Epilepsia, 47(9):1558Ð1568, 2006 Blackwell Publishing, Inc. C 2006 International League Against

Special Article Report of the ILAE Classification Core Group

Jerome Engel, Jr., Chair

Reed Neurological Research Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, U.S.A.

Summary: A Core Group of the Task Force on Classification is to present a list of types and syndromes to the ILAE and Terminology has evaluated the lists of epileptic Executive Committee for approval as testable working hypothe- and epilepsy syndromes approved by the General Assembly in ses, subject to verification, falsification, and revision. This re- Buenos Aires in 2001, and considered possible alternative sys- port represents completion of this work. If sufficient evidence tems of classification. No new classification has as yet been subsequently becomes available to disprove any hypothesis, the proposed. Because the 1981 classification of epileptic seizure seizure type or syndrome will be reevaluated and revised or dis- types, and the 1989 classification of epilepsy syndromes and carded, with Executive Committee approval. The recognition of are generally accepted and workable, they will not specific seizure types and syndromes, as well as any change be discarded unless, and until, clearly better classifications have in classification of seizure types and syndromes, therefore, will been devised, although periodic modifications to the current clas- continue to be an ongoing dynamic process. A major purpose of sifications may be suggested. At this time, however, the Core this approach is to identify research necessary to clarify remain- Group has focused on establishing scientifically rigorous cri- ing issues of uncertainty, and to pave the way for new classifica- teria for identification of specific epileptic seizure types and tions. Key Words: Epileptic — Epilepsy syndromes— specific epilepsy syndromes as unique diagnostic entities, and Classification—Terminology is considering an evidence-based approach. The short-term goal

Core Group Members ∗Although Dr. L¬uders continues to be a participating member of this working group, he does not fully agree with Jerome Engel, Jr. (Chair), Adult —Los this report and does not wish to be considered a coauthor. Angeles, CA Frederick Andermann, Child epileptologist—Montreal, The members of the Classification Core Group were Canada chosen from the Task Force on Classification and Ter- Giuliano Avanzini, Adult epileptologist—Milan, Italy minology by the ILAE Executive Committee as leaders Anne Berg, Epidemiologist—DeKalb, IL in the field of epileptology whose work has most impor- Samuel Berkovic, Adult epileptologist—Melbourne, tantly influenced the concepts of classification in recent Australia years. The group is not only representative of the major Warren Blume, Child epileptologist—London, Canada positions in the ongoing debate on classification, but also Olivier Dulac, Child epileptologist—Paris, France of the multiple professional disciplines and geographic Natalio Fejerman, Child epileptologist—Buenos Aires, regions that make up the ILAE constituency. In addition, Argentina ∗ Dr. Anne Berg was asked to join this group because of her Hans L¬uders , Adult epileptologist—Cleveland, OH background as an epidemiologist and her knowledge of the Masakazu Seino, Adult epileptologist—Shizuoka, Japan scientific process of constructing biological classification Peter Williamson, Adult epileptologist—Lebanon, NH systems. The group has met three times, first in Santa Mon- Peter Wolf, Adult epileptologist—Dianalund and ica, California, on August 25Ð27, 2003, and was joined at Copenhagen, Denmark that time by Dr. Nelson Freimer, a UCLA psychiatrist and geneticist, who has initiated the human phenome project. Accepted March 21, 2006. A second meeting was held during the American Epilepsy Address correspondence and reprint requests to Jerome Engel, Jr., Society meeting in Boston on December 7, 2003. The third Reed Neurological Research Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1769, U.S.A. E-mail: [email protected] meeting was again in Santa Monica, California, on May doi: 10.1111/j.1528-1167.2006.00215.x 27 and 28, 2005. Between meetings, deliberations have

