Epilepsy Ontology Aristea S. Galanopoulou MD PhD Albert Einstein College of Medicine, Bronx NY

American Epilepsy Society, Research and Training Council co-chair ICARE Ontology, considerations • ICARE has been extremely valuable tool to the American Epilepsy Society in assessing the AES-funded research and visualizing where funds is allotted to. • Discussions for possible updates of the ontology were prompted by realizing its utility and potential to evaluate funded research and recognizing that: • Current ontology terms were not encompassing all research areas and epilepsy/seizure types, etiologies. • Interim revisions in the working classification and coding of human epilepsies and seizures. • Distinction of human vs nonhuman, basic vs translational research is not easily/accurately derived from the current system. Having this would be very useful (different funding, design, expectations and expertise; could allow faster tracking of experts in clinical vs preclinical translational and basic science research). • Use of certain terms in various platforms (ICARE, Benchmarks, researchers) occasionally is done with variable meaning and could benefit of refinement. • Enhancement of the capability to query the database with more specific questions would greatly enhance strategic funding decisions and collaborations, attract more organizations to participate in ICARE and possibly eventually compare funded research to publications. ADEAF - Autosomal Dominant Epilepsy with Lafora Disease Auditory Features LGS - Lennox -Gastaut Syndrome iCARE ADNFLE - Autosomal-Dominant Nocturnal Frontal LKS - Landau-Kleffner syndrome Lobe Epilepsy Malformations of Cortical Development Alpers Syndrome Neonatal Seizures Angelman Syndrome Neurocysticercosis BECTS - Benign Epilepsy with Centrotemporal Nodding Syndrome Spikes Non-Epileptic Seizures BFNE - Benign Familial Neonatal Epilepsy Ohtahara Syndrome CAE - Childhood Absence Epilepsy PCDH19 Epilepsy Catamenial Seizures PME - Progressive Myoclonus Epilepsies Childhood Epilepsy PMSE - Polyhydramnios, Megalencephaly and Dravet Syndrome Symptomatic Epilepsy Syndrome Early Life Seizures PTE - Post Traumatic Epilepsy EME - Early Myoclonic Encephalopathy Rasmussen Syndrome Encephalitis Acquired Epilepsy Reflex Epilepsies Epilepsy/Seizures associated with other disorders Seizures (like Alzheimer's, Autism, Fragile X, Malaria, ...) Status Epilepticus Epilepsy/Seizures in pregnant women Sturge-Weber Syndrome Epilepsy/Seizures in the elderly Succinic Semialdehyde Dehydrogenase Deficiency Epileptic Encephalopathies SUDEP Febrile Seizures TLE - Temporal Lobe Epilepsy Focal Epilepsy TSC - Tuberous Sclerosis Complex GEFS+ - Generalized Epilepsy with Febrile Seizures West Syndrome plus Epilepsy - not otherwise specified Genetic Epilepsy Hemiconvulsion–Hemiplegia–Epilepsy Hypothalamic Hamartoma with Gelastic Seizures IS - Infantile Spasms JAE - Juvenile Absence Epilepsy JME - Juvenile Myoclonic Epilepsy KCNQ2 Encephalopathy ICARE Search ICARE search terms and classifications Research Type 1. Separating research in humans vs in animals / models Issues: Basic Basic research is the systematic study of the fundamental aspects of phenomena and of • Basic and translational research may utilize animal/model observable facts without specific development of systems or human subjects which may confound the processes, products or clinical reporting of funded research in each of these categories. applications. Projects typically include studies of the mechanisms of normal or disease related • Research using human tissue is not always clinical. processes at the molecular, cellular, systems or • Using only keywords for search for human vs animal/model organ level. research may not sufficiently differentiate the two different Translational Translational research is the process of developing types of research (keyword hits are not always specific for ideas, insights, and discoveries generated through keywords). basic scientific inquiry for the treatment or prevention of human disease. Suggestions: Separating the two types of research may help visualize and Clinical Patient-oriented research. Research conducted with human subjects (or on material of human compare more directly: origin such as tissues, specimens and cognitive - the value, productivity, and results of animal/model vs phenomena) for which an investigator directly human epilepsy research interacts with human subjects. Excluded from this definition are in vitro studies that utilize human - Expertise in animal vs human research tissues that cannot be linked to a living  Suggest to create Refine Search Criteria for: individual. Patient-oriented research typically Organism/Model: includes therapeutic interventions and applications - Nonhuman organism of new technologies, clinical trials, epidemiologic and behavioral studies, outcomes research and - Human health services research. - Other model system Research Type

