24.jpg)
Epilepsy research
Dr. Sookyong Koh has discovered evidence that children with epilepsy can benefit from a stimulating and supportive environment. Read more.
Physician-scientists in the Children’s Memorial Epilepsy Center participate in studies that are funded by the National Institute of Health and by pharmaceutical companies. In searching for ways to improve patient care, the epilepsy center also has its own investigator initiated studies.
Consequences of Prolonged Febrile Seizures in Childhood
Childhood Absence Epilepsy Rx PK-PD-Pharmacogenetics
Remission in Pediatric Epilepsy
Quality of Life in Neurological Disorders, Spanish Linguistic Validation
Emotional, behavioral, and learning problems in children with seizures
Consequences of Prolonged Febrile Seizures in ChildhoodIn a National Institutes of Health-funded, multi-center clinical study, the epilepsy center is pursuing one of epilepsy's many causes. Neurologists have long debated whether prolonged febrile seizures lead to epilepsy. Febrile or "fever" seizures are very common among children under five years old. They occur in approximately 100,000 U.S. children annually when body temperatures rapidly rise above 101°F. Studies on animals have shown an association between a rapid rise in body temperature and seizure activity. In most children these seizures have no lasting consequences. The study will focus on the three percent of children who have a febrile seizure lasting more than 30 minutes and develop scar tissue in the brain.
Previous studies have attempted to find a link between febrile seizures and epilepsy, but have lacked the funding, methodology and patient population large enough to answer the question. With five medical centers participating in the current study, investigators hope to enroll 200 children. The National Institutes of Health has agreed to continue to support the study for an additional 5 years.
This is a landmark study that will show if this population develops epilepsy as a result of scarring, and if so, what the risk factors are. The primary investigator at Children’s Memorial is Douglas R. Nordli, MD, who is also the central EEG reader for the study. The study’s principal investigator is Shlomo Shinnar, MD, at Einstein Medical School in New York City.
In addition to collecting traditional data such as a medical history, magnetic resonance images (MRIs), and EEG analysis, two new vital pieces of information will be gathered from each of the patients — evidence of previous viral infection and genetic markers. Leon G. Epstein, MD, head of Children’s Memorial’s Division of Neurology, is leading the viral component of the study.
Neuropsychological testing is also done as part of the study to primarily measure global development. At the five-year evaluation, which will precede the development of epilepsy in some cases, more detailed cognitive testing will be performed. Parents also complete questionnaires on the behavior and development of the children.
The goal of the study is to determine who is at risk by recognizing if it is this particular set of clinical characteristics, infection with this virus, or this genetic pre-disposition. The aim is to then to investigate "neuroprotective strategies" that might prevent the development of epilepsy in patients identified as high-risk.
Updated May 2009
Childhood Absence Epilepsy Rx PK-PD-Pharmacogenetics
Childhood absence epilepsy (CAE) affects 10-15 percent of all children with epilepsy. The age of onset is between 4 to10. Children with CAE have brief staring spells that occur frequently throughout the day.
The optimal treatment for CAE and the inter-individual response to therapy has not been defined. The objective of this study is to identify the optimal initial anti-epileptic medication and to determine the clinical, pharmacokinetic and pharmacodynamic factors underlying inter-individual variation in treatment response and toxicity.
This study compares initial treatment in newly diagnosed CAE and consists of a randomized, double-blind comparative study of the three commonly used anti-epileptic drugs (ethosuximide, lamotrigine, and valproate) using freedom from failure rate as the primary endpoint. There will also be pharmacokinetic and pharmacogenetic response to treatment measures. Neuropsychological and quality of life measures will also be used. If a patient fails that double-blind treatment, they will be eligible to enroll in the open-label phase of the study where the testing will be similar. The main difference will be that the medication taken by the patient will be known. The primary endpoints are seizure freedom and short and long-term tolerability.
Enrollment goals for this study have been met. All patients in the open-label phase have been transitioned to a marketed drug. Patients in the double-blind phase of the study will be transitioned to a marketed drug once it is possible to reveal which medicine each of the patients is on. The study is currently following the patients in the follow-up phase. Medical history, physical and neurological examination, a sustained and selective attention and impulsivity test, and quality of life measures are all measured as part of this part of the study.
Updated May 2009
Remission in Pediatric Epilepsy
Epilepsy is one of the most common neurological disorders affecting 2.5 million Americans. Each year, over 180,000 new cases are diagnosed. Sadly, clinical research to help those patients who have shown resistance to AEDs (anti-epileptic drugs) has not changed significantly in 50 years. In 1951 it was reported that 25 percent of children with epilepsy could not be adequately controlled. Today, after 50 years of epilepsy research, the percent of children with inadequately controlled epilepsy has improved to only 23 percent. As a result, neurologists today are unable to help patients diagnosed with epilepsy any better than neurologists 50 years ago. And in 1951, there were a limited number of AEDs — today there are over 50 antiepileptic drugs available.
