[email protected] Seizures and Epilepsy Relationship … · 2014. 9. 22. · Epilepsy...

The 2010 RevisedClassification ofSeizures and Epilepsy

Anne T. Berg, PhD; John J. Millichap, MD

ABSTRACTPurpose of Review: Classifications of epilepsies (1989) and seizures (1981) took acentral role in epilepsy care and research. Based on nearly century-old concepts,they were abandoned in 2010, and recommendations for new concepts and termi-nology were made in accordance with a vision of what a future classification wouldentail. This review outlines the major changes, the ways these changes relate to theearlier systems, the implications for the practicing health care provider, and some ofthe recommendations for future classification systems.Recent Findings: New terminology for underlying causes (genetic, structural-metabolic,and unknown) was introduced to replace the old (idiopathic, symptomatic, andcryptogenic) in 2010. The use of generalized and focal to refer to the underlyingepilepsy was largely abandoned, but the terms were retained in reference to modeof seizure initiation and presentation. The terms ‘‘complex’’ and ‘‘simple partial’’ forfocal seizures were abandoned in favor of more descriptive terms. Electroclinicalsyndromes were highlighted as specific epilepsy diagnoses and distinguished fromnonsyndromic-nonspecific diagnoses. The importance of diagnosis (a clinical goalfocused on the individual patient) over classification (an intellectual system for or-ganizing information) was emphasized.Summary: Accurate description and diagnosis of the seizures, causes, and specifictype of epilepsy remain the goal in clinical epilepsy care. While terminology andconcepts are being revised, the implications for patient care currently are minimal;however, the gains in the future of clear, accurate terminology and a multidomainclassification system could potentially be considerable.

Continuum (Minneap Minn) 2013;19(3):571–597.

INTRODUCTION AND HISTORYClassification plays a central role inclinical epilepsy and epilepsy research.The goals of the original internationalclassifications of the epilepsies and ofseizures, published in 1970,1,2 were tointroduce some standardization of ter-minology to improve communication,provide some organization to the knowl-edge concerning epilepsy at the time,and facilitate research. The classifica-tions were intended to improve patientcare through accomplishing thesegoals. Updates in 1981 for seizures3

and in 1989 for epilepsies4 did notdepart conceptually from the originaldocuments, the content of which wasbased on understandings and conceptsdating back to the late 1800s and early1900s. The language of the interna-tional classifications is also incorporatedinto the International Classification ofDiseases nomenclature; these classifi-cations are used throughout the worldand are integral to billing proceduresin the United States. In 2010, the Inter-national League Against Epilepsy (ILAE)abandoned the 1989 classification of

Address correspondence toDr Anne T. Berg, Ann &Robert H. Lurie Children’sHospital of Chicago EpilepsyCenter, 225 East Chicago St,Box 29, Chicago, IL 60611,[email protected].

Relationship Disclosure:

Dr Berg has served as aspeaker for BIAL; serves onan Advisory Panel for EisaiCo, Ltd; serves on the editorialboards of Neurology andEpilepsy & Behavior; andreceives grants from theNational Institute ofNeurological Disorders andStroke and the PediatricEpilepsy Research Foundation.Dr Millichap serves as asection editor for Neurologyand receives funding fromCURE: Citizens United forResearch in Epilepsy and theThrasher Research Fund.

Unlabeled Use of

Products/InvestigationalUse Disclosure:Drs Berg and Millichapreport no disclosures.

* 2013, American Academyof Neurology.

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Review Article

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

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the epilepsies andmodified the seizureclassification in an effort to have con-cepts and terminology that reflectedthe advances in understanding andknowledge of these disorders.5 Changehappens slowly; however, the plan-ning for the International Classifica-tion of Diseases, 11th Revision (ICD-11) is beginning to make the transitionalready.6

The aims of this review are to (1)compare and contrast a classificationversus diagnosis and consider their rel-ative importance to clinical care; (2)present the revisions to the terminol-ogy and concepts recommended by theILAE Commission on Classification andTerminology5 and the rationale behindthem as well as a translation back toprevious systems; and (3) provide anoverview of the key diagnostic entitiescentral to epilepsy care (etiologies orcauses, seizure types, and epilepsydiagnoses).

MEANING OF CLASSIFICATIONThe term ‘‘classification’’ has becomecentral to the concept of epilepsy di-agnosis but is used in reference to twodistinct and separate concepts. Classi-fication can refer to an organizationalstructure. It has also been used in lieuof diagnosis or list of diagnoses. Theresult has been that diagnosis (theclinician’s charge) and classification (ascientific process) are often conflated.

Classification as anOrganizational SystemA classification is a system for organiz-ing knowledge about the similaritiesamong and differences between itemsthat are part of some overarchinggroup. The ‘‘tree of life’’ is the classi-fication system for species of livingorganisms, as the periodic table of theelements is for chemical elements.The terminology used to identify di-mensions or subgroups within each

system and the layouts of the tree andthe table are such that the placementwithin the system of a species or ele-ment provides a host of important in-formation about that item and how it issimilar to and different from all otheritems organized within that classification.

Classification as a DiagnosisA diagnosis is the identified disease ordisorder for a particular individual thatis arrived at through the process ofconsidering history, signs, symptoms,and other clinical information. In epi-lepsy, the term ‘‘classification’’ is alsooften used to refer to the list of thedifferent forms of epilepsy organizedwithin the classification system and toan individual diagnosis itself (eg, ‘‘Thepatient’s epilepsy was classified as child-hood absence epilepsy’’).

Classification Systemversus DiagnosisWhile diagnoses can be organized withina classification structure, the classifica-tion structure is not essential to diagno-sis. One can diagnose a child as having,for example, childhood absence epi-lepsy without having to specify how thatform of epilepsy is classified in the 1989framework (in this instance, ‘‘idiopathicgeneralized epilepsy’’). Although theclassification structure has been for-mally abandoned, the individual diag-noses for epilepsy have not, even ifsome of the names have beenmodified.This is a crucial point, as the recom-mended changes in 2010 entail little orno change in what health care providersdo in daily practiceVthat is, diagnoseand treat individual patients. Further-more, new diagnoses continue to beadded to clinical practice that are notacknowledged and often do not fit wellin the 1989 framework,4 and our un-derstanding of old ones has changed insuch a way that their placement withinthe 1989 framework is undefined.

KEY POINTS

h The goals of the originalinternational classificationsof the epilepsies and ofseizures, published in1970, were to introducesome standardization ofterminology to improvecommunication, providesome organization to theknowledge concerningepilepsy at the time, andfacilitate research.

h A classification is asystem for organizingknowledge about thesimilarities among anddifferences betweenitems that are part ofsome overarching group.

h In epilepsy, the term‘‘classification’’ is alsooften used to refer tothe list of the differentforms of epilepsyorganized within theclassification systemand to an individualdiagnosis itself.

h While diagnoses canbe organized within aclassification structure,the classificationstructure is not essentialto diagnosis.

h Although theclassification structurehas been formallyabandoned, theindividual diagnoses forepilepsy have not, evenif some of the nameshave been modified.This is a crucial point, asthe recommendedchanges in 2010 entaillittle or no change inwhat health careproviders do in dailypractice (that is,diagnose and treatindividual patients).

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Revised Classification of Seizures and Epilepsy


UPDATED TERMINOLOGYAND CONCEPTThe 1989 classification had two primaryaxes, one for etiology and one formode of presentation. This rigid, one-dimensional system was abandoned.The concepts utilized in the frameworkwere redefined, and the terms used forthose concepts updated.