1558 REPORT OF THE ILAE CLASSIFICATION CORE GROUP 1559 been carried out by e-mail. The work of the Task Force until, a clearly better classification has been devised, al- can be reviewed at www.epilepsy.org/ctf. though some modifications to the current classifications The purpose of these meetings was to discuss the fea- are anticipated. sibility of creating a paradigm shift in our concept of classifications in the field of epilepsy, based on the es- BASIC CONCEPTS AND PRELIMINARY tablishment of measurable objective criteria for recog- CONCLUSIONS nizing epileptic seizure types and epilepsy syndromes EPILEPTIC SEIZURES as unique diagnostic entities or natural classes that can The ILAE has recently accepted the definition of an be reproducibly distinguished from all other diagnos- epileptic seizure as “a transient occurrence of signs and/or tic entities or natural classes (1). This process differs symptoms due to abnormal excessive or synchronous neu- significantly from that used for previous classifications ronal activity in the ” (18). Epileptic seizures result of epilepsy which, although based on the extensive ex- from specific abnormal patterns of excitability and syn- perience of experts, did not include the establishment chrony among neurons in select brain areas, usually, but of explicit specific criteria and did not until recently not necessarily, involving cortex. There are many types have the capacity to move beyond signs, symptoms, and of epileptic seizures. An epileptic seizure type that rep- EEGs, and incorporate more fundamental concepts of resents a unique diagnostic entity or natural class ought pathophysiology. to be defined on the basis of a distinct pathophysiology This report represents an initial attempt to use a variety and anatomical substrate. The anatomical substrate refers of specified criteria to identify discrete epileptic seizure to specific local neuronal networks and long-tract con- types and epilepsy syndromes as diagnostic entities. An nections, but not necessarily to areas of neocortex that approach is developed to treat these diagnostic entities subserve different normal functions. For instance, focal as testable working hypotheses, subject to verification, clonic movements caused by an epileptogenic abnormality falsification, and revision. The report consists of a brief in precentral cortex are not, in any essential way, different summary of the work of the Task Force to date, followed from unformed visual hallucinations caused by the same by a discussion of the basic concepts for identification type of epileptogenic abnormality in the calcarine cortex of discrete diagnostic entities, which are then listed and if the pathophysiologic mechanisms are the same, just as described, for both epileptic seizures and epilepsy syn- electrical stimulation-induced afterdischarge of neocortex dromes. One important purpose of this report is to stim- represents the same epileptogenic mechanism, regardless ulate future study and research, not only to construct a of the area of neocortex stimulated and the behavioral more scientifically valid classification of epileptic seizure signs and symptoms elicited. types and epilepsy syndromes, but to better understand It was noted that causes of ictal phenomena are not uni- their fundamental mechanisms and design more effective tary and static, but often evolve over time. For instance, as means of diagnosis, treatment, and prevention. shown in the Fig. 1, several separate etiologies (e. g., four sodium-channel gene mutations, A, B, C, and D) could BACKGROUND ultimately give rise to the same ictal generation, either directly (solid straight line), or by altering developmen- Since its inception in 1997, the ILAE Task Force tal patterns (dotted lines), or by some circuitous unknown on Classification and Terminology set forth its goals mechanism (wavy line). In this example, examining the for reevaluating the current classifications for epilep- etiology too early (dashed line 1) could falsely increase the tic seizures and epilepsy (2) and proposed a diagnostic scheme for describing individual patients, which includes lists of generally agreed-upon epileptic seizure types and A epilepsy syndromes (3). It also published a glossary of terms to be used when describing ictal phenomena (4), and a series of essays on concepts of classification to be B considered in the process of creating a new classification system (5Ð10). Although the ILAE General Assembly ap- proved the new diagnostic scheme and the progress of the Task Force in Buenos Aires in 2001, none of the work so C far has negated the current 1981 classification of epilep- tic seizures (11) and the 1989 classification of epilepsies, D epilepsy syndromes, and related disorders (12). It was a unanimous early agreement of the group that these two 1234 current classifications are generally accepted and work- FIG. 1. Potential developmental influence of four different etiolo- able, and that they should not be discarded unless, and gies producing the same phenotype. See text for explanation.

