The Importance of Clinical Research in Pediatric Epilepsy

Transcription

1 The Importance of Clinical Research in Pediatric Epilepsy Setting Priorities & Building a National Infrastructure Anne T. Berg, Ph.D. Lurie Children s Hospital Chicago, IL A. Berg DFS Conference June

2 Disclosures A. Berg DFS Conference June

3 Background Early life epilepsies (ELE) occur in nearly 1/500 young children in the population and affect ~ children per year in the US. They include some of the most devastating forms/causes of epilepsy. Refractory epilepsy Developmental devastation Life-long disability Early mortality A. Berg DFS Conference June

4 Epileptic Encephalopathy The epileptic activity itself may contribute to severe cognitive and behavioral impairments above and beyond what might be expected from the underlying pathology alone (e.g. cortical malformation). Interference with development of function during critical periods A. Berg DFS Conference June 2014 Berg and Cross,

5 Long-term potentiation: Synaptic learning Lamprecht and LeDoux, Nature Neurosci Rev, 2004 A. Berg DFS Conference June

6 Learning in the developing brain Ben-Ari: The song of the young neuron The symphony of the mature brain A. Berg DFS Conference June

7 Epileptic cacophony in the developing brain A. Berg DFS Conference June

8 Over past ~2 decades Major advances in Understanding specific diagnoses Syndromic Genetic causes Neuroimaging Treatments Drugs Diet Surgery Steroids, immune A. Berg DFS Conference June

9 Diverse rare electro-clinical syndromes Syndromes Benign familial neonatal epilepsy (BFNE) KCNQ2 encephalopathy Early myoclonic encephalopathy (EME) Ohtahara syndrome Epilepsy of infancy with migrating focal seizures West syndrome / spasms Myoclonic epilepsy in infancy (MEI) Benign familial infantile epilepsy Dravet syndrome Febrile seizures plus (FS+) EFMR FIRES Myoclonic encephalopathy in non progressive disorders Epilepsy with myoclonic atonic(seizures) Nonsyndromic Unknown cause Known or infered cause A. Berg DFS Conference June

10 Diverse, often rare specific causes SLC2A1 CDKL5 TSC1, TSC2 PCDH19 MECP2 STXBP1 ARX PLCB1 SLC25A22 SPTN1 SLC19A3 KCNQ2 KCNQ3 UBE3A STK9 EPM1 EPM2 KCNMA1 PPT1 TPP1 CLN3 CTSD SCN2A Genetic- Metabolic Structural-genetic Lissencephaly Hemimegalencephaly Septo-optic dysplasia Aicardi syndrome Bilateral PV heterotopia Double cortex Muscle-eye-brain disease HIE misdiagnosed IVH Congenital infections Autoimmune Trauma, accidents A. Berg DFS Conference June

11 Treatments for epilepsy Acetazolamide ACTH Amantadine Brivaracetam Bromides Carbamazepine Clobazam Clonazepam Dexamethasone Diazepam Eslicarbazepine Ethosuximide Ethotoin Ezogabine Felbamate Gabapentin Ketogenic diet Lacosamide Levetiracetam Lamotrigine Lorazepam Mephobarbital Methylprednisolone Modified Atkins diet Oxcarbazepine Perampenel Phenobarbital Phenytoin Primidone Prednisone Prednisolone Pregabalin Pyridoxine (vitamin B6) Rufinamide Stiripentol Sulthiame Surgery Tiagabine Topiramate Vigabatrin VNS Valproic acid A. Berg DFS Conference June Zonisamide

12 Questions Are we doing a better job of treating infantile epilepsies? How can we improve the processes and outcomes further? A. Berg DFS Conference June

13 Diverse RARE electro-clinical syndromes & causes Syndrome Incidence/live births Ohtahara syndrome 1/1,000, (?) West syndrome / spasms 2.5-6/10,000 ~1500 Dravet syndrome 1/30,000 ~150 KCNQ2 encephalopathy unknown? Glut1 Deficiency syndrome Unknown? EFMR unknown? Hemimegalencephaly unknown? Annually in US A. Berg DFS Conference June

14 These figures depend on accurate, precise diagnosis being made At initial diagnosis, most children have nonsyndromic presentations and nonsyndromicdiagnostic labels. Causes are not diagnosed How often are they truly investigated? Do we know how to do this? A. Berg DFS Conference June