Etiologies/CausesTo refer to groups of causes, the terms‘‘genetic,’’ ‘‘structural-metabolic,’’ and‘‘unknown’’ were recommended in 2010.These are explicitly defined in Table 1-1and contrasted with the earlier termi-nology and concepts, which predatedmodern neuroimaging and genetic test-ing. A brief rationale for the changesis also provided. Those interested inthe details of the reasoning and thedebates that ensued are referred tothe original report5 and subsequentcommentaries.7Y9

The revised terminology has sub-stantial advantages for clarity and com-munication; relative to the old, itprovides greater transparency withwords more directly reflecting the asso-ciated concepts (eg, genetic is referredto as genetic rather than ‘‘idiopathic’’; astructural lesion is referred to as struc-tural rather than ‘‘symptomatic’’). ‘‘Un-known’’ (instead of ‘‘cryptogenic’’) is anhonest expression of lack of knowl-edge. The old terms, particularly ‘‘idio-pathic’’ and ‘‘symptomatic,’’ had alsotaken on connotations regarding theseverity of disease. Idiopathic was linkedto the notion of a benign disorder, easilytreated, often self-remitting, with fewif any ancillary consequences and nodisability, whereas the meaning of symp-tomatic was expanded to mean ‘‘badoutcome.’’ Dravet syndrome, a severeinfantile-onset form of epilepsy causedby a sodium channel gene mutation(SCN1A), is sometimes called symptom-atic not because of its cause but

because of its poor prognosis andassociated disability.10,11 The revised ter-minology separates cause from con-sequences and reflects the changingknowledge of the nature of many ge-netic disorders.

Problems still exist with the revisedterminology. New genetic factors areidentified every year. Without under-standing the function of the proteinproduct and how its malfunction leadsto seizures, the specific definition ofgenetic from the 2010 report is diffi-cult to apply. Currently, the best ex-emplars of genetic epilepsies are thechannelopath ies , and perhapschannelopathies alone could be a cate-gory, although recent work on the roleof neuroinflammation in epilepsy hasalso demonstrated the potential foracquired channelopathies.12,13 Thestructural-metabolic distinction willrequire further consideration; theseeasily could represent separate but po-tentially overlapping categories. Otherfactors such as immune-mediated/inflammatory processes are not explic-itly recognized, but their importance asa precipitating cause of epilepsy andas part of a process induced by fre-quent seizures and exacerbating thetendency to further seizures is increas-ingly recognized.14,15

Mode of Onset and PresentationThe terms ‘‘generalized’’ and ‘‘focal’’were retained for describing seizuresbut carefully redefined with referenceto networks, a concept that has re-placed the older notion of a discreteanatomical region (Table 1-2). Inaddition, the role of subcortical struc-tures can be more transparently rec-ognized,16,17 as well as the role ofbrainstem mechanisms in general andin highly specific disorders such ashyperekplexia, a rare disorder withonset in the neonatal period and char-acterized by prolonged tonic seizures

KEY POINTS

h To refer to groupsof causes, the terms‘‘genetic,’’‘‘structural-metabolic,’’and ‘‘unknown’’ wererecommended in 2010.

h The revised terminologyseparates cause fromconsequences andreflects the changingknowledge of thenature of many geneticdisorders.

h Currently, the bestexemplars of geneticepilepsies are thechannelopathies. Perhapschannelopathies couldbe a category of theirown, although recentwork on the role ofneuroinflammationin epilepsy has alsodemonstrated thepotential for acquiredchannelopathies.

h Other factors such asimmune-mediated/inflammatory processesare not explicitlyrecognized in the 2010report, but theirimportance as aprecipitating cause ofepilepsy and as partof a process induced byfrequent seizures andexacerbating thetendency to have moreseizures is increasinglyrecognized.



often provoked by sounds or otherstimuli.18 Hyperekplexia could be de-scribed as a brainstem epilepsy due toa channelopathy.

For describing the epilepsies them-selves, generalized and focal werelargely abandoned. Previous thinkingin the field of epilepsy often mixedseizure types (ie, the manifestations)with the epilepsy itself (ie, the under-

lying disorder affecting the brain)(Table 1-2). The earlier classificationspredated modern neuroimaging, andfocal and generalized were used toinfer the presence or absence of struc-tural lesions. This classification systemcan be appreciated in its historicalcontext; however, it fails today giventhe increasing information about thesedisorders provided by the advances in

TABLE 1-1 New Terminology and Concepts Contrasted With Older Terminology

Old Term and DefinitionaNew Term andConcept/Definitionb

Rationale for NewTerminology

Idiopathic: No underlyingcause other than a possiblehereditary predispositionexists. Idiopathic epilepsiesare defined by age-relatedonset, clinical andelectroencephalographiccharacteristics, and apresumed genetic etiology.

Genetic: Epilepsy is the directresult of a known or presumedgenetic defect(s) in which seizuresare the core symptom of thedisorder. The knowledge regardingthe genetic contributions may derivefrom specific molecular geneticstudies that have been wellreplicated and even becomethe basis of diagnostic tests orthe evidence for a central roleof a genetic component maycome from appropriatelydesigned family studies.

The notion that epilepsy hasno cause and that a geneticpredisposition can only bepresumed is antiquated. Further,the term idiopathic was used fordisorders that did not have clearevidence of a genetic basis butwere self-limited and had anexcellent prognosis and nomajor associated disability. Thus,idiopathic was used to connotebenign.

Symptomatic: Symptomaticepilepsies and syndromesare considered theconsequence of a knownor suspected disorderof the CNS.

Structural/metabolic: A distinctstructural or metabolic condition ordisease has been demonstrated tobe associated with a substantiallyincreased risk of developing epilepsyin appropriately designed studies.

All epilepsies and seizures arecaused by something, thus thedefinition of symptomatic iscircular. In practice it was usedto infer an underlying brainlesion and also connoted badoutcome. As various geneticencephalopathies have beenreported recently, this definitionis at odds with the currentscientific literature.

Cryptogenic: Refers to adisorder whose causeis hidden or occult.Cryptogenic epilepsiesare presumed to besymptomatic, but theetiology is not known.

Unknown: Meant to be viewedneutrally and to designate that thenature of the underlying cause isas yet unknown; it may have afundamental genetic defect atits core or it may be theconsequence of a separate orunrecognized disorder.

Many of the formerlycryptogenic epilepsies havebeen shown to have a geneticbasis (eg, Dravet syndrome,autosomal dominant nocturnalfrontal lobe epilepsy). Ratherthan feign knowledge abouta symptomatic cause, thepreference is to say that thecause is unknown.

a Data from Commission on Classification and Terminology of the International League Against Epilepsy, Epilepsia.4 onlinelibrary.wiley.com/doi/10.1111/j.1528-1157.1989.tb05316.x/abstract.

b Data from Berg AT, et al, Epilepsia.5 onlinelibrary.wiley.com/doi/10.1111/j.1528-1167.2010.02522.x/full.

KEY POINT

h Previous thinking in thefield of epilepsy oftenmixed seizure types (ie,the manifestations) withthe epilepsy itself (ie, theunderlying disorderaffecting the brain).




onlinelibrary.wiley.com/doi/10.1111/j.1528-1157.1989.tb05316.x/abstract


onlinelibrary.wiley.com/doi/10.1111/j.1528-1167.2010.02522.x/full

diagnostic modalities used to studythem. The current emphasis is toseparate the manifestations from theunderlying cause.

For the traditional group of ‘‘idio-pathic generalized epilepsies’’ largelycomprised of childhood absence epi-lepsy, juvenile absence epilepsy, andjuvenile myoclonic epilepsy, general-ized was retained, although the labelwas revised to ‘‘genetic generalizedepilepsies.’’ For epilepsies secondaryto a discrete structural lesion, the term‘‘focal epilepsy’’ will likely be retained;

however, it is really the underlyinglesion that is focal, and the processesaffected in the brain may be morewidely distributed.

These changes acknowledge that‘‘generalized’’ seizures may arise fromdiscrete, focal lesions, and that focalmanifestations are not necessarily in-consistent with a diffuse (generalized)epileptic process. The implicationsfor clinical care are profound, asmany forms of epilepsy, especially ininfants and toddlers, do not clearlyfit meaningfully into the generalized

KEY POINT

h The current emphasisis to separate themanifestations from theunderlying cause.

TABLE 1-2 Definitions and Concepts for Focal and Generalized Seizures and Epilepsy in the1981/1989 and 2010 Systems

1981a/1989b 2010c

Generalized seizures Generalized seizures are those inwhich the first clinical changesindicate initial involvement ofboth hemispheres.

Generalized epileptic seizuresare conceptualized as originatingat some point within, and rapidlyengaging, bilaterally distributednetworks. They can includecortical and subcortical structuresbut do not necessarily includethe entire cortex.