2. Improving distinction of basic and translational research

Issues: Expectations from basic vs translational (preclinical) research may be different in terms of grant review, study design and performance.

Distinction is not always clear producing overlap of hits when using the current system.

Suggestions:  May consider more specific definitions of how to differentiate and log basic vs translational research. Research classification

Classification Definitions

Research included in this category aims to identify the causes or origins of epilepsy - genetic, infectious, Etiology metabolic, environmental, or other factors, and the interactions between these factors

Research included in this category looks at the biology of how epilepsy/seizures starts and progresses as Mechanism of Disease well as normal biology relevant to these processes

Research included in this category looks at identifying interventions which reduce the risk of developing epilepsy by reducing exposure to risk factors and/or increasing protective factors. Interventions aimed at Prevention prevention of complications of epilepsy or its co-occurring conditions may also be included. Interventions may target lifestyle or may involve drugs or vaccines

Research included in this category focuses on identifying and testing biomarkers, technology methods or Early Detection/ Diagnosis/Prognosis predictive models that are helpful in detecting and/or diagnosing as well as predicting the outcome or chance of recurrence Research included in this category focuses on identifying and testing treatments, such as novel Treatment therapeutics, devices or other interventions. Research included in this category includes a broad range of areas: surveillance and epidemiology; ethics, education and communication approaches for health care professionals, patients and families, and Outcomes community members; patient care and health care services research; effectiveness research and phase 4 trials

Research included in this category looks at the development of new animal models, cell cultures and Model Systems computer simulations and their application to other studies across the spectrum of epilepsy research Research Classification

Same terms across ICARE, Epilepsy benchmarks epilepsy researchers are not used with the same meaning

Examples:

Prevention of epilepsy / co—occurring conditions and consequences: - ICARE: intervention-oriented research. - Benchmarks - II: includes mechanisms, biomarkers, interventions - I, III and IV: may also address prevention Prevention research, Benchmark II: ~837.5K Benchmark IV:~461K AES-funded Prevention Research:~145K Benchmark II funded research: Prevent epilepsy and its progression (2016)  no hits for prevention Research Classification Same terms across ICARE, Epilepsy benchmarks and in epilepsy research are not always used with the same meaning

Example: prevention of epilepsy / co—occurring conditions and consequences: - ICARE: intervention-oriented research - Epilepsy Benchmarks - II: includes mechanisms, biomarkers, interventions - III and IV: may also address prevention - Search hits may not always capture the research classification done, as coded Suggestions: Recoding may probably not be the best solution, since each coding method has its advantages and different information Perhaps:  More specific terms coding research classification to track key areas of prevention research (e.g, anti-epileptogenesis, disease modification, etc) ?  Refining search tools by allowing to select or exclude classifications or search keywords (AND, OR, NOT) ? Epilepsy syndromes, seizures, special populations, consequences SEIZURES SYNDROMES Epilepsy/Seizures associated with other disorders (like Dravet Syndrome Alzheimer's, Autism, Fragile X, Malaria, ...) EME - Early Myoclonic Encephalopathy Febrile Seizures Epileptic Encephalopathies Non-Epileptic Seizures Hemiconvulsion–Hemiplegia–Epilepsy Seizures IS - Infantile Spasms Status Epilepticus West syndrome LGS - Lennox -Gastaut Syndrome SPECIAL POPULATIONS LKS - Landau Kleffner syndrome Early Life Seizures Ohtahara Syndrome Neonatal Seizures PTE - Post Traumatic Epilepsy Childhood Epilepsy Rasmussen Syndrome Epilepsy/Seizures in pregnant women Nodding Syndrome Catamenial Seizures Epilepsy/Seizures in the elderly