15 Questions Are we doing a better job of treating infantile epilepsies? How can we improve the processes and outcomes further? A. Berg DFS Conference June

16 Two Initiatives Priorities in Pediatric Epilepsy Research Stake-holders workshop The Pediatric Epilepsy Research Consortium A national effort A. Berg DFS Conference June

17 PRIORITIES FOR PEDIATRIC EPILEPSY RESEARCH Improving Children s Futures Today October 23-24, 2012 Made possible by the generosity of CURE: Citizens United for Research in Epilepsy AND Ann & Robert H. Lurie Children s Hospital of Chicago A. Berg DFS Conference June

18 Participants Susan Axelrod* Steve White Bogdan Ewendt* Kathy Evans* Brent Allen* Terry Biaggi* Brenda Niemi* Janna Moore* Tracy Dixon-Salazar* Phil Gatone* Pat MaGoon Alicia Goldman Russ Saneto Bill Gaillard Doug Nordli Nan Rothrock Leon Epstein Tobias Loddenkemper Lorie Hamiwka Christine Bower Barbara Vickrey Lisa Gorshels Dennis Dlugos Joe Sullivan Sucheta Joshi Kelly Knupp Cindy Stack Sooky Koh Frank Zelko Don Shields Michael Smith Warren Kibbe Christine Karam Jouku Isojarvi A. Berg DFS Conference June

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20 Stakeholders and factors the influence the diagnostic and treatment process Stake holder factor The child, seizure presentation and epilepsy severity Parent and family Medical care providers The healthcare system Examples Severity (motorinvolvement, duration) of seizures, neurodevelopmental impairment in child. Parent education, health literacy, family history of epilepsy, employment, language, cultural beliefs and preferences, personal styles Training, knowledgeattitudes, race/ethnicity, language, communication skills, clinical style (communication and shared decision making), concerns about lost practice revenue. Limited availability of specialty care: geographic barriers, waiting time, financial barriers. Uncoordinated care Community Systems Birth-to-three and specialeducation services, voluntary advocacy organizations, other services agencies. A. Berg DFS Conference June

21 Examples of inputs from different factors and stakeholders. While these are actual incidents, the frequency with which any of them, desirable or otherwise, occurs is unknown. Workshop theme or factors Examples involved in diagnosis and care process Seizure presentation & parent We thought our child was just playing. (parent delay in seeking medical attention for staring spells) Family characteristics (family history of epilepsy) Pediatrician Pediatrician My father saw my son having these staring spells and said they could be seizures. He knows because he has the same kind of seizures. When our pediatrician saw our child having spasms in the office, he ordered an EEG that day and we had an appointment with a neurologist a few days later. 1. We asked the pediatrician about our baby s whole body crunches, and he said they were normal baby movements. 2. The pediatricians said they (later diagnosed as spasms) were temper tantrums. Neurologist Child with absence epilepsy was misdiagnosed as having focal seizures and treated for years with drugs that were highly inappropriate for absence seizures with resulting cognitive impairment in young adulthood. Communication with parents It took three years before I heard the word epilepsy used for my child s condition, and that was only after I got the medical records and read the word for myself. A. Berg DFS Conference June

22 Workshop theme or factors involved in diagnosis and care process Neurologist, communication with parents compounded by medical error. Parents; access to the medical chart. Communication and tone taken with parents. Health systems break down in complex care System limitations, inadequate availability of specialists for referral Health insurance School Examples I found an article about GLUT1 deficiency syndrome. It described exactly what my child had. My child s neurologist, she said that my child couldn t have that because he was not severe enough and besides, the CSF glucose had come back normal. In fact, the CSF glucose had never been reported back by the lab. It took some years longer before he was tested and we got the correct diagnosis of GLUT1. The child has suffered cognitive consequences attributed to ongoing seizures during the delay to diagnosis. Seizures are now controlled with ketogenicdiet. When I told the nurse that we thought our child might have MAE (myoclonicatonic epilepsy) she that was impossible, our child would be a vegetable if she had that. A developmentally delayed child without seizures was referred to a genetics program for evaluation of delay. During the prolonged evaluation process, the child developed myoclonic jerks. Genetics noted jerking movements reported by parents but did not refer to neurologist for further evaluation. We have no one to whom to refer a child with developmental delay or autism Drug XYZ is only approved for Lennox-Gastautsyndrome, not for Dravet. (Insurance company denying a specific medication) The school teachers arranged to keep our child in a cooler environment and use a cooling vest (for heat-triggered seizures) A. Berg DFS Conference June

