Administrative Data" presented at the American Medical Informatics Association meeting, San Francisco, CA 2015. "Predicting Frequent Emergency Visits – The Pediatric Epilepsy Emergency Room Score (PEER). Development and Validation in Three Datasets" presented at the AES meeting, Philadelphia, PA 2015. "Predicting Frequent ED Use Among Children with Epilepsy: A Retrospective Cohort Analysis using Electronic Health Data from Two Centers and Statewide Data from Two States" presented at the Child Neurology Society meeting Vancouver BC 2016. "Care Management for Children with Epilepsy at a Pediatrics Accountable Care Organization (ACO): A Qualitative Analysis presented at AES, Houston TX 2016. "The Pediatric Epilepsy Emergency Risk Score (PEER) – Predicting Frequent ED Use with Data from an Electronic Health Record System" presented at the Child Neurology Society meeting National Harbor, MD 2015. The following manuscript has been accepted for publication. 1."Care Coordinator at a Pediatric Accountable Care Organization (ACO): A Qualitative Analysis" in the journal Epilepsy & Behavior. The following manuscripts are currently under review: 2."Predicting Frequent ED Use Among Children with Epilepsy: A Retrospective Cohort Analysis Using Electronic Health Data from Two Centers" and 3."Evaluation of a Care Coordination Checklist for Children with Epilepsy".

We proposed initiating a study through a national consortium of pediatric epilepsy centers that would provide fundamental and currently unavailable information concerning newly diagnosed early life epilepsy (in the first three years of life). The information included the types of epilepsy (e.g. syndrome), the underlying causes as understood at the time of diagnosis and based on the initial diagnostic evaluations, the treatments selected, and the response to those treatments over the course of one year. With these data, we planned to perform a series of comparative effectiveness analyses to determine which treatments seemed to be the most successful in which circumstances. With the exception of infantile spasms, there are no guidelines for treatment, so our expectation was that there would be an element of randomness (although not formal randomization in the use of medications), which would allow for a preliminary assessment and contribute to planning randomized trials. This is still the case, although the variability in prescription practice for these children is far less than initially anticipated. Another benefit was to provide unprecedented overview of the use of genetic testing in newly diagnosed epilepsy of this age group.

In 2014 the investigators revised the original recruitment goal of 2400 children to 750. In April 2015 recruitment closed with 784 children enrolled. The goals for the study were met. As of May 2017, data analysis is ongoing.

This project resulted in multiple presentations at American Epilepsy Society meetings, including one for a Pediatric Highlights presentation. The first manuscript "Early Life Epilepsies and the Emerging Role of Genetic Testing" has been accepted for publication by JAMA Pediatrics. Other manuscripts to follow are by Grinspan "Comparative Effectiveness"; Shellhaas "Treatment Patterns in the 2010s"; Coryell "Use and Yield of MRI" and Berg "Etiological Patterns Between Spasms and Non-spasms".

This grant was requested to support ongoing operations of the TSC Natural History Database (NHD) project. This ongoing project started in 2006 and will continue for the foreseeable future as a resource for future collaborative TSC research initiatives. The TSC NHD Steering Committee and External Advisory Committee convened in June 2015 to re-evaluate the status and future strategy of the database. Three sub-projects are being added to collect additional data. The newly launched TSC Biosample Repository Project began enrolling participants who are enrolled in the TSC Database so that researchers will receive clinical data with biosamples.

The purpose of the grant was to fund current basic science research that would identify changes in transcription factor expression of developing oligodendrocytes in a mouse model of hypoxia induced white matter injury. As preterm infants are at a higher risk for epilepsy, identifying the changes that occur with hypoxia will allow the exploration of targeted therapies that may prevent or improve white matter injury in the preterm infant. Dr. Pardo completed her research on this project in November, 2015. They identified specific transcription factor determinants involved in the pathogenesis of white matter injury related to hypoxic injury (Olig 1 and AscII). These transcription factors may have identified two potential therapeutic targets that may be applied in future studies to ameliorate white matter injury in premature infants.

