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TRANSCRIPT
Anne T. Berg, PhDProfessor
Epilepsy CenterChildren’s Memorial Hospital
Chicago, Illinois
Update on Classificationsfor Seizures and Epilepsies
Disclosures
Name of Commercial Interest Type of Financial RelationshipChildren’s Memorial FacultyPractice Foundation
Salary
Dow Agro Science Consulting feeEsai HonorariaNational Institutes of Health Federal funding
ILAE Classificationsof Epilepsy and Seizures
§ 1969 – Gastaut – Proposals seizures and epilepsies§ 1970 – Gastaut – Classification seizures§ 1970 – Merlis – Classification epilepsies§ 1981 – Commission – Classification seizures§ 1985 – Commission – Classification epilepsies§ 1989 – Commission – Classification epilepsies§ 1993 – Commission – epidemiological standards§ 2001 – Blume – Glossary of ictal semiology§ 2001 – Engel – Proposed diagnostic scheme§ 2005 – Fisher – Definition of seizure and epilepsy§ 2006 – Task Force – report – seizures and epilepsies
Civil Discourse
Respectful, Collegial Exchanges
Oh Dear!
Purpose of the InternationalClassification of Seizures and Epilepsies
§ “To provide a common internationalterminology and classification – aprecondition for comparability of results inresearch and therapy and for meaningfulexchange of ideas”
§ Largely for clinical (treatment) purposes
§ Research into causes and mechanisms wasnot a dominant focus
Scientific Advances Since the1950s and 1960s§ Genomic technology§ Molecular cell biology and geneticsú Techniques and concepts
§ Neuroimagingú Structural and functional
§ Neurophysiology§ Computational capabilities§ Therapeutic options§ …
1989 Classification of the Epilepsies
1. Localization Related
1.1 Idiopathic
Specific epilepsies
1.2 Symptomatic
Specific epilepsies
1.3 Cryptogenic
Specific epilepsies
2. Generalized
2.1 Idiopathic
Specific epilepsies
2.2 Cryptogenic / Symptomatic
Specific epilepsies
2.3 Symptomatic
Specific epilepsies
3. Undetermined
3.1 With both partial and generalized features
Specific epilepsies
3.2 Without unequivocal partial or generalized features
Unclassified
Too Difficult, Too Complicated…(Too Lazy) …Too Arbitrary
§ Dravet – 80% linked to SCN1A mutationsú Not idiopathic?
§ BECTS – idiopathic “presumed genetic”ú Where is the evidence?
§ West – generalizedú Arises from a focal pathology? Focal semiology?
§ Atonic seizures – generalized?ú Callosotomy
§ LennoxGastaut – generalized epilepsy?ú Occurs with focal seizures?
20052009 Commission Report,Epilepsia. 2010;51:676685
Classification
§ The actual items in a classification (ie,sparrows, bats, bees)§ The process of recognizing objects as
members in a classification§ The language and system for organizing
“objects” (the Tree of Life, Periodic Table ofthe Elements)
Main Changes, Modifications
§ The language and structure for organizing“objects”ú Generalized vs Focalú “Etiology”ú Diagnostic specificityú Organization
Generalized – Reconceptualized
§ For seizuresú Generalized epileptic seizures are conceptualized as
originating at some point within, and rapidly engaging,bilaterally distributed networks. … can include corticaland subcortical structures, but not necessarily includethe entire cortex
ú Paradigmatic breakthrough Generalized seizures could arise from focal lesions Epileptic spasms Atonic seizures Tonic seizures …
Generalized Seizures
Tonicclonic (in any combination)
Absence Typical Atypical Absence with special features
Myoclonic absenceEyelid myoclonia
Myoclonic Myoclonic Myoclonic atonic Myoclonic tonic
Clonic
Tonic
Atonic
Seizure types we “think” occurwithin and result from rapidengagement of bilaterallydistributed systems
Focal Reconceptualized
§ For seizuresú Focal epileptic seizures are conceptualized as
originating within networks limited to onehemisphere. These may be discretely localized ormore widely distributed …
Tools forStudying Networks?