CONSEQUENCES SUDEP Not complete list of epilepsies or Condition: Current epilepsy ontology etiologies GENETIC or GENETIC-STRUCTURAL ACQUIRED • Only TLE among focal Genetic Epilepsy Encephalitis Acquired Epilepsy epilepsies ADEAF - Autosomal Dominant Epilepsy with Hypothalamic Hamartoma with • Focal but no generalized Auditory Features Gelastic Seizures epilepsy coding ADNFLE - Autosomal-Dominant Nocturnal Frontal Some epilepsies are represented by Lobe Epilepsy FOCAL vs GENERALIZED specific etiologies only, eg BECTS - Benign Epilepsy with Centrotemporal Focal Epilepsy • ADNFLE (no FLE) Spikes TLE - Temporal Lobe Epilepsy Etiologies are not systematically BFNE - Benign Familial Neonatal Epilepsy captured or listed in the same CAE - Childhood Absence Epilepsy OTHER EPILEPSIES manner, eg KCNQ2 Encephalopathy Epilepsy - not otherwise specified • metabolic etiologies Lafora Disease Epilepsy/Seizures associated with • neurocysticercosis vs PCDH19 Epilepsy other disorders (like Alzheimer's, epilepsy/seizures associated TSC - Tuberous Sclerosis Complex Autism, Fragile X, Malaria, ...) with other disorders PME - Progressive Myoclonus Epilepsies Some names have been revised or PMSE – Polyhydramnios, Megalencephaly and ETIOLOGY may have additional variations of Symptomatic Epilepsy Malformations of Cortical names, eg Reflex Epilepsies Development • benign vs self-limited GEFS+ - Generalized Epilepsy with Febrile Neurocysticercosis • GEFS+: Genetic…. Seizures plus Succinic Semialdehyde No coding for comorbidities, co- Alpers syndrome Dehydrogenase Deficiency occurring conditions I E POSITION PAPER ILAE POSITION PAPER I

Operational classification of seizure types by the I LAE classification of the epilepsies: Position paper of the International League Against Epilepsy: Position Paper of ILAE Commission for Classification and Terminology the ILAE Commission for Classification and Terminology "'Robert S. Fisher, t J. Helen Cross, :j:Jacqueline French, §Norimichi Higurashi, 1 Edouard 1 •2• 3 1ngrid E. Scheffer, 1 Samuel Berkovic, 4Giuseppe Capovilla, 5 Mary B. Connolly, A. Hirsch, #Floor E. Jansen, >l<>l< Ueven Lagae, ttSolomon L. Moshe, :j::j:Jukka Peltola, §§Eliane Roulet 6Jacqueline French, 7 Laura Guilhoto, 8• 9 Edouard Hirsch, 10Satish Jain, 11 Gary W. Mathern, Perez, 111ngrid E. Scheffer, and ##"' >l<>l< Sameer M. Zuberi 12Solomon L. Moshe, 13Douglas R. Nordli, 14Emilio Perucca, 15 Torbjorn Tomson, 16Samuel Wiebe, 17Yue-HuaZhang,and 18• 19Sameer M. Zuberi Epilepsia , 58(4):522- 530, 20 17 doi: 10. ll ll/epi.13670 Epilepsia, 58(4):512-521, 2017 doi: l 0. l l l l/epi.l 3709