Epilepsia, Vol. 47, No. 9, 2006 1560 J. ENGEL number of pathophysiologic mechanisms and anatomic situations. Given the prevalent usage, and the therapeutic substrates, while observing the end point (dashed line 4) implications, of the terms “focal” and “generalized,” we would give the mistaken impression that there was only have decided to retain them, with the understanding that one mechanism. Where along the causal pathway (dashed the former does not necessarily imply that the epilepto- line 2 or 3) the correct determination of the mechanisms genic region is limited to a small circumscribed area, nor should be made, however, remains unclear. does the latter imply that the entire brain is involved in The following criteria were used to select specific initiation of the epileptogenic process. Epileptic seizure seizure types as possibly unique diagnostic entities, for types are shown in Table 1. further hypothesis testing. Self-Limited Epileptic Seizure Types • Pathophysiologic mechanisms: Including electro- physiological features, neural networks, neurotrans- I. GENERALIZED ONSET mitter evidence if known (e. g., increased excitation A. Seizures with Tonic and/or Clonic Manifesta- and decreased inhibition for generalized tonicÐclonic tions and some neocortical seizures vs. increased excita- 1. TonicÐclonic seizures: involve brain stem, pos- tion and increased inhibition, leading to hypersyn- sibly prefrontal, and basal ganglia mechanisms. Ictal ini- chronization for absences and some hippocampal tiation of primarily bilateral events are predominantly dis- seizures). inhibitory, but other mechanisms are responsible for ictal • Neuronal substrates: For these purposes, the neocor- evolution to the clonic phase, involving gradual periodic tex is considered a single substrate regardless of ex- introduction of seizure-suppressing mechanisms. Several act location, unless specific pathophysiologic mech- discrete types might be identified: Future investigation is anisms differ. Other brain structures and networks needed to determine which of these types represent unique should be included (e. g., thalamic reticular nucleus phenomena. for absence seizures vs. brain stem for generalized • Reactive GTCS (acutely provoked seizures). tonicÐclonic seizures [GTCS]). • • Response to AEDs: Selective responsiveness to or ex- GTCS of idiopathic generalized epilepsies. • GTCS of symptomatic generalized epilepsies. acerbation associated with specific drugs can suggest • a specific mechanism of seizure generation. GTCS evolving from myoclonic seizures (e. g., • Ictal EEG patterns: Specific ictal EEG patterns can clonicÐtonicÐclonic seizures in Juvenile myoclonic be necessary diagnostic features of specific seizure epilepsy (JME) and epilepsy with myoclonic astatic seizures). types (e. g., 3/sec s/w for absences). These should • reflect specific pathophysiologic mechanisms and GTCS evolving from absence seizures. anatomical substrates. And several questions can be raised: • Propagation patterns and postictal features: Pat- • terns of propagation, or lack of propagation, and Do patients with idiopathic focal epilepsies have postictal features, or lack of them, help to define primarily generalized as well as secondarily gen- pathophysiologic mechanisms and anatomic sub- eralized seizures? Some data suggest that GTCS strates (e. g., typical absences have no postictal dys- in Benign childhood epilepsy with centrotemporal function; contralateral propagation is slow for hip- spikes (BCECTS) are secondarily generalized, al- pocampal seizures vs. fast for neocortical seizures; though some patients with this condition may have some seizures are strictly local, others are more primarily generalized GTCS as well. • widespread). What are clonicÐtonicÐclonic seizures? Are GTCS • Epilepsy syndrome(s): Syndromes that are associated that evolve from myoclonic seizures the only form, with this seizure type. or are there also true clonicÐtonicÐclonic seizures (as may be seen in forms of progressive myoclonus Although the dichotomy of focal (partial) versus gen- epilepsy [PME])? eralized has been criticized, and we have recommended • How should we regard hemi-generalized seizures that in an earlier report that these terms should eventually be manifest unilaterally in the immature brain owing to discarded because no seizures or syndromes are truly gen- poor myelinization of the corpus callosum? In this eralized, nor is it likely that