What the IOM Report Means for Basic and Clinical Research December 1, 2012

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1 What the IOM Report Means for Basic and Clinical Research December 1, 2012 Story C. Landis, PhD Director, National Institute of Neurological Disorders and Stroke American Epilepsy Society Annual Meeting 1

2 Disclosure No disclosures to report American Epilepsy Society Annual Meeting

3 Learning Objectives Identify recommendations and priorities in the IOM report that relate to biomedical research Understand NIH activities relevant to IOM report priorities and identify future research opportunities Learn about other NIH epilepsy research activities American Epilepsy Society Annual Meeting

4 The IOM Report and NIH NINDS contributed to funding for the IOM report, along with National Institute on Aging (NIA) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) National Institute of Mental Health (NIMH) The IOM committee s charge focused on public health dimensions beyond biomedical research NINDS coordinates the Epilepsy Research Benchmarks community-wide priorities for basic, translational, and clinical research NIH shares the IOM report s vision for reducing burden of epilepsy Opportunities for NIH to contribute to addressing recommendations 4

5 Epilepsy Research Benchmarks Curing Epilepsy 2000: Focus on the Future White House-initiated conference Developed the first Epilepsy Research Benchmarks No seizures, no side effects, and the prevention of epilepsy Curing Epilepsy 2007: Translating Discoveries into Therapies Reviewed progress of the 2000 Benchmarks Updated the Benchmarks: epileptogenesis, new and improved treatments, comorbidities and SUDEP Curing the Epilepsies 2013: Pathways Forward April 17-19, 2013 Epilepsy Research Benchmarks Progress report and NINDS RFI: 5

6 The Benchmarks make a difference Raise awareness of research gaps SUDEP and comorbidities of epilepsy Expansion in research since added to the Benchmarks Inform priority-setting for NINDS investments Epilepsy Centers without Walls program Genetic causes, SUDEP, epileptogenesis Provide a framework for tracking progress How far have we come? What challenges remain? Have new opportunities emerged? 6

7 Epilepsy Benchmarks and IOM recommendations: separate, but complementary Prevent epilepsy and its consequences Benchmarks: understand the causes of epilepsy, identify biomarkers, develop strategies to prevent epileptogenesis IOM report: prevention of epilepsy due to established risk factors Improve healthcare Benchmarks: optimize existing therapies and develop new therapies and technologies IOM report: early identification and referral, guidelines and quality measures, improving access to care Comorbidities Benchmarks: identify predictors and underlying mechanisms that contribute to comorbidities, determine optimal treatments IOM report: emphasizes the early identification of comorbidities and more effective and coordinated care 7

8 IOM report priorities and relevant NIH/NINDS activities Recommendation 1: Validate and implement standard definitions and criteria for epilepsy case ascertainment, health care and services use and costs, and quality of life measures. Recommendation 2: Continue and expand collaborative surveillance and data collection efforts. Recommendation 3: Develop and Evaluate Prevention Efforts for Epilepsy and its Consequences 8

9 Standard Definitions and Criteria 9

Surveillance - SUDEP Sudden Death in the Young Registry NINDS and NHLBI collaboration seeks to expand the CDC s Sudden Unexpected Infant Death (SUID) Case Registry to include SUDEP and Sudden Cardiac

10 Surveillance - SUDEP Sudden Death in the Young Registry NINDS and NHLBI collaboration seeks to expand the CDC s Sudden Unexpected Infant Death (SUID) Case Registry to include SUDEP and Sudden Cardiac Death in individuals to age 24 in up to 15 states first comprehensive, prospective surveillance system for SUDEP in the United States collect clinical information and biospecimens for research work with medical examiners and coroners to develop standard protocols for evaluating SUDEP cases and collecting specimens 10

11 Preventing epilepsy and its consequences NINDS Epilepsy Centers without Walls program Planning grants toward potential SUDEP Center Prevention and Risk Identification of SUDEP Mortality Sam Lhatoo, Case Western Reserve University CTSA (lead) Surveillance register of SUDEP by monitoring a multicenter cohort of epilepsy patients undergoing seizure monitoring Capacity for comparative studies of SUDEP/near-SUDEP cases vs. cohort survivors to identify risk factors (with a focus on brainstem and serotonergic dysfunction) SUDEP Center Research Pipeline Jeff Noebels, Baylor College of Medicine (lead) Basic science, human genetics, and clinical physiology approaches to validate a combined genetic and clinical SUDEP risk profile for screening and treating individuals with epilepsy 11

12 Preventing epilepsy and its consequences NINDS Epilepsy Centers without Walls program Planning grants toward potential anti-epileptogenesis Centers Potential EEG biomarkers and anti-epileptogenic strategies for epilepsy in Tuberous Sclerosis Complex (TSC) Martina Bebin, UAB Develop biomarker to identify TSC patients at risk for epilepsy and establish parameters for anti-epileptogenic drug trial Epilepsy Bioinformatics Study (EpiBioS) Pete Engel, UCLA bioinformatics approach to develop biomarkers for epilepsy risk and epileptogenesis after an insult to the brain Prevention of Temporal Lobe Epilepsy Jim McNamara, Duke Identify biomarkers for development of TLE after febrile status epilepticus in childhood, leveraging FEBSTAT cohort and data 12