23 Pediatric Epilepsy Care Workshop Themes Theme Patient Outcomes Diagnosis The Role of Parents Resources Outside the Medical System The single most important outcome for parents of children with epilepsy is seizure freedom. This was seen as a key to optimizing all other outcomes. Early, accurate diagnosis not only of epilepsy, per se, but also the specific form of epilepsy, or syndrome, as well as of the seizure types and the underlying cause is critical to optimizing treatment for children with epilepsy Shared decision making with parents and parental participation in the care process is critical to effective communication and optimal treatment. Voluntary and community advocacy agencies and services including the school system play an essential role by providing information and ancillary services to both children and parents A. Berg DFS Conference June

24 Examples of questions generated during the workshop deliberations. Steps in diagnosis and care Establishing the diagnosis Treatment Evaluation Questions identifying gaps in knowledge regarding those steps. In what proportion of children is an accurate, specific diagnosis made and how does that vary based on the providers training and experience? In what proportion of children are there no specific guidelines to aid in treatment selection? Are current imaging guidelines followed? Who interprets the EEG? Information conveyed to parent What information are parents first given about their children s diagnosis, by whom, and in what form? What information are parents given about potential cognitive and behavioral difficulties their children may encounter? What information are they given about the risks of seizures including seizure-related death and SUDEP in particular? A. Berg DFS Conference June

25 Examples of questions generated during the workshop deliberations. Steps in diagnosis and care Questions identifying gaps in knowledge regarding those steps. Barriers and Delays How quickly are children with poorly controlled seizures referred for comprehensive evaluation? What is an ideal interval versus what is too long (delayed). What factors (child, parent, provider, system) influence delays? Other therapies When should the ketogenic diet or surgery be considered according to parents? Providers? Insurers? Information needed for decision making What information do parents need and want in order to make the best decisions for their children about the use of the diet or surgery? A. Berg DFS Conference June

26 Table 3: Examples of questions generated during the workshop deliberations. These are questions the answers to which could be used Examples to help change of how questions care is delivered. generated during the workshop deliberations. Steps in diagnosis and care Questions identifying gaps in knowledge regarding those steps. Communication with parents Are parents given a treatment plan and an understanding of how treatment success will be assessed and treatments changed if necessary? Outcomes What do parents and providers understand about the seriousness of seizures and the need to control them as soon as possible? In difficult to control epilepsy, do providers and parents develop treatment goals together to achieve better if less than perfect seizure outcomes? A. Berg DFS Conference June

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29 Barriers to Implementing Speciality (Tertiary) Epilepsy Care First Resource intensive Against self-interest of some individuals and institutions No evidence to guide the approach What is specialitycare? What is comprehensive care? How is it implemented? No evidence that it makes a difference Improve patient outcomes Better value A. Berg DFS Conference June

30 Overcoming barriers Collect the necessary evidence to demonstrate the value of the specialitycare first approach. Disseminate the evidence Publish, work with voluntary and professional groups Implement RESEARCH Clinical& Health Services A. Berg DFS Conference June

31 PERC Steering Committee : Kelly Knupp Elaine Wirrell Anne Berg Joseph Sullivan Nicole Ryan A. Berg DFS Conference June

32 Pediatric Epilepsy Research Consortium Multicenter collaboration of US-based pediatric epilepsy centers. Inspired by and modeled after» Pediatric Oncology Group (POG)» Pediatric Heart Transplant Consortium» Brain tumor consortium» Canadian Pediatric Epilepsy Network (CPEN) A. Berg DFS Conference June

33 Long-term Vision Develop an enduring, national infrastructure capable of rapidly addressing important treatment and management questions for children with epilepsy and their families. Rapidly lead to improvements in care and outcomes Creating research experiences and opportunities for junior investigators and develop research capacity for the future A. Berg DFS Conference June

34 Initial Goals: Multicenter collaboration of US-based pediatric epilepsy centers. Facilitate communication and some standardization of terminology and protocols across centers. Implementsimple recruitment and data collection protocols in a consistent manner across sites. Play Nice! Develop a working network Lay foundation for practice-changing research studies A. Berg DFS Conference June