many, if any, seizures or syn- case, the disorder is bilateral, but the onset is clearly dromes are due to a discretely focal epileptogenic process, unilateral. Do these only occur in infants, or do they the Core Group has recognized the value of distinguishing also occur in children and adults? In some infants, epileptic seizures that begin in a part of one hemisphere, hemi-generalized seizures have focal onset. from those that appear to begin in both hemispheres at the same time. The Core Group, however, has been un- Some experimental evidence suggests that the mecha- able to come up with simple terms to describe these two nisms of ictal initiation could be different for some or even

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TABLE 1. Seizure types sents the phasing in of seizure-suppressing mechanisms, whereas in clonic seizures, the repetitive discharges ap- Self-limited epileptic seizures I. Generalized onset pear to be due primarily to rhythmic excitatory discharges. A. Seizures with tonic and/or clonic manifestations There may be several types of generalized clonic seizures. 1. Tonic-clonic seizures 3. Tonic seizures: The mechanism of tonic 2. Clonic seizures 3. Tonic seizures seizures is probably not the same as that of the tonic phase B. Absences of GTCS. Generalized tonic seizures typically occur in 1.Typical absences LennoxÐGastaut syndrome and occasionally in epilepsy 2. Atypical absences 3. Myoclonic absences with myoclonic astatic seizures. C. Myoclonic seizure types B. Absences 1. Myoclonic seizures 1. Typical absences: Although the pyknoleptic 2. Myoclonic astatic seizures 3. Eyelid myoclonia manifestations of typical absences in Childhood absence D. epilepsy (CAE) have been suggested to differ by shorter E. Atonic seizures duration from the longer-duration, less-frequent absences II. Focal onset (partial) A. Local of Juvenile absence epilepsy (JAE), based on what we cur- 1. Neocortical rently know, it seems likely that they do not represent two a. Without local spread mechanisms, but merely the evolution of a single mech- i Focal clonic seizures ii Focal myoclonic seizures anism as the brain matures. Phantom absences also are iii Inhibitory motor seizures likely to be a result of brain maturation. A working group iv Focal sensory seizures with elementary symptoms will be convened to study whether absences of CAE and v Aphasic seizures b. With local spread JAE represent two seizure types or a spectrum of the same i Jacksonian march seizures seizure type, and to better define associated motor com- ii Focal (asymmetrical) tonic seizures ponents. iii Focal sensory seizures with experiential symptoms 2. Hippocampal and parahippocampal 2. Atypical absences: There are variable manifes- B. With ipsilateral propagation to: tations of this ictal event, some involving hypotonia and 1. Neocortical areas (includes hemiclonic seizures) atonia. Better criteria for characterizing atypical absences 2. Limbic areas (includes gelastic seizures) C. With contralateral spread to: will also be discussed by the working group on atonic 1. Neocortical areas (hyperkinetic seizures) seizures. 2. Limbic areas (dyscognitive seizures with or 3. Myoclonic absences: The myoclonic compo- without automatisms [psychomotor]) 1 1 D. Secondarily generalized nents of these seizures are rhythmic (2 2 Ð4 2 Hz) clonic 1. Tonic-clonic seizures rather than myoclonic and have a tonic component. The 2. Absence seizures seizure type should be called something else, but there is 3. Epileptic spasms (unverified) III. Neonatal seizures no agreement on another name at this time. C. Myoclonic Seizures Types I. Epilepsia partialis continua (EPC) 1. Myoclonic seizures: The distinction between A. As occurs with Rasmussen syndrome B. As occurs with focal lesions myoclonic seizures and clonic seizures is not clear. Clas- C. As a component of inborn errors of metabolism sically, clonic seizures are rapid rhythmically recurrent II. Supplementary motor area (SMA) status epilepticus events, whereas myoclonic seizures are single, or irregu- III. continua IV. Dyscognitive focal (psychomotor, complex partial) larly recurrent events. The prototype of generalized my- status epilepticus oclonic seizures are those occurring with JME. These are A. Mesial temporal typically bilateral and symmetrical, but localized reflex B. Neocortical V. Tonic-clonic status epilepticus myoclonus can also occur. The slowly rhythmic events VI. Absence