FEBSTAT Shinnar S, et al; August 2012 Nordli DR, et al; November 2012 Prospective study

(11.5%); developmental abnormalities (10.

with evidence of acute brain injury For some children, FSE may injure the brain; for

13 FEBSTAT Shinnar S, et al; August 2012 Nordli DR, et al; November 2012 Prospective study of febrile status epilepticus (FSE) outcomes MRI (hippocampus): signs of acute injury (11.5%); developmental abnormalities (10.5%) EEG: abnormal findings in nearly half the children with FSE; more likely in those with evidence of acute brain injury For some children, FSE may injure the brain; for others, pre-existing abnormalities could underlie susceptibility to FSE How will these or other markers relate to risk for developing TLE? 13

14 Preventing epilepsy and its consequences Translational research NINDS Anticonvulsant Screening Program (ASP) Contract at Univ. of Utah (PI: H. Steve White) Recruitment of John Kehne as new Director (Nov 5, 2012) Sustained commitment to the early identification of novel anti-seizure drugs; compound submission remains robust Novel models of treatment-resistant epilepsy being developed Numerous operational improvements implemented in 2012 Future plans of ASP include the establishment of a parallel screening track focused on antiepileptogenesis and disease modification 14

Preventing epilepsy and its consequences Targeting known risk factors NIH research on the prevention and treatment of established risk factors for epilepsy, such as stroke, perinatal

15 Preventing epilepsy and its consequences Targeting known risk factors NIH research on the prevention and treatment of established risk factors for epilepsy, such as stroke, perinatal hypoxia-ischemia, TBI, brain tumor, and infections, should aid in the prevention of epilepsy Need to incorporate epilepsy as an outcome in studies of these conditions Highlights and opportunities TBI $30 million donation from the NFL for research on medical conditions in athletes and relevant to the general population, including TBI NINDS/NIH and Department of Defense building a research database for TBI, to promote data sharing and comparative effectiveness research Stroke Recent NINDS effort to identify potential high priority initiatives to advance stroke research, in terms of prevention, treatment, and recovery 15

strategy to reduce thalamocortical neuron activity sufficient to

16 New insights into post-stroke epilepsy Thalamocortical neurons become hyperexcitable after cortical stroke in a rat model Optogenetic strategy to reduce thalamocortical neuron activity sufficient to interrupt seizures Potential therapeutic implications for intractable epilepsies 16

17 Additional NIH Research Activities Risk factors for epilepsy of unknown and genetic/presumed genetic cause Epilepsy Phenome/Genome Project; Dan Lowenstein, UCSF Epilepsy Center without Walls: Epi4K project; International collaboration to identify genetic causes of epilepsy by analyzing at least 4000 patient genomes FY2013 NINDS funding opportunity for additional collaborations Comparative effectiveness studies Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy; Tracy Glauser, Cincinnati Children s Hospital Ethosuximide provided best combination of seizure control and fewest attentional side effects after 16 weeks; NEJM 2010; 362 (9) Continuation to determine relative benefits over longer term NIA-funded study of elderly nursing home residents treated with phenytoin, lamotrigine, and levetiracetam; Angela Birnbaum, Univ. Minnesota Twin Cities 17

Metabolic error in syndrome of autism, epilepsy, and intellectual disability Mutations identified in the gene BCKDK (Branched Chain Ketoacid

18 Metabolic error in syndrome of autism, epilepsy, and intellectual disability Mutations identified in the gene BCKDK (Branched Chain Ketoacid Dehydrogenase Kinase) in consanguineous families Dietary supplementation improved neurological symptoms, including seizures, in Bckdk knockout mice 18

19 Additional NIH Research Activities Comorbidities of epilepsy Longitudinal studies to understand contributing factors and outcomes Basic and clinical research on mechanisms Autism-Epilepsy Workshop, May 2012 NINDS, NICHD, Autism Speaks, CURE Research on these conditions more generally may be applicable to their occurrence in people with epilepsy Seizure medications and birth outcomes The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) Study Kim Meador, Emory University Pregnant women with epilepsy on AED monotherapy from 1999 to 2004 to determine long-term neurodevelopmental effects across four common AEDs (carbamazepine, lamotrigine, phenytoin, valproate) Results associating adverse cognitive and other outcomes with valproate are already contributing to changes in clinical practice NINDS and NICHD are supporting a continuation of the study to include maternal outcomes, more drugs, and polytherapies 19

20 NIH and the broader epilepsy community ICARE: Interagency Collaborative to Advance Research in Epilepsy NIH, other Federal agencies, and the research and patient advocacy communities Annual meetings provide forum for sharing information, highlighting advances, discussing needs and opportunities, and promoting collaboration NINDS/NIH participation in: Vision 2020 HHS-wide epilepsy working group 20

21 Curing the Epilepsies 2013: Pathways Forward April 17-19, 2013 Send us your best ideas! 21

TBI Research at NIH. Ramona Hicks, PhD NIH/NINDS

TBI Research at NIH. Ramona Hicks, PhD NIH/NINDS TBI Research at NIH Ramona Hicks, PhD NIH/NINDS Objectives 1. Overview of TBI research opportunities at NIH 2. Highlight a few projects Common Data Element Project Federal Interagency TBI Research Informatics