Generalized epilepsy Generalized epilepsies andsyndromes are epileptic disorderswith generalized seizures, ie,‘‘seizures in which the first clinicalchanges indicate initial involvementof both hemispheres. . . . The ictalencephalographic patterns initiallyare bilateral.’’b

The term is largely abandoned.

Focal seizures Partial seizures are those in which thefirst clinical and EEG changes indicateinitial EEG activation of a system ofneurons limited to a part of onehemisphere.

Focal epileptic seizures areconceptualized as originatingwithin networks limited to onehemisphere. These may bediscretely localized or morewidely distributed.

Focal epilepsy Localization-related epilepsiesand syndromes are epilepticdisorders in which seizuresemiology or findings atinvestigation disclose alocalized origin of the seizures.b

The term is largelyabandoned.

a Data from Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia.3 onlinelibrary.wiley.com/doi/10.1111/j.1528-1157.1981.tb06159.x/abstract.

b Data from Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia.4 onlinelibrary.wiley.com/doi/10.1111/j.1528-1157.1989.tb05316.x/abstract.

c Data from Data from Berg AT, et al, Epilepsia.5 onlinelibrary.wiley.com/doi/10.1111/j.1528-1167.2010.02522.x/full.








or focal categories. Focal seizure se-miology (ie, the specific motoric,behavioral, autonomic, sensory, andexperiential manifestations of a sei-zure) and EEG findings, such as maybe seen in Dravet syndrome, epilepsyin females with mental retardation,and other genetic epilepsies, are notindications for surgical consideration(Case 1-1, Figure 1-1). Generalized

presentations as often seen in West orLennox-Gastaut syndromes are notcontraindications to a surgical evalua-tion (Case 1-2, Figure 1-2). The terms‘‘generalized’’ or ‘‘focal’’ to refer tothe epilepsy are somewhat of a ‘‘redherring’’ in these situations and per-haps in some adults as well, althoughthis group has not been as carefullystudied.

Case 1-1A 3-year-old boy presented with persistent monthly seizures. Seizure onset was at 4 months oldwith recurrent hemiclonic seizures and status epilepticus, at times triggered by fever. Initial interictalEEG was significant for rare focal sharp-wave discharges in the right frontal region, and the original

differential diagnosis for the etiology of his epilepsy included focal structural lesion andinfantile-onset epilepsy. Magnetic resonance neuroimaging at the age of 6 months was normal.Subsequent SCN1A testing at age 1 was positive, consistent with Dravet syndrome. By 2 years old, thepatient had approximately three to five seizures per month characterized by eye blinking andeye deviation, sometimes followed by hemiconvulsion or generalized convulsion. Video EEGcharacterized myoclonic, atypical absence, and focal seizures. Development was normal duringinfancy, but he now had signs of developmental delay.

Comment. This patient’s presentation illustrates that there may be focal neurophysiologic findingsin situations where surgical treatment is not indicated (Figure 1-1). The early referral of patients withrefractory epilepsy for presurgical evaluation is important but should be contemporaneous withcareful clinical evaluation and accurate epilepsy syndrome diagnosis. The history of prolongedalternating hemiconvulsions, among other seizure types, is typical of Dravet syndrome, and thediagnosis was supported by the positive SCN1A testing.

FIGURE 1-1 Epoch of wake EEG of a patient at 3 years old showing brief bursts of generalized, bifrontal predominant,irregular 2- to 3-Hz polyspike/spike and slow-wave discharges. At times, the epileptiform discharges had afocal right hemisphere predominance or lead-in (arrows).




Case 1-2An 11-month-old boy presented with pharmacoresistant epilepsy with infantile spasms. Infantilespasms began several months earlier, characterized by clusters of brief bilateral arm extension.Seizures continued to occur multiple times daily despite treatment with adrenocorticotropichormone, vigabatrin, and several standard anticonvulsants. There was no developmental progressafter the seizures began. The EEG background activity continued to show hypsarhythmia during sleep(Figure 1-2A) and several habitual spasms were recorded with video-EEG monitoring (Figure 1-2B).

Magnetic resonanceneuroimaging showed afocal structural lesion in theleft frontal lobe, suspiciousfor a malformation of corticaldevelopment (Figure 1-2C).After further presurgicalevaluation, the lesion wassuccessfully resected, andpathology was determinedto be consistent with focalcortical dysplasia, type IIB.The patient was seizure freeafter the surgery.

Comment. This patient’spresentation illustrates thepotential for generalizedseizures and generalizedinterictal EEG findingsdespite a focal epileptogenicstructural lesion.

FIGURE 1-2 EEG and neuroimaging studies for a patient with infantile spasms.A, EEG epoch from sleep showing hypsarhythmia, characterizedby symmetric discontinuous high-voltage (9300 2V) polymorphic

delta slow-wave activity with admixed multifocal spike-wave discharges. B, EEGepoch showing three representative infantile spasms from a cluster that lasted for11 minutes with more than 20 spasms. Each clinical spasm was accompanied bya concurrent high-voltage, broad, diffuse slow wave with attenuation of voltage(arrows). The cluster was associated with a period of relative decrease in interictalepileptiform activity. C, T2-weighted, axial brain MRI showing hyperintensity inthe left middle frontal gyrus extending toward the left lateral ventricle (arrows).



DIAGNOSTIC TARGETS: ETIOLOGY,SEIZURE TYPES, EPILEPSYEtiologyTable 1-3 provides a partial but rep-resentative list of factors that play arole in causing epilepsy. Diagnosingthe specific cause for the individualpatient can have important implica-tions for treatment at all levels. Forexample, tuberous sclerosis is a ge-netic disorder that causes structuralbrain lesions.19 There is a key molec-ular pathway through which it works,mammalian target of rapamycin(mTOR).20 Diagnosis of a genetic disor-der has implications for geneticcounseling, a structural lesion hasimplications for surgical treatment,and a molecular pathway has implica-tions for potential pharmacologic in-terventions. A specific organization orclassification of causes has yet to beproposed but would clearly be mostuseful if it could capture these clinicallyrelevant features.

Seizure TypesSeizures are the defining manifestationof epilepsy. They are highly varied intheir semiology and can take the formof virtually any phenomenon that brainactivity can produce. The 1981 reportprovided a limited number of catego-ries for seizures. These are updated inthe revised terminology (Table 1-4).

The 2010 report recommends thatseizures be clearly described accordingto their motor, cognitive, autonomic,and sensory-experiential manifesta-tions. When these occur in sequence,that sequence can be described as well.Consequently, focal-onset seizures areno longer designated as complex orsimple partial, a distinction largelyintended to represent impairment ofresponsiveness or consciousness andnot based on any single mechanism orspecific treatment implication. Thischange is meant to facilitate clearer,

more precise communication at manylevels. Of note, the original 1981 reportdescribes many semiologic featuresincluded in a glossary of ictal semiol-ogy,21 but typically ignored in theeffort to fit seizures into the simple/complex dichotomy. In addition, cer-tain well-acknowledged seizure types(eg, hypermotor, hemiconvulsion) didnot fit comfortably into any of the pre-vious categories and were likely incon-sistently labeled.

For generalized-onset seizures, mostof the previous seizure types were re-tained in the 2010 update. Some newseizure types were added: myoclonic-tonic, myoclonic absence, and eyelidmyoclonia. Myoclonic-astatic wasrenamed myoclonic-atonic. Theseterms directly communicate the sei-zure semiology.21

Epileptic spasms, which were not rec-ognized in the 1981 document, repre-sent a unique seizure type with distinctsemiology and electrographic and elec-tromyographic correlates (Table 1-5).Although they are frequently bilaterallysymmetric, spasms often occur in thecontext of focal brain pathology andmay have focal semiology. It is not clearwhether they are of generalized orfocal onset or perhaps both, depend-ing on the individual. Often thought tooccur in infancy only (hence ‘‘infantilespasms’’), this seizure type can and doesoccur at older ages, either as a con-tinuation of spasms beginning in in-fancy or de novo.22,23 Whether theyare correctly recognized in clinicalpractice is unclear, and it is not un-common to see patients whose spasmsare labeled as myoclonic seizures or asfocal motor seizures if asymmetric insemiology, or are simply missed alto-gether because the ictal correlate is nottypical of most seizures involving thecortex (Figure 1-3A). Spasms are dis-tinct from myoclonic (Figure 1-3B)and tonic (Figure 1-3C) seizures,

KEY POINTS

h ‘‘Generalized’’ seizuresmay arise from discrete,focal lesions, and‘‘focal’’ manifestationsare not necessarilyinconsistent with adiffuse (generalized)epileptic process. Theimplications for clinicalcare are profound, asmany forms of epilepsy,especially in infants andtoddlers, do not clearlyfit meaningfully intothe generalized orfocal categories.

h The 2010 reportrecommends thatseizures be clearlydescribed according totheir motor, cognitive,autonomic, andsensory-experientialmanifestations. Whenthese occur in sequence,that sequence can bedescribed as well.

h Epileptic spasms, whichwere not recognized inthe 1981 document,represent a uniqueseizure type withdistinct semiology andelectrographic andelectromyographiccorrelates.