status epilepticus of Subacute sclerosing panencephalitis (SSPE) used to A. Typical and atypical absence status epilepticus be considered epileptic myoclonus but are more accu- B. Myoclonic absence status epilepticus VII. Myoclonic status epilepticus rately epileptic spasms; those with biPEDs (bilaterally VIII. Tonic status epilepticus synchronous PLEDs) in comatose patients also are not IX. Subtle status epilepticus necessarily epileptic, and their cause is usually not clearly defined. Differential diagnosis between myoclonic and all of these subtypes of GTCS, and that there may even be clonic seizures can be difficult because a single jerk can more than one mechanism of initiation within each of the be a fragment of a clonic seizure. subtypes. Working groups will be convened to specifically eval- 2. Clonic seizures: Clonic seizures are fast rhyth- uate myoclonic epileptic phenomena, including nega- mic events (1Ð2 Hz), associated, or not, with impaired tive myoclonus and atonic seizures, compare them with consciousness. Mechanisms are different from those of the nonepileptic myoclonic phenomena, and develop uniform clonic phase of GTCS. In the latter, the clonic phase repre- criteria and terminology for these diagnoses.

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2. Myoclonic astatic seizures: These seizures oc- initiation, which may not be absolutely correlated cur typically in epilepsy with myoclonic astatic seizures. with location, and there may be other ictal onset pat- There is a question as to whether the astatic component is terns indicative of other initiating mechanisms that an atonic seizure. have not yet been well described. 3. Eyelid myoclonia: The degree to which these • Location, not with respect to differences in ictal semi- recurrent events (5Ð6 Hz) are associated with impairment ology that reflect differences in the normal func- of consciousness has not been adequately documented, tion of cortex, but to differences in neurophysiologic and should be. In some patients, they can be provoked by properties and anatomical connections unique to spe- eye closure. The seizure type, however, does exist as a cific areas of cortex, for example, those that cause unique entity. brief and clustered seizures with little or no postic- D. Epileptic Spasms: The mechanism of epileptic tal disturbances and nocturnal predilection typical spasms is unknown. The semiology and pathophysiology of some frontal areas, as compared to longer, less- of epileptic spasms in the more mature brain need to be frequent events with profound postictal disturbances better defined. in other areas, and those that cause fast distant prop- E. Atonic Seizures: A number of seizure types in- agation from some areas and localized, slower prop- volve an atonic component, some of which may be vari- agation in others. ants of atypical absences, others of which can have an initial brief tonic or myoclonic component. When these Factors influencing seizure-induced progressive distur- events are very short, they have been referred to as negative bances in neuronal function and structure at the site of, myoclonus. A working group will be convened to review and downstream from, ictal onset. videotapes of various types of atonic seizures, and to de- A. Local velop criteria to distinguish between negative myoclonus, 1. Neocortical atonic seizures, and perhaps some atypical absences. a. Without local spread i Focal clonic seizures are brief focal mo- tor events that are distinguished from focal myoclonic II. FOCAL ONSET seizures by their rhythmic repetition. Localization to the The anatomical substrates of a substantial number of primary motor cortex is implied. manifestations have now been sufficiently ii Focal myoclonic seizures most likely con- established to include this information in their description. sist of many types. These events, including multifocal my- Because focal seizures represent dynamic events that usu- oclonus, will be discussed by the working group on my- ally involve propagation, and clinical manifestations can oclonus. There is no unanimity of opinion as to whether reflect discharges at the site of ictal onset, and/or sites of the myoclonic events in PME which have no EEG corre- propagation, the organization of focal seizures here takes late are epileptic. At least in Lafora, there is evidence to into account the various patterns of ictal propagation. In suggest a cortical site of initiation. addition, a