This study aims to collect similar and consistent data on epilepsy patients from multiple epilepsy centers and then categorize the data in a similar fashion. The multi-site study will include Douglas Nordli, MD, at Children’s Memorial Epilepsy Center, William Galliard, MD at National Children’s Hospital, Washington, DC, and Helen Cross, MD, PhD, at Great Ormond Street Hospital for Children, London, UK. Data will be collected from medical charts at each site and deidentified prior to entry onto a secure web-based database designed and maintained by Malek Adjouadi, PhD, at Florida International University. It is hoped that by collecting and sharing the histories of a large number of children with epilepsy that treatment for those with hard to treat epilepsies can be improved.
Updated May 2009
Quality of Life in Neurological Disorders, Spanish Linguistic Validation
Many of the traditional clinical or functional measures of disease status, such as tests of muscle strength or counts of seizure frequency, do not adequately represent the full scope of the impact of chronic neurological disorders and their treatments on individuals. More subjective aspects of patients’ functioning, such as social, psychological, and mental well-being, may be more important components of an intervention or disease. Measurement of patient-oriented outcomes is a particular concern in clinical trials, where differences in clinical measurements or imaging results may or may not translate into important benefit to the patients.
Some aspects of health-related quality of life (HRQL) have been incorporated into many recent or current clinical trials in neurology, usually as secondary outcome measures. Many measurement scales have been developed for use in various disease settings; however, some of the existing scales have questionable validity and there is no consensus on what HRQL assessment methods should be used within or across studies or disease areas. Because of the lack of consensus about the best tools or measurement approaches, it is not possible to compare the relative burden of various neurological conditions to each other or to non-neurological diseases; nor is it possible to compare the relative benefits of one treatment over another based on the same patient-centered outcome. Investigators are reluctant to design trials with the primary objective of comparing quality of life, presumably because HRQL outcomes appear to be too subjective, too hard to define concisely, too complex to administer, and too difficult to interpret. There are not very many condition-targeted quality of life surveys for persons with neurological diseases that are reliable, valid, responsive, and brief enough to be feasibly administered in a clinical trials setting. The availability of such a tool for persons with neurological diseases would greatly increase the probability that the research community would incorporate patient-centered measures as primary and secondary outcomes in clinical trials.
Childhood onset epilepsy is often the result of co-morbid conditions such as mental retardation and cerebral palsy. Children with epilepsy often face even more complex psychosocial consequences than individuals who develop the disease as adults. The pediatric epilepsy population has approximately a threefold increased risk of subnormal mental ability and other learning and behavior problems, twice the referral rate for mental health services, and a threefold increase in utilization of special education services. Adolescents with epilepsy are also noted to have a higher frequency of behavioral problems than do peers who are healthy or have other chronic health problems.
While it has been established that epilepsy HRQL measures developed for adults are not appropriate for use in the pediatric and adolescent populations, there are several factors that complicate assessment of HRQL in the pediatric and adolescent epilepsy populations. These include: development-related change in basal functioning; difficulties associated with proxy-assessment; handicaps related to learning ability, behavioral disorders and motor handicap; and the episodic nature of the disease. Recently, pediatric and adolescent measures have been designed to address, at least in part, the above concerns.
The goal of the study is to enroll 800 patients across 10 sites in the United States and Puerto Rico. The goal for Children's Memorial Hospital is to enroll 30-50 patients.
The primary investigator the project is David Cella, PhD.
Updated May 2009
Double-Blind, Placebo-Controlled, Efficacy and Safety Study of Clobazam (0.25, 0.5 and 1.0 mg/kg/day) in Patients with Lennox-Gastaut Syndrome
Lennox-Gastaut syndrome (LGS) is a catastrophic childhood epileptic encephalopathy characterized by a slow spike and wave electroencephalogram (EEG), multiple seizure types, and usually an abnormal developmental state and behavioral disturbances. Onset of LGS, as determined by the appearance of the characteristic seizures, generally occurs between 3 and 10 years of age, with peak occurrence between 3 and 5 years and usually before 8 years. LGS is estimated to represent 1 to 2 percent of all childhood epilepsy cases. The quality of life and long-term prognosis for patients with LGS is poor; only a very small proportion of patients (approximately 10 percent) experience full seizure remission, although cognitive deficits usually persist. Most patients continue to have refractory epilepsy, progressive neurocognitive impairment, frequent episodes of status epilepticus, and continual development deterioration that persists into adulthood. Indicators of poor prognosis include onset of symptoms before age 3 years, high seizure frequency, repeated episodes of status epilepticus, and prior history of infantile spasms.
Lennox-Gastaut syndrome poses a significant treatment challenge. No single anti-epileptic drug provides satisfactory relief for all or most patients with LGS and a combination of treatments is often required. Even with combination therapy, many LGS patients show resistance to treatment. Adjunctive therapy with newer anticonvulsant medications has demonstrated efficacy for some patients, although polytherapy and high medication doses are often associated with unfavorable adverse event profiles.