TABLE 1-3 Examples of Known Causes of Epilepsy and Types of Epilepsy With Which TheyMay Be Associated

Causes of Epilepsy Examples of Epilepsy Syndromes or Diseases

Genetic (single gene)a

Channelopathies (SCN1A; SCN1B;SCN2A; GABRG1; GABRG2; KCNQ2;KCNQ3; CHRNA4; CHRNB2; CHRNA2;KCNA1; CACNA1A)

Dravet syndrome; generalized epilepsy with febrileseizures plus; benign familial neonatal convulsions;early myoclonic epilepsy; Ohtahara syndrome;autosomal dominant nocturnal frontal lobe epilepsy;juvenile myoclonic epilepsy; episodic ataxia types 1 and 2

Progressive myoclonic epilepsies(CLN3; CLN5; CLN6; CLN8; CSTB; CTSD;EPM2A; MFSD8; NHLRC1; PPT1;PRICKLE1; TPP1; NEU1; DRPLA)

Unverricht disease; neuronal ceroid lipofuscinoses;Lafora body disease; sialidosis;dentatorubral-pallidoluysian atrophy

Infantile developmental/geneticencephalopathies (ALDH7A1; ARX;ATP6AP2; CDKL5; PCDH19; PNPO; SCN1A;SLC2A1; SLC25A22; SPTAN1; STXBP1; TSC1;TSC2; UBE3A; CNTNAP2; SCL9A6; NRXN1;TCF4; SYN1; FMR1; ZEB2; PNKP)

Early myoclonic epilepsy; Ohtahara syndrome;West syndrome; pyridoxine-dependent epilepsy;glucose transporter type 1 deficiency syndrome;tuberous sclerosis complex; lissencephaly;early-onset absence epilepsy

Malformations of cortical developmentb

(hamartomas, lissencephaly, periventricularnodular heterotopias, schizencephaly,double-cortex, heterotopias, cobblestonemalformation, holoprosencephaly,polymicrogyria, etc)

Generally associated with nonspecific epilepsypresentation as well as with West andLennox-Gastaut syndromes. Specific neurologicsyndromes are associated with thesemalformations, eg, Walker-Warburg syndrome,Fukuyama congenital dystrophy

Neurometabolic/mitochondrial (POLG;SURF1; ADSL; mitochondrial DNAmutations; GAMT; PSAP; MMACHC;OTC; PDHA1; PDHB; GALC)

Generally associated with a nonspecific epilepsypresentation but cause specific neurologic syndromes orconditions, eg, Alper syndrome; Leigh syndrome;adenylosuccinate lyase deficiency; myoclonic epilepsywith ragged red fibers; mitochondrial encephalomyopathy,lactic acidosis, and strokelike episodes; creatine deficiencysyndrome; Gaucher disease; cobalamin C deficiency;ornithine transcarbamylase deficiency; pyruvatedehydrogenase deficiency; Krabbe disease

Other genetic (LGI1; trisomy 21) Autosomal dominant epilepsy with auditory features(also known as autosomal dominant lateral temporallobe epilepsy; Down syndrome; Ring chromosome 20

Neoplasms with known orsuspected genetic contributions

Dysembryoplastic neuroepithelial tumor; hypothalamichamartoma; glioma; ganglioglioma; meningioma

Acquired insults

Cerebrovascular Hypoxic-ischemic encephalopathy; infarction;hemorrhage; arteriovenous malformation; cavernousmalformations (cavernous angiomas, cavernomas,cavernous hemangiomas)

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although combinations of these threeand other seizure types may occur invarying sequence (eg, Figure 1-3D).

Clinical diagnosis and care could beenhanced by greater descriptive clari-ty, both for events that can be charac-terized as having only one semiologiccomponent and for compound eventssuch as those described above. Table 1-6provides some of the extended termi-nology for seizure description.21,24 Theamount of detail regarding seizures willlimit precision of description. Detailedinformation often requires video mon-itoring and frequent enough seizuresto be captured during a short hospitalstay. Seizure terminology needs to applyto everyone, however. Information canbe inadequate about seizure manifesta-tions for patients seen outside of tertiarycenters where video monitoring can beperformed and can greatly help clarifythe nature and manifestation of theevents. The difficulty is particularly ac-

centuated in newly presenting patientswho have only had a few events, whichmay not be well described, and inpatients seen in resource-poor areas orin epidemiologic surveys.25 Ultimately, ahierarchically consistent and consis-tently used terminology is required topermit communication between epi-lepsy care providers and researchersworking at all levels from public healththrough tertiary care settings.

Epilepsies and EpilepsyDiagnosisEpilepsy diagnoses vary in their spec-ificity from highly specific to relativelynonspecific. Age at initial presentationis a fundamental organizing axis forarriving at an epilepsy diagnosis, andfor any patientVnew, established, orreferredVthe first question should bethe age at onset of seizures. Knowl-edge of age at onset can steer thediagnosis toward a few and away from

TABLE 1-3 Examples of Known Causes of Epilepsy and Types of Epilepsy With Which TheyMay Be Associated (continued )

Causes of Epilepsy Examples of Epilepsy Syndromes or Diseases

Trauma Traumatic brain injury; skull fracture; ventricularshunt placement

Infection Neurocysticercosis; subdural empyema; viral/bacterialmeningitis/encephalitis; abscess; malaria; fungalinfections, tuberculosis; HIV; nonencephalitic febrilestatus epilepticus (mesial temporal sclerosis)

Autoimmune/inflammation Paraneoplastic antibody encephalitis (antineuronalnuclear antibody [ANNA] 1 [Hu], collapsin responsemediator protein [CRMP] 5, N-methyl-D-aspartate[NMDA] receptor, ,-aminobutyric acid [GABA] B receptor,!-amino-3-hydroxy-5-methylisoxazole-4-propionicacid [AMPA] receptor; voltage-gated potassium channel[VGKC]; glutamic acid decarboxylase [GAD] 65); LGI1;febrile infection-related epilepsy syndrome (FIRES);Rasmussen syndrome

Neoplasms Acquired, metastases to braina A one-to-one correspondence between genes and epilepsy syndromes does not always exist. Further, some of the genes may beassociated with disorders that do not involve epilepsy. The association between genes and epilepsy syndromes is complex.

b Many malformations of cortical development have known genetic bases. See Barkovich AJ, et al, Brain19 for more information.




TABLE 1-4 Seizure Types and Terminology Used in the 1981 Classification of Seizures andRecommended in the 2010 Reporta,b

Mode of Onset 1981 Seizure Typesc 2010 Seizure Descriptionsd

Focal Simple partial

With motor signs

With sensory symptoms

With autonomic symptoms

With psychic symptoms (butno impaired consciousness)

Without impairment of consciousnessor awareness:

With observable motor or autonomiccomponents

Involving subjective sensory or psychicphenomena only, corresponding to theconcept of an aura

Complex partial

Consciousness impaired at onset

Simple partial onset followedby impairment of consciousness

With impairment of consciousness orawareness. Dyscognitive is a term thathas been proposed for this concept.21

Partial evolving to secondarilygeneralized seizure (tonic,clonic, or tonic-clonic)

Simple evolving to generalizedtonic-clonic

Complex evolving to generalizedtonic-clonic (including thosewith simple partial onset)

Evolving to a bilateral, convulsiveseizure (involving tonic, clonic,or tonic and clonic components).

