EPILEPSY ONTOLOGY ARISTEA S. GALANOPOULOU MD PHD ALBERT EINSTEIN COLLEGE OF MEDICINE, BRONX NY AMERICAN EPILEPSY SOCIETY, RESEARCH AND TRAINING ...
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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.
iCARE
ADEAF - Autosomal Dominant Epilepsy with Lafora Disease
Auditory Features LGS - Lennox -Gastaut Syndrome
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
• Basic and translational research may utilize animal/model
fundamental aspects of phenomena and of
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
compare more directly:
with human subjects (or on material of human
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
SUDEPCondition: Current epilepsy ontology Not complete list of epilepsies or
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 conditionsI
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
1•2 •3 1ngrid
E. Scheffer, 1 Samuel Berkovic, 4 Giuseppe Capovilla, 5 Mary B. Connolly, "'Robert S. Fisher, t J. Helen Cross, :j:Jacqueline A. French, §Norimichi Higurashi, 1 Edouard
Hirsch , #Floor E. Jansen, >ll< Ueven Lagae, ttSolomon L. Moshe, :j::j:Jukka Peltola, §§Eliane Roulet
6 Jacqueline French, 7 Laura Guilhoto, 8 •9 Edouard Hirsch, 10Satish Jain, 11 Gary W. Mathern, Perez, 111ngrid E. Scheffer, and ##"'>ll< Sameer M. Zuberi
12 Solomon L. Moshe, 13 Douglas R. Nordli, 14 Emi lio Perucca, 15 Tor bjorn Tomson,
16 Samuel Wiebe, 17Yue-HuaZhang,and 18 • 19 Sameer 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 of Seizure Types
ILAE 2017 Classification o•f Seizure Types Expanded Version 1
Seizure types* ( Generalized Onset ] [ Unknown Onset
Etiology [~
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Epilepsy types epileptJc spasms 2
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Unclas.sified 3
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Epilepsy Syndromes focal to bilateral tonlc-clonicEpilepsyDiagnosis.org (from https://www.ilae.org/education/diagnostic-manual/epilepsydiagnosis-org)
2013-2016, all funding
Etiology
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 causesGenetic
Infection
Immune
Condition: Localization
Structural
Metabolic
proposal for update Frontal
Parietal
Associated with other Occipital
Temporal
disorders • Etiology
Other Multifocal
Generalized
• Epilepsy Onset
Focal Populations
Generalized Neonatal/Infantile
• Seizure Combined Childhood
Cognitive
Unknown Adolescent/Adult
Behavioral
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 eventsEpilepsies / 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 ontologyEpilepsies / 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 ontologyGenetic epilepsies
EPILEPSIES BY ETIOLOGY
Genetic - Chromosomal Genetic - Gene abnormalities NPRL3 HOPKIN
AKT3 FKTN
15q13.3 MICRODELETION SYNDROME FLNA PCDH19 SYNDROME)
ARFGEF2
PIK3CA TSC1
18q- SYNDROME ARHGEF9 FMR1 (FRAGILE X
PIK3R2
INV-DUP (15) OR IDIC (15) ARX SYNDROME) TSC2
FOXG1 PLCB1
CACNA1A TUBA1A
DEL 1p36 CACNB4 GABRA1 PNKP
POMT1 WDR62
ANGELMAN SYNDROME CDKL5 GABRD ZEB2
GABRG2 POMT2
DOWN SYNDROME (TRISOMY 21) CHD2
PRRT2 (MOWAT
CHRNA2 GLI3
KLEINFELTERS SYNDROME (XXY) GNAQ RELN WILSON
CHRNA4
MILLER DIEKER SYNDROME (DEL 17p) GRIN2A SCN1A SYNDROME)
CHRNB2
SCN1B
PALLISTER KILLIAN SYNDROME (TETRASOMY 12p) CLCN2 KCNQ2
SCN2A
RING 14 (r14) SYNDROME COL4A1 KCNQ3
KCNT1 SLC2A1
DCX
RING 20 (r20) SYNDROME DEPDC5 LARGE SLC25A22
TRISOMY 12p LGI1 SPTAN1
EFHC1
LIS1 STXBP1
WOLF-HIRSCHHORN SYNDROME (DEL 4p) TBC1D24
MECP2
TCF4 (PITT
(from https://www.ilae.org/education/diagnostic-manual/epilepsydiagnosis-org)Immune –
Rasmussen’s
By Etiology
Antibody mediated
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 epilepsyConsiderations
• 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
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