35 Pediatric Epilepsy Research Consortium -History Originally two groups with overlapping purposes Infantile spasms only (Kelly Knupp&Elaine Wirrel) All early life epilepsies (Doug Nordli, Bill Gaillard, Anne Berg) Agreed to collaborate: bring as many interested investigators together toward a common purpose. A. Berg DFS Conference June

36 Initial Research Projects Early Onset Epilepsy Consortium (EOEC) All newly diagnosed epilepsies Onset < 3 years Prospective 12-month follow-up through charts National Infantile Spasms Consortium (NISC) All newly diagnosed epileptic spasms New-onset epilepsy Newly evolved spasms Onset <18 months Prospective 3-month follow-up through charts A. Berg DFS Conference June

37 Overlap and interaction between the two projects Newly diagnosed epilepsy, Onset <3 y, diagnosis by 3.5y In Both New-onset spasms New-onset epilepsy or newly evolved <18 months A. Berg DFS Conference June

38 Goals of the Initial Studies Provide Contemporary Assessment of: Current causes and type of early life epilepsies (ELE) and spasms in particular. Determine utilization and yield of tests (genetic in particular) Characterize the patterns of treatment selection For spasms, attempt to obtain a consensus on some treatment protocols (ACTH, VGB, Prednisone) Document Seizure outcomes Perform a nonrandomized comparative effectiveness assessment of the MANY treatments used in early life epilepsies. Demonstrate ability to collaborate productively Lay the foundation and develop the capacity for becoming a clinical trial and clinical research network. Rapid deployment and completion of targeted trials Get answers fast, move on! A. Berg DFS Conference June

39 As of June 26, US centers have joined the consortium 21 actively participating in one or both ongoing studies. National Infantile Spasms Consortium Early Onset Epilepsy Consortium 464 patients enrolled so far!!!! A. Berg DFS Conference June

40 Our Data Base A. Berg DFS Conference June

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43 As of June 26, 2014 A. Berg DFS Conference June

44 Genetic Testing&Diagnosis Number with Dravet? N=1 Genetic testing as part of diagnostic evaluation Total Other 27% 15% Genetic cause found 10% 8% A. Berg DFS Conference June

45 Pediatric Epilepsy Research Consortium Dravet Syndrome Early Life Epilepsies GENETICS SEMIOLOGY Infantile Spasms MRI EEG Ketogenic Diet PERC Centralized Infrastructure Development, Cognition Behavior Surgery Steroids Randomized Trials Health Services Care Models A. Berg DFS Conference June

46 Projects Emerging from the Priorities Workshop and being implemented through consortium sites Yield and clinical impact of epilepsy panels in children with epilepsy With John Millichap and Shannon Haymond A Delphi process to develop expert opinion-based recommendations for the evaluation and treatment of children with Dravet Syndrome With Elaine Wirrell, Kelly Knupp, Linda Laux, Joe Sullivan, Elizabeth Donner, Ian Miller A. Berg DFS Conference June

47 Projects Emerging from the Priorities Workshop and being implemented through consortium sites Delays to getting the initial diagnosis of epilepsy? With Christine Baca and Tobias Loddenkemper(Epilepsia, 2014) Barriers to referral for epilepsy surgery With Christine Baca, Jeff Ojemann, Lorie Hamiwka Ketogenicdiet suveys: Centers, Physicians, and Parents With SuchetaJoshi & DaeunJung + Nancy McNamara A. Berg DFS Conference June

48 Survey of North American Ketogenic Diet Centers Jung et al., in review A. Berg DFS Conference June

49 Projects Emerging from the Priorities Workshop and being implemented through consortium sites Comprehensive pediatric epilepsy care in the US, what is it? Lorie Hamiwka Pediatric epilepsy surgical practice in the US, what are centers doing? David Clarke, KyLee A. Berg DFS Conference June

50 Questions Are we doing a better job of treating infantile epilepsies? How can we improve the processes and outcomes further? A. Berg DFS Conference June

51 Rare Disorders Need a Common, Collaborative Solution National effort Dedicated pediatric epilepsy specialists and researchers Focus on patient-centered needs and results Rigorous demonstration of effectiveness through high quality clinical research Dissemination & Implementation A. Berg DFS Conference June