Generalized onset Tonic-clonic Tonic-clonic (in any combination)

Myoclonic Myoclonic

Myoclonic

Myoclonic-atonic

Myoclonic-tonic

Absence

With various accompanyingmanifestations

Atypical

Absence

Typical absence

Atypical absence

With special features

Eyelid myocloniae

Myoclonic absence

Clonic Clonic

Tonic Tonic

Atonic (astatic) Atonic

Not clear Anything that does not fit in above,eg, rhythmic eye movements,chewing, swimming movements

Epileptic spasms

a Data from Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia.3 onlinelibrary.wiley.com/doi/10.1111/j.1528-1157.1981.tb06159.x/abstract.

b Data from Data from Berg AT, et al, Epilepsia.5 onlinelibrary.wiley.com/doi/10.1111/j.1528-1167.2010.02522.x/full.c The order has been rearranged to correspond to the order in the 2010 report.d See Table 1-5 for a more complete listing of semiologic features relevant to describing any type of seizure.e Many have commented that pure eyelid myoclonia should have been considered as a myoclonic seizure and not an absence seizure.






a large number of specific diagnoses(Table 1-7).

Electroclinical syndromes are themost specific form of epilepsy diagno-sis. These are clinical entities definedon the basis of age at onset, seizuretypes, specific electroclinical patterns,and, to a varying extent, the underly-ing cause. In some instances, the cause-syndrome connection is so specific thatthere is a desire to call the syndromean epilepsy disease. In fact, understand-ing of the cause-syndrome link isbecoming increasingly complicatedas investigators report very differ-ent electroclinical syndromes asso-ciated with the same gene or lesion

type. Table 1-827Y37 provides somerecent examples. Identification of asyndrome does not preclude the im-portance of identifying a specific causeif one or more are known to be asso-ciated with the syndrome. An excellentreview of the diagnostic criteria andtypical findings in most of the well-recognized pediatric syndromes waspresented by Drs Wirrel and Nickels inthe previous issue onEpilepsy in 2010.11

In addition to the traditional genetic-developmental electroclinical syndrome,some epilepsies that are frequently re-fractory and have specific implicationsfor surgical therapy should also be

KEY POINT

h Electroclinicalsyndromes are the mostspecific form of epilepsydiagnosis. These areclinical entities definedon the basis of age atonset, seizure types,specific electroclinicalpatterns, and to avarying extent, theunderlying cause.

TABLE 1-5 Comparison of Epileptic Spasms, Myoclonic and Tonic Seizures, and a CompoundSeizure Eventa

Epileptic Spasm Myoclonic Seizure Tonic Seizure Myoclonic-Tonic Seizure

Semiology Sudden extensionof both arms andflexion of the neck

Single or multiplequick jerks ofthe body or asingle limb

Brief stiffening fora few seconds

Jerk is directly followedby a tonic stiffening ofthe limbs that lastsa few seconds

EEG Concurrenthigh-voltage,broad, diffuseslow wave withattenuation ofvoltage andoverlyinglow-voltage fastactivity; typicallyassociated with aperiod of relativedecrease ininterictalepileptiform activity

Diffuse burst ofpolymorphicspike/polyspike-and-wavedischargesfollowed byvoltage attenuation

Diffuse voltageattenuation withoverlyinglow-voltagefast activity

Diffuse burst ofpolymorphic spike/polyspike-and-wavedischarges followed byvoltage attenuation withoverriding low-voltagefast activity

EMG signature Rhomboid-shapeddischarge

Brief (usuallyG100 ms)discharge

Sustainedcontraction

Myoclonic dischargefollowed by briefattenuation and thensustained contraction

Typical examples(longitudinalbipolar montage;EMG overdeltoid muscle

Refer toFigure 1-3Afor example

Refer toFigure 1-3Bfor example

Refer toFigure 1-3Cfor example

Refer toFigure 1-3Dfor example

a These seizure types are often seen in encephalopathic forms of epilepsy presenting in infancy and early childhood.




FIGURE 1-3 Typical examples of seizure types. A, EEG of epileptic spasm; B, EEG of myoclonic seizure;C, EEG of tonic seizure; D, EEG of myoclonic-tonic seizure.



TABLE 1-6 Extended Terminology for Description of Ictal Semiology That May Be Used toDescribe Any Seizure Type Regardless of Onset, Generalized, Focal, or Unknowna

Categories forSemiologic Features

Specific Typesof Phenomena Definitions and Comments

Elementary motor phenomenainvolve movements thatare relatively elementary,unnatural, and similar tomovements elicited bycortical stimulation ofthe primary motor areas(Brodman areas 4 and 6).

Myoclonic Sudden, brief (G100 ms), involuntary, single ormultiple, irregular contraction(s) of musclesor muscle groups of variable topography (axial,proximal limb, distal).

Clonic Regularly repetitive contraction, which involvesthe same muscle groups, at a frequency of2Y3 cycles/s and is prolonged.

Tonic A sustained increase in muscle contractionlasting a few seconds to minutes. This mayinclude vibratory symptoms.

Versive A sustained, forced conjugate ocular, cephalic,and/or truncal rotation or lateral deviation fromthe midline.

Spasms A sudden flexion, extension, or mixed flexion-extension of predominantly proximal andtruncal muscle that is usually more sustainedthan a myoclonic movement, but not assustained as a tonic seizure (1Y5 s). Althougharms, legs, and trunk are most commonlyimplicated, limited forms may occur involvinggrimacing and head nodding.

Negative motor eventsare characterized bymainly ‘‘negative’’ motorsigns. Consciousness maynot be impaired or notbe assessable.

Atonic Sudden loss or diminution of muscle tonewithout apparent preceding myoclonic or tonicevent lasting Q1Y2 s involving head, trunk, jaw,or limb musculature.

Negativemyoclonic

Interruption of tonic muscular activity for G500 mswithout evidence of preceding myoclonus.

Akinetic Refers to events characterized by the inability toinitiate or maintain movements and should berestricted to patients without disturbance ofawareness.

Hypomotor/behavioral arrest

Refers to events characterized by a decrease inor total absence of motor activity (behavioralarrest). This category is reserved for patientsin whom it is not possible to test consciousnessduring or after the seizure, such as newborns,infants, or severely cognitively impairedindividuals.






(continued )


Specific Types ofPhenomena Definitions and Comments

Complex or automotorphenomena/automatismrepresent more- orless-coordinated, repetitivemotor activity usuallyoccurring when cognitionis impaired and for whichthe subject is usuallyamnesic. This oftenresembles a voluntarymovement and mayconsist of an inappropriatecontinuation of ongoingpreictal motor activity.

Oroalimentary Lip smacking, lip pursing, chewing, licking,tooth grinding, or swallowing.

Mimetic Facial expression suggesting an emotionalstate, often fear.

Manual/pedal Indicates principally distal components,bilateral or unilateral. Fumbling, tapping,manipulating movements.

Gestural Often unilateral.1. Fumbling or exploratory movements with

the hand, directed toward self or environment.

2. Movements resembling those intended tolend further emotional tone to speech.

Dacrystic Bursts of crying.

Vocal Single or repetitive utterances consistingof words, phrases, or brief sentences.

Hyperkinetic/hypermotor

1. Involves predominantly proximal limb oraxial muscles producing irregular sequentialballistic movements, such as pedaling, pelvicthrusting, thrashing, or rocking movements.

2. Increase in rate of ongoing movements orinappropriately rapid performance of amovement.

Dyscognitive is used tocharacterize events inwhich the disturbanceof awareness/responsiveness and/orcognition is the predominantor most apparent feature.

Dyscognitive eventsmay involve alteredawareness orresponsiveness,amnesia, aphasia,or delirium

Determination of the precise components of adyscognitive event may require considerableexpertise and opportunity to interact with apatient during a seizure. In the absence of suchdetailed information, events may simply becharacterized as dyscognitive without furtherqualification.

Autonomic ictal featuresrepresent symptoms dueto excessive activity of theautonomic nervous system.

Features may includegoose bumps, pallor,tachycardia, nausea,and vomiting

Apnea may be an autonomic featuredepending on the mechanisms of the apnea.