Classification of the Epilepsies Operational Classification ofSeizure Types

ILAE 2017 Classification o•f Seizure Types Expanded Version 1

Seizure types* ( Generalized Onset ] [ Unknown Onset Etiology [~__ _ __ F-=--o-=--c-=--a_l~-o- -n_::-s_e__ t______~ ) Focal Genera Ii zed Impaired Motor Aware Motor Awareness tonic-clonic tonic-donic 19%11 clonlc eplleptlc spasms V) Motor Onset tonic Nonmotor Q) automatisms myoclonic __ .... behavior arrest .... ______atonic 2 myoclonlc-tonlc- clonlc +-" donlc myodonic-atonic "'O epileptJc spasms 2 atonic ·- Epilepsy types epileptic spa.sms ..0 hyperldnetic Unclas.sified 3 L.. myodonic Nonmotor (absence) 0 -Comb ined Generafized tonic typical Foca l Generalized E Nonmotor Onset atypical I & myoclonic Focal autonomic eyelid myodonla 0 - ...... ------...... ------~ behavior arrest cognitive emotional u D - sensory Epilepsy Syndromes - focal to bilateral tonlc-clonic EpilepsyDiagnosis.org

(from https://www.ilae.org/education/diagnostic-manual/epilepsydiagnosis-org) Etiology 2013-2016, all funding

Most of the funded research addresses mechanisms / etiologies and yet the codes for such research are minimal and not systematically captured.  Suggest adding a crude sub- classification for : “Etiology”: •Genetic •Infection •Immune •Structural Although these can be searched with keywords, adding this •Metabolic research classification may allow for (a) more specific search, •Other (b) capturing epilepsies in these broader categories, when it may become too complex to add codes for all the specific causes Genetic Infection Immune Condition: Localization Structural Frontal Metabolic proposal for update Parietal Associated with other Occipital disorders • Etiology Temporal Other Multifocal Generalized • Epilepsy Onset Focal Populations Generalized Neonatal/Infantile • Seizure Childhood Cognitive Combined Adolescent/Adult Behavioral Unknown Special populations Affective Epilepsy syndrome • Other Endocrine Other • Co-occurring condition Syncope and anoxic seizures SUDEP • Consequences Behavioral / Psychological and Psychiatric disorders Fetal/neonatal Sleep related conditions development Paroxysmal movement disorders Quality of life • Epilepsy imitators Migraine associated disorders Other Miscellaneous events Epilepsies / Seizures / Syndromes by Population

NEONATAL/INFANTILE CHILDHOOD Self-limited neonatal seizures Epilepsy with myoclonic-atonic seizures Self-limited familial neonatal epilepsy Epilepsy with eyelid myoclonias Self-limited familial and non-familial infantile Lennox-Gastaut syndrome epilepsy CAE - Childhood absence epilepsy EME – Early myoclonic epilepsy Epilepsy with myoclonic absences Ohtahara syndrome Panayiotopoulos syndrome West syndrome Childhood occipital epilepsy (Gastaut syndrome) Dravet syndrome Photosensitive occipital lobe epilepsy Myoclonic epilepsy in infancy BECTS - Childhood epilepsy with centrotemporal spikes Epilepsy in infancy with migrating focal seizures Atypical childhood epilepsy with centrotemporal spikes Myoclonic encephalopathy in non progressive Epileptic encephalopathy with continuous spike-and- disorders wave during sleep Febrile seizures plus, genetic epilepsy with febrile LKS – Landau Kleffner syndrome seizures plus Autosomal dominant nocturnal frontal lobe epilepsy Febrile seizures

In blue: updates / revisions from existing ontology Epilepsies / Seizures / Syndromes by Population

ADOLESCENT / ADULT SPECIAL POPULATIONS JAE – Juvenile absence epilepsy Early Life JME – Juvenile myoclonic epilepsy Neonatal / Infantile FAME – Familial adult onset myoclonic epilepsy Childhood Epilepsy with generalized tonic-clonic seizures alone Pregnant women Autosomal dominant epilepsy with auditory features Catamenial Other familial temporal lobe epilepsies Elderly