Three anti-epileptic drugs (AEDs) — felbamate, lamotrigine and topiramate — have demonstrated clinical efficacy and are approved by the Food and Drug Administration (FDA) for the treatment of LGS; however, none are effective in all patients and loss of efficacy occurs in some patients who initially show response.
The goal is to enroll patients with Lennox-Gastaut Syndrome between the ages of 2 and 60 years old weighing ≥12.5 kg from approximately 60-65 sites from the United States (US) and countries either where CLB is not already approved or not readily available. Additionally, the patients must have been <11 href="https://secure.childrensmemorial.org/findadoc/bios.aspx?id=743" title="Dr. Koh bio" style="border-top-width: 0px; border-right-width: 0px; border-bottom-width: 0px; border-left-width: 0px; border-style: initial; border-color: initial; font-family: inherit; font-size: 13px; font-style: inherit; font-weight: inherit; margin-top: 0px; margin-right: 0px; margin-bottom: 0px; margin-left: 0px; outline-width: 0px; outline-style: initial; outline-color: initial; padding-top: 0px; padding-right: 0px; padding-bottom: 0px; padding-left: 0px; vertical-align: baseline; color: rgb(0, 64, 148); text-decoration: underline; ">Sookyong Koh, MD, PhD.
Updated May 2009
A Multi-Centered clinical Open-Labeled Trial on the Safety and Efficacy of KetoCal® Use in Patients with Drug Resistant Epilepsy
The ketogenic diet has been used since the 1920s for treatment of epilepsy. Recently, there has been resurgence in its use to manage refractory epilepsy. The ketogenic diet’s mechanism of action is unknown; however, it is thought that the ketone bodies produced as an end product of beta-oxidation may have an anti-convulsant effect. A study in 1998 concluded that the ketogenic diet was well tolerated and was effective. Of 150 children with difficult to control epilepsy, 50% of the children had a >50 percent decrease in their seizures. A systematic review of the medical literature concluded that approximately half of children with refractory epilepsy can have a clinically meaningful improvement after treatment with the ketogenic diet. Further, the ketogenic diet is effective in reducing frequency of seizures. Positive effects on quality of life have also been noted, along with a reduction in use, or complete discontinuation, of anti-epileptic medications.
KetoCal® is a complete formula developed to specifically meet the nutritional profile of the ketogenic diet and may be consumed as a sole source of nutrition for children older than 1 year of age. KetoCal® reduces potential errors in making modular feeds and is easier for parent(s)/caregiver(s) to prepare. A short intervention study was conducted in of a total of fourteen children (ages 1 to 10) in which KetoCal® was substituted for the previous modular feeds, KetoCal® was shown to be effective in maintaining the previous level of ketosis compared to when a subject was taking modular feed. In addition, a series of 10 case reports in children over a minimum 8-week period has shown that KetoCal® is effective in attaining and maintaining ketosis.
The goal of the study was to enroll 15 subjects ages 1 to 10 that meet eligibility criteria to end up with 10 completers across two United States sites and four European sites — five from Children’s Memorial. The sites will enroll patients with drug resistant epilepsy, covering at least 80 percent of their energy requirements with KetoCal ® either via a tube or orally.
Children's Memorial Hospital enrolled 9 patients. 6 patients will complete the study. The study is no longer enrolling patients and will end in November 2009, a year from when the last patient was enrolled. The Primary Investigator for the study is Steven Yannicelli PhD, RD. Robyn Blackford, RD, LDN is the primary investigator at Children's Memorial Hospital.
Updated May 2009
Transcriptional Regulation of Hippocampal Epileptogenesis/Therapeutic Efficacy of Environmental Enrichment After Early-life Seizures
Sookyong Koh, MD, PhD, studies the underlying causes of epilepsy and the effects of seizures on the developing brain with the goal of finding new therapies. She is also studying the therapeutic effects of environmental enrichment and rehabilitation, such as special education and increased social interaction, in reversing the damaging effects of early-life seizures. For other information about the work of Dr. Koh, see 
our physicians’ journal, and a partial summary of her publications in the National Library of Medicine.
Emotional, behavioral, and learning problems in children with seizures
Sigita Plioplys, MD, is a child psychiatrist who studies emotional, behavioral, and learning problems in children with seizures. She examined the risk factors that influence development of emotional and behavioral problems in children with new-onset seizures early in the course of illness, prior to treatment with antiepileptic medications. She has investigated development and psychiatric characteristics of psychogenic non-epileptic seizures. These behavioral spells look like seizures but are psychological in origin and do not result from abnormal electrical brain activity. Her findings will significantly improve care of these children, who often are undiagnosed for years, and receive unnecessary and potentially harmful treatment with antiepileptic drugs. She has developed new clinical educational programs for child psychiatry fellows focused on multidisciplinary care model for children with epilepsy. For more information on Dr. Plioplys’ work, see our physician journal, The Child’s Doctor, and a summary of her publications in her CV.
No comments:
Post a Comment