Auras are subjectivesensory or experientialfeatures.

Sensory phenomenamay include somatosensory,visual, auditory, olfactory,gustatory, or painfulsensations

Epigastric auras are reported abdominaldiscomforts including nausea, emptiness,tightness, churning, butterflies, malaise, pain,and hunger; sensation may rise to chest orthroat. Epigastric auras may sometimes reflectictal autonomic dysfunction.

Cephalic auras are sensations in the headincluding light-headedness, tingling, or headache.





(continued )


Specific Types ofPhenomena Definitions and Comments

Psychic-experiential Affective, mnemonic, or composite perceptualphenomena including illusory or compositehallucinatory events; these may appear alone orin combination. Feelings of depersonalizationare also included. These phenomena havesubjective qualities similar to those experiencedin life but are recognized by the subject asoccurring outside of actual context.

Autonomic A sensation reported by the patient that isconsistent with involvement of the autonomicnervous system, including cardiovascular,gastrointestinal, sudomotor, vasomotor, andthermoregulatory functions, eg, palpitations,chest pain, urinary urge, sexual urges, andtemperature sensations of hot or cold.

a Data from Blume WT, et al, Epilepsia,21 onlinelibrary.wiley.com/doi/10.1046/j.1528-1157.2001.22001.x/full and Schuele SU, et al, Demos.24

TABLE 1-7 Organization of the Epilepsies Proposed in 2010 According to Specificity ofEpilepsy Diagnosis and Age at Onset

Level of Epilepsy Diagnosis Epilepsy Diagnosisa

Electroclinical syndromes arrangedby typical age at onset

Neonatal period

Benign familial neonatal epilepsy2.1

Early myoclonic encephalopathy2.3

Ohtahara syndrome2.3

Hyperekplexia**b

Infancy

Epilepsy of infancy with migrating focal seizures**

West syndrome2.2

Myoclonic epilepsy in infancy2.2 c

Benign infantile epilepsy**

Benign familial infantile epilepsy**

Dravet syndrome3.1

Myoclonic encephalopathy in nonprogressive disorders**

Childhood (>1 y)

Epilepsy in females with mental retardation (can start G1 y)**

Febrile seizures plus (can start G1y)**

Panayiotopoulos syndrome**

Epilepsy with myoclonic atonic (previously astatic) seizures2.2






TABLE 1-7 Organization of the Epilepsies Proposed in 2010 According to Specificity ofEpilepsy Diagnosis and Age at Onset (continued )


Benign epilepsy with centrotemporal spikes1.1

Autosomal-dominant nocturnal frontal lobe epilepsy**

Late onset childhood occipital epilepsy (Gastaut type)1.1

Epilepsy with myoclonic absences2.2

Lennox-Gastaut syndrome2.2

Epileptic encephalopathy with continuousspike-and-waveduring sleep3.1

Landau-Kleffner syndrome3.1

Childhood absence epilepsy2.1

Adolescence to Adult

Juvenile absence epilepsy 2.1

Juvenile myoclonic epilepsy 2.1

Epilepsy with generalized tonicYclonic seizures alone2.1d

Progressive myoclonus epilepsies2.3

Autosomal dominant epilepsy with auditory features**

Other familial temporal lobe epilepsies**

Less specific age relationship

Familial focal epilepsy with variable foci (childhood to adult)**

Reflex epilepsies1.1, 1.2, 2.1

Surgical syndromes1.2 Mesial temporal lobe epilepsy with hippocampal sclerosis1.2

Rasmussen syndrome1.2

Gelastic seizures with hypothalamic hamartoma1.2

Epilepsy with structural-metaboliccauses1.2, 3.1, 3.2

Malformations of cortical development (hemimeganencephaly,heterotopias, etc)

Neurocutaneous syndromes (tuberous sclerosis complex,Sturge-Weber syndrome, etc)

Tumor

Infection

Autoimmune/inflammation

Trauma

Angioma

Perinatal insults

Hypoxic ischemic encephalopathy/intraventricular hemorrhage

Stroke

Neurometabolic conditions

Neurodegenerative conditions

Etc




recognizedVfor example, Rasmussensyndrome, gelastic seizures secondaryto hypothalamic hamartoma, and someforms of mesial temporal lobe epilepsy(Figure 1-438). These may at times bereferred to as surgical syndromes evenif surgery is not always performed.

Epilepsy syndromes and adult neu-rologists. Pediatric neurologists tend tohandle the initial diagnosis and care ofthe vast majority of patients who havediagnosable electroclinical syndromes.These syndromes are still important foradult neurologists to recognize andtreat appropriately, as many adults haveepilepsy of childhood onset. This phe-nomenon is recognized in the temporallobe surgery literature but frequentlyignored for some of the most develop-mentally disabled adults whose epilep-sy dates from infancy, such as in thecase of Dravet syndrome.39 Many, al-though not all, transitioning patientstoday are referred to an adult neurol-ogist with their diagnoses accuratelyestablished; however, many currentadult patients with long-standing epi-

lepsy did not benefit from today’simproved diagnostic capabilities whenthey were children, and their diagno-ses may now bear revisiting. In someinstances, a beneficial change in treat-ment may result.

In addition to caring for adults withchildhood-onset epilepsy, adult neu-rologists should find the electroclinicalsyndromes relevant to their practice,as some genetic syndromes and spe-cific conditions are now recognized ashaving their onset in adulthood.35,40,41

The importance of ‘‘syndromes’’ toadult practitioners will likely increasewith improvements in the availabilityand affordability of genetic testing.

In children and adolescents, approx-imately 40% to 50% of patients withepilepsy in the general population mayreceive a specific electroclinical diagno-sis. The two most common diagnosesare benign epilepsy with central tem-poral spikes and childhood absenceepilepsy, each accounting for nearly10% of pediatric epilepsy overall andapproximately 40% of childhood-onset

TABLE 1-7 Organization of the Epilepsies Proposed in 2010 According to Specificity ofEpilepsy Diagnosis and Age at Onset (continued )


Epilepsies of unknown cause No specific arrangement to these at this time; however,by presenting seizure type or age at onset would belogical1.3, 3.2

Other scenarios in which seizuresoccur but not considered epilepsy

Benign neonatal seizures4.0

Febrile seizures4.0

a The classification category in the 1989 system for each entity is indicated by the superscripts as follows:1.1Partial idiopathic1.2Partial symptomatic1.3Partial cryptogenic2.1Generalized idiopathic2.2Generalized cryptogenic/symptomatic2.3Generalized symptomatic3.1Undetermined with both focal and generalized features3.2Undetermined without clear generalized or focal features4.0Special syndromes**Not included in 1989 list of syndromes

b There is no universal agreement as to whether hyperekplexia should be considered a form of epilepsy, a movement disorder, or both.c Formerly modified by the word benign, this name was changed in 200626 because the disorder is not necessarily benign.d In the past, this syndrome was qualified as seizures on awakening only. That qualification has been removed.

KEY POINT

h Diagnosableelectroclinicalsyndromes are stillimportant for adultneurologists torecognize and treatappropriately, as manyadults have epilepsy ofchildhood onset.