number of factors will need to be investigated in iii Inhibitory motor seizures are not a unique order to develop more definitive criteria for distinguishing seizure type. The clinical manifestation merely represents between different types of focal seizures. These include: the function of the involved cortex, just as focal mo- • Factors that might distinguish between focal seizures tor seizures and unformed visual hallucinations reflect due to discretely localized lesions, as occur with fo- seizures in precentral gyrus and calcarine cortex. cal symptomatic epilepsy, and focal seizures due to iv Focal sensory seizures with elementary more distributed network disturbances, as might oc- (visual, somatosensory, vestibular, olfactory, gustatory, or cur with some focal idiopathic epilepsies (e. g., those auditory) symptoms manifest themselves as a variety of responsible for the transverse dipole of BCECTS), or sensory phenomena that can be produced by activation of even in idiopathic generalized epilepsies. primary sensory cortices. • Maturational factors. v Aphasic seizures can consist of inability • Modes of precipitation, as in reflex seizures. to speak when Broca’s area is principally involved, or • Pathology, that is, focal seizures due to various mal- more complex disturbances of speech production or re- formations of cortical development may be different ception when other language cortical areas are principally from each other and from those due to other lesions. involved. • Pathophysiologic mechanisms, for example, hyper- b. With local spread synchronous ictal onsets, which most commonly oc- i Jacksonian march seizures refers to the cur in hippocampus, versus low voltage fast ictal clinical manifestations of the slow ephaptic propagation of onsets, which most commonly occur in neocortex. epileptic discharge along the motor cortex, although sim- These electrophysiological features clearly reflect ilar progression can sometimes be seen in other primary different pathophysiologic mechanisms of seizure cortical areas as well.

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ii Focal (asymmetric) tonic seizures can be D. Secondarily Generalized associated with seizure origin from practically anywhere 1. TonicÐclonicseizures that are secondarily gener- in the neocortex. In their purest form, focal tonic seizures alized probably consist of multiple types and may involve are seen in the explosive motor seizures of supplementary different pathophysiologic mechanisms and anatomical motor area origin. substrates, at least initially, than generalized tonicÐclonic iii Focal sensory seizures with experiential seizures with generalized onset. symptoms are those with complex, usually formed, dis- 2. Absence seizures can rarely represent propaga- torted and/or multimodal, sensory symptoms implying tion from localized cortical areas, usually in the frontal seizure initiation in association cortices, such as the lobe. There may be a continuum between these events and temporo-parieto-occipital junction, with connections to generalized atypical absences. multiple sensory areas. 3. Although epileptic spasms can occur in infants 2. Hippocampal and parahippocampal seizures with focal lesions, the mechanism by which these gener- almost always require local spread for clinical manifes- alized events are generated is unknown. tation, which may involve insula, amygdala, hypothala- III. NEONATAL SEIZURES mus, and other limbic structures. Autonomic features such Neonatal seizures: Although the components of neona- as a sensation of epigastric rising is common, as well tal seizures can be described in terms of the seizure types as emotional experiences such as fear, dysmnesias, fo- itemized above, they often display unique organizational cal sensory seizures with olfactory or gustatory symp- features. Therefore, a study group will be created to more toms, and vague bilateral sensory phenomena such as completely define and characterize the various types of tingling. neonatal seizures. B. With Ipsilateral Propagation to: Status Epilepticus 1. Neocortical areas Mechanistically, status epilepticus represents the fail- a. Same manifestations as II. A.1. a. and b. ure of the natural homeostatic seizure-suppressing mech- b. Hemiclonic seizures occur early in the de- anisms responsible for seizure termination (14). Although velopment before myelinization of the corpus callosum an operational definition of status