The following paper "Region specific oligodendrocyte transcription factor expression in a model of neonatal hypoxic injury" was published in the International Journal of Developmental Neuroscience (61 (2017) 1-11).

This project established a multicenter (7) registry to document the etiology, management and short-term outcomes of children with neonatal seizures. These centers follow the American Clinical Neurophysiology Society guidelines for electroencephalography monitoring of high-risk neonates. The registry has provided data to establish baseline features of clinical and electrographic neonatal seizures. All goals outlined in the original grant were met.

The study group recently secured a PCORI grant ($2.8m) "Continued Anticonvulsants After Resolutions of Neonatal Seizures: A Patient-Centered Comparative Effectiveness Study" based on data from this project.

Multiple abstracts have been presented at the Child Neurology Society, International Brain Monitoring and Neuroprotection Meeting and American Epilepsy Society. Papers published from this work include: 1. "Treatment duration after acute symptomatic seizures in neonates: a multicenter cohort study" J Pediatr 2017 Feb; 181:298-301. 2. "Contemporary Profile of Seizures in Neonates: A Prospective Cohort Study. J Pediatr 2016 Jul;174:98-103. 3."Treatment variability for seizures in newborns: results from the multicenter neonatal Seizure Registry" J Peds. In press. 4. "Profile of Neonatal Epilepsies: Characteristics of a Prospective US Cohort" Neurology. In press. 5. "Seizures in Preterm Neonates: A Multicenter Observational Cohort Study" is currently under review.

This was a pilot study to develop a protocol to identify, recruit, study and follow infants and young children with newly diagnosed epilepsy. This pilot study allowed the investigators to fine tune the protocol for implementation at multiple sites. The tools developed included a Manual of Operations (MOP), data collection forms, consent forms, IRB application for other sites and a final protocol.

Based on the results of this project, PERF funded a subsequent project by Anne Berg for a multi-center "Early Onset Epilepsy Consortium" in 2013.

The purpose of the database project is to facilitate additional clinical research in areas affecting children and adults with tuberous sclerosis complex, such as epilepsy, autism and tumor growth. This project is ongoing. The database is still open and has enrolled 2,092 subjects.

The TSC Database is utilized to identify potential participants for NIH studies conducted at TSC Database sites. The TS Alliance TSC Database is collecting data aligned with the European TSC Registry (TOSCA) core data fields, which will enable collaborative sharing in the future. In November 2012, the TS Alliance executed an agreement with Novartis Pharmaceuticals to partially underwrite the ongoing cost of operations of the project. Limited datasets from the TSC Database are being shared with Novartis to analyze targeted questions of interest to Novartis. Data from this project helped the Tumor/SEGA group develop their final recommendations on the frequency of MRI brain scans and are included in the 2012 International TSC Clinical Consensus Conference Recommendations for Surveillance and Management. Data from this project was used by Novartis to develop Everolimus.

Objective was to determine the frequency and predictors of seizures in pediatric stroke. 150 patients enrolled at 21 sites. 36 neonates and 114 children. Twenty-two (22) neonates and 32 children had an acute (<7 days) symptomatic seizure. Stroke involving temporal lobe predicted acute seizure but gender, AIS, hemorrhage, vascular territory and cortical infarct did not. Conclusion: Seizures are frequent within the first week of pediatric stroke onset. Nearly 1 in 20 developed recurrent remote seizures within 4 months of stroke. The International Pediatric Stroke Study (IPSS) group is an ongoing collaborative research effort.

As a result of this project, a manuscript was published in 2017 in the Journal of Developmental Medicine and Child Neurology (2017 Jan (10):38-44) entitled "Prolonged or recurrent acute seizures after pediatric arterial ischemic stroke are associated with increasing epilepsy risk". Three presentations were made: "Acute symptomatic seizures with pediatric stroke predict recurrent remote seizures" presented at the Child Neurology Society meeting, Austin 2013; "Younger age predicts acute seizures and epilepsy after pediatric stroke" Child Neurology Society meeting, National Harbor, 2015; and "Epilepsy is associated with poorer neurologic outcome after pediatric stroke" presented at the American Heart Association, International Stroke Conference, Los Angeles, 2016.