TABLE 1-8 Examples of Specific Genes First Associated With One Epilepsy Syndromeand Then Found to be Associated With Very Different Epilepsy Syndromesa

Gene(Protein Function)

Associated ElectroclinicalSyndromes Brief Description of Syndrome

SCN1A (!-1 subunitof the neuronalvoltage-gated sodiumchannel)

Dravet syndrome27,28 Onset G1 y old; multiple seizure types, oftenprolonged hemiconvulsions; progressivecognitive impairment; EEG evolves fromnormalto background slowing with admixed multifocalpolyspike-wave discharges

Epilepsy in femaleswith mentalretardation29

Onset G1 y old (often G6 mo old); focal seizureswith prominent autonomic features (apnea,flushing, cyanosis); progressive cognitiveimpairment; EEG background slowing withadmixed multifocal spike-wave discharges

Generalized epilepsywith febrile seizures plus30

Onset in early childhood;mayhave febrile seizuresinitially, but continue to have fever-triggeredseizures of all types after 6 y old; developmentmay be normal, variable; EEG is normal orabnormal (generalized or multifocal)

SLC2A1(glucose-transportprotein 1)

Severe glucose transportertype 1 (GLUT1) deficiencysyndrome31

Onset in infancy; epileptic encephalopathywithmultiple seizure types; progressive cognitivedecline;movementdisorder; acquiredmicrocephaly;EEG shows background slowing withgeneralizedormultifocalspike-wavedischarges

Early-onset absence32 Onset G4 y old; refractory absence seizures;initially normal development, but may decline;EEG shows generalized spike-wave discharges

Doose syndrome33,34 Onset in early childhood; multiple seizuretypes, but predominantly myoclonic and atonicseizures; development may be normal,variable; EEG background may evolve fromnormal to diffuse background slowing;generalized polyspike-wave discharges

Nonsyndromic focal35 Epilepsies with predominantly focalelectrographic and semiologic manifestations,the features of which do not correspond toany well-delineated electroclinical syndrome;such epilepsies are occasionally found inassociation with genetic errors that themselvesare typically associated with very distinctelectroclinical syndromes

KCNQ2 (neuronalpotassium channel)

Benign familialneonatal epilepsy36

Onset at birth; multiple seizures types;development normal; interictal EEG normal

KCNQ2 encephalopathy37 Onset at birth to first weeks/months; myoclonusor brief tonic seizures as an infant, but seizuresusually well controlled by 3 y old; poorneurodevelopmental outcome; EEGbackgroundseverely abnormal with suppression-burstduring infancy and gradually evolves towardnormal after several years

a Such evidence challenges the one-gene, one-disease assumption.



epilepsy from 3 to 9 years of age. Othercommon electroclinical syndromesinclude West syndrome (accountingfor one-quarter or more of epilepsyoccurring in infancy) and juvenile myo-clonic epilepsy and juvenile absenceepilepsy (each accounting for about10% in children aged 10 to 15 years)(Figure 1-542,43).

Approximately 50% of childhood-and adolescent-onset and 90% ormore of adult-onset epilepsy patientsdo not present with a clear elec-troclinical signature. The remainingpatients have nonsyndromic presenta-

tions. In the future, their epilepsiesmay clearly fit criteria for an electro-clinical syndrome. Currently, either be-cause the syndrome has not yet beendescribed or the information availableabout the patient is limited, no elec-troclinical diagnosis has been made inthese cases.

In many patients with nonsyn-dromic epilepsy, a specific structurallesion or metabolic or inflammatorycondition can be identified. Thesealone are specific even if the epilepsypresentation (ie, age at onset, seizuretype, electrographic features) may not

FIGURE 1-4 Epilepsies secondary to a structural cause. A, Serial T2-weighted brain MRI showing changes over time inuntreated Rasmussen syndrome. Earliest abnormal MRI at 3 years 2 months of age during the acute phaseshows increased cortical signal (arrows). B, C, MRIs at 13 years 9 months in the residual phase show severe

unilateral atrophy of the entire right hemisphere with normal signal intensity. D, Brain MRI of a 10-year-old girl withpharmacoresistant epilepsy with gelastic seizures secondary to hypothalamic hamartoma. This is a T2 fast-spin echo, coronalview, and E, postcontrast T1 inversion-recovery fast-spin gradient echo, sagittal view, showing a lesion centered in the leftaspect of the hypothalamus and extending into the third ventricle (arrows). F, Brain MRI performed on a 3-Tesla scannerfor presurgical evaluation of an 11-year-old boy with pharmacoresistant epilepsy with focal seizures arising from the lefttemporal lobe. This is a T2 fast-spin echo, coronal view, showing asymmetrical volume loss of the left medial temporal lobewith hyperintensity and obscuration of the hippocampal internal architecture (arrow).

Panels A, B, and C with permission from Millichap J J, Goldstein J L, Neurology.38 B 2010, American Academy of Neurology. www.neurology.org/content/75/20/e85.full.




www.neurology.org/content/75/20/e85.full

www.neurology.org/content/75/20/e85.full

appear to be. This may be changing,however; in some circumstances, theclinical presentation is highly indica-tive of a specific underlying cause, asis the case with N-methyl-D-aspartate(NMDA) receptor autoimmunity (Case1-3, Figure 1-644). In general, treat-ment (eg, surgical decisions, use of theketogenic diet, or immunomodulatorytherapies) and patient counseling mayoften hinge on the specific cause.

In the past, these nonsyndromic con-ditions were often referred to as symp-tomatic focal or symptomatic generalizedepilepsies, depending on the semi-ologic and electrographic manifesta-tions, but this did not guide specifictreatment decisions. For nonsyn-dromic epilepsies, a brief descriptionof the cause and manifestations (eg,‘‘epilepsy secondary to focal corticaldysplasia with focal clonic seizures’’ or

FIGURE 1-5 Distribution of epilepsy diagnoses overall and by age (G3, 3Y9, and 10Y15 years). Blue shaded groups arenonsyndromic and nonspecific diagnoses. Pink shaded groups are specific syndromic diagnoses that are commonand in which the seizures are generally easily controlled and, in many cases, the epilepsy fully

resolves in time and neurodisability is not a feature associated with the epilepsy. The solid colors represent other syndromes, manyof which are pharmacoresistant and associated with moderate to severe developmental disability. The frequency of these differenttypes of epilepsy diagnoses varies considerably by age at onset. In adult-onset epilepsy, 90% to 95% of epilepsies would fall inthe blue-shaded regions.

GGE = genetic generalized epilepsy (contains other specific electroclinical syndromes but also less-specific presentations thatare considered likely part of the GGE spectrum); JME = juvenile myoclonic epilepsy; JAE = juvenile absence epilepsy; CAE =childhood absence epilepsy; BECTS = benign epilepsy with centrotemporal spikes; LKS = Landau-Kleffner syndrome; EMA =epilepsy with myoclonic absence seizures; MAE = myoclonic-atonic epilepsy; LGS = Lennox-Gastaut syndrome; Dravet = Dravetsyndrome; BFN-IS = benign familial neonatal-infantile seizures; West = West syndrome; NSE-GEN = nonsyndromic epilepsy withgeneralized features; NSE-focal-unknown = nonsyndromic epilepsy with focal features and unknown cause; NSE-foc/plus =nonsyndromic epilepsy with focal features with underlying structural metabolic condition or neuroimpairment.

Data from Berg AT, et al, Brain,42 brain.oxfordjournals.org/content/132/10/2785.full and Berg AT et al, Epilepsia.43 onlinelibrary.wiley.com/doi/10.1111/j.1528-1157.2000.tb04604.x/abstract.



brain.oxfordjournals.org/content/132/10/2785.full



Case 1-3A 15-year-old girl presented with focal seizures and personality changes.44 Initial video EEG capturedthe seizures that were clinically characterized by sitting up in bed, staring, and stiffening of thelimbs. These eventslasted up to 1 minute.Electrographically,there was a midlineand bilateralfrontal-central,low-voltage, sinusoidal,10- to 12-Hz rhythmthat evolved torhythmic-theta andthen rhythmic-deltafrequencies. As theclinical seizure continued,the amplitude of theictal pattern graduallyincreased anddischarges becamegeneralized. IVfosphenytoin initiallycontrolled the seizurescompletely. Thepatient’s conditionprogressed to periodsof agitation andconfusion alternatingwith catatonia. CSFshowed pleocytosis.AntiYN-methyl-D-aspartate (NMDA)receptor antibodieswere detected in theCSF and serum. Almost1 month after the initialpresentation, newseizures developed,clinically characterizedby bradycardia andoxygen desaturation.Video-EEG monitoringcaptured three seizureswith left-temporal onsetand associated asystole(Figure 1-644). Anovarian teratoma wasdiagnosed by pelvicultrasound and CT, andsurgical resection was

FIGURE 1-6 EEG and neuroimaging studies in a case of N-methyl-D-aspartate (NMDA)receptor antibody encephalitis with seizure-associated cardiac asystole(sensitivity: 10 2V/mm; bars = 1 s). A, Epoch of EEG recorded just after the

onset of seizure in left anterior-midtemporal region with rhythmic-theta-alpha pattern thatspread to the left frontal region. B, An EEG of the same seizure 80 seconds after onsetshowing generalized epileptiform discharges with asystole (arrow) that lasted 28 seconds.C, Sequential axial fluid-attenuated inversion recovery (FLAIR) MRIs of the brain 2 weeksafter initial presentation. Subtle increased FLAIR signal in the left posterior temporal lobecortex (arrows), with associated subtle gyral thickening is shown. Also note the mildincreased FLAIR signal in the medial temporal lobes.