Classification of Partial FocalSeizures§ Focal seizuresú Do not fall into any recognized set of natural classes
based on any current understanding of themechanisms involved
ú Complex partialú Simple partialú Partial with secondary generalization
Focal Seizures
Descriptors of focal seizures from the Glossary of Ictal Semiology, Blume et al, Epilepsia, 2001
Without impairment of consciousness or awareness+ With observable motor or autonomic components
“Focal clonic”“autonomic”“hemiconvulsive” etc.
+ Involving subjective sensory or psychic phenomena onlyAura, specific types
In which the alteration of cognition is the predominant most apparent feature“Dyscognitive” (Blume et al., 2001)(a) Perception(b) Attention(c) Emotion(d) Memory(e) Executive function (including speech)
Evolving to a bilateral, convulsive seizure Involving tonic, clonic, or tonic and clonic components
Classification of Seizures
§ Who knows?!ú Epileptic spasms
Epilepsies
ú Generalized and Focal are abandoned Apparently generalized manifestations associated
with a clearly focal lesion West syndrome secondary to FCD or TSC
Focal seizures associated with diffuse geneticdisorders Dravet, GEFS+, ADNFLE
§ Separate manifestations from underlyingprocess
Terminology for Etiology
§ Idiopathic – “There is no underlying cause other than a possible hereditarypredisposition. Idiopathic epilepsies are defined by agerelated onset,clinical and electroencephalographic characteristics, and a presumedgenetic etiology.”
§ Commission Report, Epilepsia, 1989
Recent insights into the molecular geneticsand pathophysiology of the idiopathicepilepsies have threatened to make theterm “idiopathic” obsolete.
M. Wong, 2010
Terminology for Etiology
§ Symptomatic epilepsies and syndromes areconsidered the consequence of a known orsuspected disorder of the central nervoussystem (CNS)
§ Commission Report, Epilepsia, 1989
Terminology for Etiology
§ Cryptogenic refers to a disorder whose causeis hidden or occult. Cryptogenic epilepsies arepresumed to be symptomatic, but theetiology is not known
ñ Commission Report, Epilepsia, 1989
§ Presumed based on what?????ú ADNFLEú Dravetú GEFS+
Terminology for Etiology
§ Idiopathic – “There is no underlying cause other than a possiblehereditary predisposition. Idiopathic epilepsies are defined byagerelated onset, clinical and electroencephalographiccharacteristics, and a presumed genetic etiology”
§ Symptomatic epilepsies and syndromes are considered theconsequence of a known or suspected disorder of the centralnervous system (CNS)
§ Cryptogenic refers to a disorder whose cause is hidden or occult.Cryptogenic epilepsies are presumed to be symptomatic, but theetiology is not known
ñ Commission Report, Epilepsia, 1989
Genetic
§ The Concept: the epilepsy is the direct result ofa known or inferred genetic defect(s). Seizuresare the core symptom of the disorderú Channelopathies – probably best case for “genetic”
§ The Evidence: Specific molecular geneticstudies (well replicated) or evidence fromappropriately designed family studies
Structural Metabolic
§ The Concept: There is a distinct otherstructural or metabolic condition or diseasepresentú ? Separate structural and metabolic?