OTHER Familial focal epilepsy with variable foci Reflex epilepsies PME - Progressive myoclonus epilepsies Epilepsy not otherwise specified Seizures Status epilepticus Nonepileptic events / seizures In blue: updates / revisions from existing ontology Genetic epilepsies

EPILEPSIES BY ETIOLOGY Genetic - Gene abnormalities Genetic - Chromosomal NPRL3 HOPKIN AKT3 FKTN PCDH19 SYNDROME) 15q13.3 MICRODELETION SYNDROME ARFGEF2 FLNA PIK3CA 18q- SYNDROME ARHGEF9 FMR1 (FRAGILE X TSC1 PIK3R2 ARX SYNDROME) TSC2 INV-DUP (15) OR IDIC (15) PLCB1 CACNA1A FOXG1 TUBA1A PNKP DEL 1p36 CACNB4 GABRA1 POMT1 WDR62 ANGELMAN SYNDROME CDKL5 GABRD POMT2 ZEB2 CHD2 GABRG2 DOWN SYNDROME (TRISOMY 21) PRRT2 (MOWAT CHRNA2 GLI3 KLEINFELTERS SYNDROME (XXY) RELN WILSON CHRNA4 GNAQ SCN1A MILLER DIEKER SYNDROME (DEL 17p) CHRNB2 GRIN2A SYNDROME) SCN1B CLCN2 KCNQ2 PALLISTER KILLIAN SYNDROME (TETRASOMY 12p) SCN2A COL4A1 KCNQ3 RING 14 (r14) SYNDROME SLC2A1 DCX KCNT1 SLC25A22 RING 20 (r20) SYNDROME DEPDC5 LARGE SPTAN1 TRISOMY 12p EFHC1 LGI1 STXBP1 WOLF-HIRSCHHORN SYNDROME (DEL 4p) LIS1 MECP2 TBC1D24 TCF4 (PITT (from https://www.ilae.org/education/diagnostic-manual/epilepsydiagnosis-org) Immune – Rasmussen’s Antibody mediated By Etiology Anti-NMDA receptor Voltage gated potassium channel Structural – GAD65 antibody Malformation of cortical development GABAB receptor antibody Steroid responsive encephalopathy with thyroid disease Vascular malformations Celiac disease, epilepsy and cerebral calcification syndrome Hippocampal sclerosis Other Hypoxic-ischemic Traumatic brain injury Infectious - Tumors Bacterial meningitis or meningoencephalitis Porencephalic cyst Malaria Cerebral Toxoplasmosis CMV Metabolic – HIV Biotinidase and holocarboxylase synthase deficiency Neurocysticercosis Cerebral folate deficiency Tuberculosis Creatine disorders Viral encephalitis Other (Lyme disease, toxocariosis, schistosomiasis) Folinic acid responsive seizures Glucose transporter 1 (GLUT1) deficiency Associated with other diseases Mitochondrial disorders (Alzheimer’s, Autism, Fragile X, Rett syndrome, Malaria, etc) Peroxisomal disorders Pyridoxine dependent epilepsy / PNPO deficiency Unknown Febrile infection related epilepsy Considerations • The coding is oriented towards human classifications of epilepsies / seizures. • Working classification for animal models of seizures and epilepsies is in progress (ILAE/AES Joint Translational Task Force) and could be considered in the future. • New revised terms could be added as alternatives / equivalent to existing ones so as not to revise coding from past years. • It would be useful, if easily feasible, to allow: • multiple choices of ontology terms from same categories or keywords • enhanced search tools allowing direct comparisons, head to head, of data from various search keywords. This additional search flexibility could minimize the need in the future for ontology revisions. Thank you!

• AES • Eileen Murray • Penny Dacks • AES Research & Training Council