Reprinted with permission from Millichap JJ, et al, Pediatrics.44 B 2011, American Academy of Pediatrics.pediatrics.aappublications.org/content/127/3/e781.full?sid=84eceb04-945a-46dc-b7a2-708bd2e8122e.

Continued on page 593




pediatrics.aappublications.org/content/127/3/e781.full?sid=84eceb04-945a-46dc-b7a2-708bd2e8122e

followed by gradual improvement in the patient’s neuropsychiatric symptoms. In addition toanticonvulsants, she was also treated with two courses of IV immunoglobulin and received apacemaker.

Comment. This patient’s presentation illustrates the typical clinical and neuroimaging findingsin anti-NMDA receptor antibody encephalitis. Ictal asystole is a rare finding in autoimmuneencephalitis (and possibly related to the origin of seizures in the left temporal lobe in this case), butcardiac dysrhythmia and other autonomic symptoms and sleep disturbances are commonplace. TheEEG findings in this case were not specific, and the diagnosis was based primarily on the specificclinical course and collection of presenting symptoms.12

TABLE 1-9 Examples of Well-Known Electroclinical Syndromes and Their Placement Withthe 1989 Classification Scheme and Their Characterization With Respectto Dimensions Recommended in the 2010 Report

DravetSyndrome

WestSyndrome

ChildhoodAbsence Epilepsy

Benign EpilepsyWith CentralTemporalSpikes

Epilepsy WithHypothalamicHamartoma

1989‘‘Classification’’category

Undeterminedwith both focaland generalizedfeatures

Generalizedsymptomaticor cryptogenic

Generalizedidiopathic

Localization-relatedidiopathic

Symptomaticfocal

Knowncauses orantecedents

SCN1A mutationor copy numbervariant in 80%of cases

Multiple Complex genetic Unknown, buthas somenonspecificgenetic influence

Geneticdevelopmentaltumor

Developmentalor cognitivedisability

Typicallymoderateto severe

Oftenmoderate tosevere

Typically normal,although learningdisorders arecommon

Typically normal,although selectivelanguage processingdisorders are common

Variable, fromnormal tosevere disability

Self-limited? No No 75%Y80% ofchildren completelyremit withoutfurther relapse

999% of childrencompletely remit

No

Responses tomedication

Pharmacoresistantin almost all cases

Variable;even whenimmediatelycontrolled,seizuresmay reoccur

Easily controlled byfirst or secondmedication in 75%of patients

Easily controlledby firstmedicationalthough oftennot treated

Variable

Surgicaloptions

Not anappropriateoption

May be highlyappropriate ifcaused byresectablestructurallesion

Resection is not anappropriate option;in very rare instancesvagus nervestimulation may beused if seizuresdo not respondto medication

Not an appropriateoption

Surgery ispreferredoption

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‘‘epilepsy with atonic seizures’’) is en-couraged, as it is clinically relevant andhas value in treatment.

For the remaining nonsyndromicepilepsies, no specific cause can be iden-tified. Although these were previouslylabeled as cryptogenic, the current rec-ommendations refer to them as epilep-sies of unknown cause, with the caveatthat unknown depends on the extentof the investigations.

‘‘Special syndromes’’ include con-ditions that do not meet standardcriteria for diagnosing epilepsy (ie,recurrent unprovoked seizures). Thisgroup includes febrile seizures in chil-dren, an isolated unprovoked sei-zure (including status epilepticus),and other seizures occurring in the im-mediate context of an acute CNS insult(eg, acute metabolic disturbance or atoxic event).

NEW TERMS AND CONCEPTSTo improve communication, additionalterms were suggested.5 While theyare somewhat informal, they also re-place the use of older terms (idio-pathic and symptomatic in particular)that had taken on connotations re-garding neurologic impairment andseizure prognosis, thus confusing causewith outcome.

Epileptic EncephalopathyThis concept is not new45 and reflectsthe clinical impression that seizures,especially in the developing brain,actually alter the course of normaldevelopment. It was carefully definedin 20105: ‘‘Ithe epileptic activity it-self may contribute to severe cognitiveand behavioral impairments aboveand beyond what might be expectedfrom the underlying pathology alone(eg, cortical malformation), and thatthese can worsen over time. Theseimpairments may be global or moreselective and they may occur along a

spectrum of severity.’’ Three impor-tant points must be assimilated:

1. The process of epilepticencephalopathy may occur along aspectrum and affect anyone atany age, although it is thoughtto be most severe and somewhatirreversible in the developing brain.

2. Many early forms of epilepsyare due to genetic/metabolicdisturbances that, independentof any seizures, may best beconstrued as genetic-developmentalencephalopathies, the severity ofwhich may be independent of orcompounded by seizures.

3. Epileptic encephalopathy refers toa process that is inferred fromobservations. The term is also usedto refer to a group of epilepsysyndromes (chief among themWest, Lennox-Gastaut, Dravet, andLandau-Kleffner syndromes, as wellas others) in which the occurrenceof seizures and disorderedelectrographic activity is thought tocontribute to the developmentaldisability commonly, although notobligatorily, seen in association withthese syndromes.

Self-LimitedThe notion that an epilepsy may or maynot resolve on its own is of great utility,especially for anticipatory guidance andongoing management decisions. Theterm does not have to be absoluteand, when information is available, canbe attached to a probability. For exam-ple, benign epilepsy with central-temporal spikes completely resolvesby late adolescence 99% or more ofthe time and is therefore virtually al-ways self-limited. Childhood absenceepilepsy is self-limited 75% to 80% ofthe time. Juvenile myoclonic epilepsyrarely if ever resolves on its own andtherefore is generally not a self-limitedform of epilepsy, although there is

KEY POINT

h Although the remainingnonsyndromic epilepsieswere previously labeledas cryptogenic, thecurrent recommendationsrefer to these asepilepsies of unknowncause, with the caveatthat unknown dependson the extent of theinvestigations.




continued debate about this.46 For non-syndromic epilepsies, the likelihood ofcomplete resolution is largely a func-tion of the presence of structural/metabolic insults, at least based on cur-rent knowledge.

Pharmacoresponsive orPharmacoresistantFrom the point of initial diagnosis, onecan predict likely response to medicationfor certain forms of epilepsy. Many of theinfantile-onset epilepsies such as Dravetsyndrome or epilepsy in females withmental retardation are unlikely to re-spond fully to any current forms oftherapy and are thus highly pharma-coresistant forms of epilepsy. By con-trast, although not self-limited, juvenilemyoclonic epilepsy is generally respon-sive to medication and usually wellcontrolled if medications are taken asrecommended.

Table 1-9 provides examples ofmany of the constructs and terms dis-cussed above, as applied to examples ofwell-known syndromic epilepsies, andcontrasts them with their classificationswithin the 1989 framework.

SUMMARYThe 2010 report has recommendedsubstantial changes to the terminologyused for describing key features ofepilepsy and seizures. No changes weremade to the specific diagnostic entities(electroclinical syndromes) that wererecognized in the 1989 report; how-ever, many more entities have beenrecognized in practice since then. Therigid and outdated classification struc-ture from 1989 was abandoned, and nospecific classification structure has re-placed it. The authors recommend thata multidimensional, flexible structurethat can accommodate any number ofspecific purposes be developed. Ulti-mately, a classification of the epilepsiesdoes not by itself improve epilepsy

care. Accurate diagnosis of the underly-ing cause, the type of epilepsy, and itsmanifestations and management arecentral to appropriate treatment andare the key factors for epilepsy care.These diagnoses can exist and be uti-lized without reference to the 1989system. Ultimately, accurate diagnosisand appropriate treatment should befacilitated, and not impeded, by anyclassification system or terminologythat is adopted by the field. This is awork in progress and will undoubtedlychange in the future.

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