§ The Evidence: Credible studies must havedemonstrated a substantially increased riskof developing epilepsy in association with thecondition
Unknown
§ Concept: The nature of the underlying cause isas yet unknown
§ Cases in point: ADNFLE, Dravet, GEFS+ (etc.)were cryptogenic (presumed symptomatic)ú Lesional?ú Now channelopathies (to extent know)
Syndromes… Diseases…
Not All Epilepsy Diagnoses AreEqual
ú DEND (developmental delay, epilepsy, and neonatal diabetes) –monogenic systemic disease associated with neurologicalmanifestations (including seizures)
ú Dravet syndrome: ~monogenic epilepsy disease
ú Cryptogenic parietal lobe epilepsy: an incomplete description atbest
Most Specific:Electroclinical Syndrome§ Clinical entity reliably identified by a cluster of
electroclinical characteristicsú Age at onsetú Antecedents and developmentú Seizure typesú EEG featuresú MRI findingsú Patterns and triggers of seizure occurrenceú Other
§ Thought to share common cause(s) ormechanism(s) and implications for treatment
Less Specific:StructuralMetabolic Epilepsy§ Epilepsies due to specific structural or
metabolic lesions or conditions
§ Do not currently fit a specific electroclinicalpattern (per current understanding)§ Could change in the future
§ Epilepsy presentation is not necessarilyspecific, but underlying cause is
Least Specific:Epilepsies of Unknown Cause
§ Can be grouped according to manifestations,age, other features…
1989 Classification of the Epilepsies1989 Classification of the Epilepsies
1. Localizationrelated
2. Generalized
3. Undetermined
1.1 Idiopathic
1.2 Symptomatic
1.3 Cryptogenic
2.1 Idiopathic
2.2 Cryptogenic / symptomatic
2.3 Symptomatic
3.1 With both partial andgeneralized features
3.2 Without unequivocal partialor generalized features
Syndromes / epilepsies
Syndromes / epilepsies
Syndromes / epilepsies
Syndromes / epilepsies
Syndromes / epilepsies
Syndromes / epilepsies
= “nonclassified”
Syndromes / epilepsies
THERE ISNO NEWCLASSIFICATION
What Should a ClassificationDo? Why Bother?
§ The organization of items in such a way as torepresent their fundamental relationshipsú Represent essential similarities and differences
with respect to one or more key featuresú Be useful
Earth worm
snake
bee
cat
ostrich
gorillabat
trout
dog
sparrow
human
turtle
dolphin
clam
mouse
Flying things
Walk on2 legs
Cute, furry, suitableas pets
round worm
Long, slimyicky
Things thatlive
in water
Earthworm
snakebeecat
ostrich
gorillabatdogsparrow
turtlemouse
trout
clam
human
dolphin
primates
Mammalia
Vertebrata
roundworm
Reptilia
Tetrapoda
Dimensions Reflecting Mechanisms orClinically Relevant Features§ Age at onset§ Underlying cause
ú Channelopathy Voltage gated Ligand gated
ú mTORopathyú MRC defectú GLUT1 deficiencyú Glioma
Ganglio Oligodendro
ú Malformation of cortical development FCD type I FCD type II Hemimegalencephaly Lissencephaly…
§ EEGú Generalized spike and waveú Burst suppression pattern…
§ Seizures types§ Triggers (nocturnal, photic stimulation… )§ Developmental courseú Prior to onsetú After onsetú Language disturbance…
Are We Ready for a New Classification?
Organize Epilepsies to Reflect Our KnowledgeElectroclinical syndromes BY AGE, other...
Neonatal period: eg, Benign familial neonatal epilepsy (BFNE)
Infancy eg, Epilepsy of infancy with migrating partial seizures
Childhood eg, Childhood absence epilepsy (CAE)
Adolescence – adult eg, Juvenile absence epilepsy (JAE)
Less specific age relationship eg, Familial focal epilepsy with variable foci (childhood toadolescence)
Constellations
eg, MTS w/ HA
Epilepsies associated with structural or metabolic conditions
eg, By condition (malformations, MRC deficiencies… )
eg, By age at onset
eg, Condition and age, … other
Epilepsies of unknown cause
eg, By age at onset
eg, By predominant seizure manifestations… other
An Ancient Chinese Classification of AnimalsAnimals are divided intoo Those that belong to the Emperoro Embalmed oneso Those that are trainedo Suckling pigso Mermaidso Fabulous oneso Stray dogso Those that are included in this classificationo Those that tremble as if they were mado Innumerable oneso Those drawn with a very fine camel’s hair brusho Otherso Those that have broken a flower vaseo Those that resemble flies from a distance
Jorge Luis Borges, Other Inquisitions