epilepticus has been and do not necessarily have localizing value. They can proposed (15,16) and is in common use in the clinical and alternately affect both hemispheres, as in epidemiological literature, it does not adequately reflect and ischemic encephalopathy, or only one hemisphere in the underlying mechanisms involved in status epilepticus, the case of focal disturbances. nor is it always useful for clinical purposes (17). Regard- 2. Limbic areas less of the specific operationalized definition, however, a. Same manifestations as II. A.2. the mechanisms involved in initiation and spread of the b. Gelastic seizures are clearly unique ictal various types of status epilepticus are, in general, similar events when they are initiated in relation to structural ab- to those of self-limited ictal events, but additional factors normalities of the hypothalamus, which are usually hamar- that need to be considered in determining criteria for clas- tomas. The mechanism is unknown, but initiation, at least, sification include: is distinct from gelastic seizures arising from other areas, • such as mesial temporal lobe and cingulate. Different mechanisms that can prevent seizure termi- C. With Contralateral Spread to: nation, for example, mechanisms that prevent active 1. Neocortical areas. Hyperkinetic seizures, also inhibition, desynchronization of hypersynchronous referred to by some as hypermotor seizures, involve bilat- discharges, and depolarization block. • eral forceful limb movements, sometimes with vocaliza- Progressive features that contribute to subsequent tions. Frontal lobes are implicated in these behaviors. functional and structural brain disturbances. • 2. Limbic areas. Dyscognitive seizures with or Maturational factors. without automatisms (psychomotor) are not exactly syn- I. EPILEPSIA PARTIALIS CONTINUA (EPC) OF KO- onymous with the current term “complex partial seizures,” JEVNIKOV which were defined on the basis of impaired conscious- This is a combination of focal seizures with continuous ness only and do not necessarily involve limbic areas. This twitching in the same area. The clinical and EEG features new term, as well as the term “psychomotor,” conforms permit distinction of three conditions that correlate with more to the original intent of the term “complex partial etiology. seizures” in the 1970 ILAE Classification of Epileptic A. As Occurs with Rasmussen Syndrome. EPC in Seizures (13). It is implied that mesial temporal limbic this subacute lateralized encephalitis of unknown cause areas and their immediate connections are involved in the (half the cases show the clinical expression of this en- clinical manifestations, although seizures may have been cephalitis) combines focal myoclonus and focal seizures initiated elsewhere. affecting various areas of the same hemisphere, with or

Epilepsia, Vol. 47, No. 9, 2006 1564 J. ENGEL without clear EEG correlation of the myoclonic jerks, and gin. For example, occipital status epilepticus might present at times persistence of the jerks in sleep. There is pro- with unexplained blindness while dysphasia or aphasia gressive slowing of the background EEG activity on the could represent focal status in language cortex. affected side. B. As Occurs with Focal Lesions. Various dysplastic, V. TONICÐCLONIC STATUS EPILEPTICUS: vascular, or tumor lesions produce EPC lasting a few days, Generalized tonicÐclonic status epilepticus can be an weeks, or months before the patient returns to baseline. acute symptomatic event; it can be primarily general- EPC is also seen with nonketotic hyperglycemia. The jerks ized in idiopathic and symptomatic generalized epilep- affect the same area as the focal seizures, and have an EEG sies; and it is commonly secondarily generalized from correlate; they do not persist in sleep. focal epilepsies. Occasionally, the manifestations can be C. As a Component of Inborn Errors of Metabolism. unilateral. Various conditions affecting energy metabolism, namely, VI. ABSENCE STATUS EPILEPTICUS Alpers disease or Myoclonus epilepsy with ragged-red A. Typical and Atypical Absence Status Epilep- fibers (MERRF), produce uni- and then bilateral rhythmic ticus: When absence status epilepticus occurs in the id- jerks that persist in sleep, with EEG correlates. iopathic epilepsies, it has features similar to atypical ab- II. SUPPLEMENTARY MOTOR AREA (SMA) STA- sence and can be terminated by antiepileptic drugs. In the TUS EPILEPTICUS: generalized symptomatic epilepsies, there is overlap with Frequently repeated seizures from the SMA usually focal status epilepticus due to lesions of certain frontal present as a type of focal status epilepticus with preserved lobe areas. The absence status epilepticus occurring in consciousness and individual tonic motor seizures occur- elderly patients without a prior history of epilepsy, as ring every few minutes all night long. Another type of well as drug-induced and drug-withdrawal absence status SMA status epilepticus consists of secondarily general- epilepticus, have been characterized and most likely rep- ized seizures that evolve into repetitive asymmetrical tonic resent similar mechanisms; however, there may be several motor seizures with profound impairment of conscious- different types of typical and/or atypical absence status ness. epilepticus. III. AURA CONTINUA B. Myoclonic Absence Status Epilepticus: My- Aura continua is a rare but well-described manifesta- oclonic absence status epilepticus consists of proximal, tion of focal epilepsy. The symptoms depend on the lo- predominantly upper extremity myoclonic jerks corre- calization. The attacks are usually without impairment of sponding with 3 Hz spike-wave discharges in the EEG. consciousness. The symptoms wax and wane, often for It can last hours or even days and is usually very resistant hours, and may be associated with a motor component, to therapy. depending on the spread. Dysesthesia, painful sensations, VII. MYOCLONIC STATUS EPILEPTICUS and visual changes are examples. Limbic aura continua is Myoclonic status epilepticus consists of irregular, usu- the most common clinical pattern. Fear, an epigastric ris- ally bilateral or generalized myoclonic jerking without ing sensation, or other features may recur every few min- interference with consciousness. Duration may be up to utes for many hours, or more than a day without going on hours. It is most often seen in patients with insufficiently to seizures with impairment of awareness. Electrographic controlled JME, Dravet syndrome, and in nonprogres- correlation is variable. Diagnosis must be entertained, par- sive in infancy, particularly Angelman ticularly in patients with well-established epilepsy. syndrome. In myoclonic-astatic epilepsy, it predominates in the extremities of the upper limbs and around the mouth, IV. DYSCOGNITIVE FOCAL (PSYCHOMOTOR, the areas most represented in the precentral gyrus. COMPLEX PARTIAL) STATUS EPILEPTICUS A. Mesial Temporal: Focal status epilepticus pre- VIII. TONIC STATUS EPILEPTICUS dominantly involving mesial limbic structures consists of Tonic status epilepticus most commonly occurs in pa- serial dyscognitive focal ictal events without return of tients with symptomatic , but may clear consciousness in-between. Onset can be limited to occur in patients with idiopathic generalized epilepsy. one side, or can alternate between hemispheres. In some of these patients, there appears to be an over- B. Neocortical: Focal status epilepticus originat- lap of symptoms of idiopathic and symptomatic general- ing in various neocortical regions can present with a wide ized epilepsy. Characteristically, when the patient is lying variety of unpredictable clinical patterns. Status epilepti- down, the neck is flexed, and the arms are flexed at the el- cus from some frontal foci can resemble absence status or bow and slightly elevated. The tonic spasms are brief and generalized tonicÐclonic status. It can present as repetitive can continue at brief intervals for hours. In symptomatic discrete behavioral seizures. To some extent, this type of generalized epilepsy the duration of the status epilepticus status epilepticus can reflect the neocortical region of ori- can be much longer.

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IX. SUBTLE STATUS EPILEPTICUS pathic categories.” It is beyond the scope of this report to This has become an accepted concept, although its debate whether the term “cryptogenic” should be limited accurate diagnosis is often controversial. It refers to an to conditions that are probably symptomatic, as originally end stage of prolonged generalized tonicÐclonic status intended, to all conditions with unknown etiology, as it is epilepticus characterized by focal or multifocal myoclonic currently used by epidemiologists, or remain unclarified. movements, coma, and pseudoperiodic lateralized epilep- In any event, it was decided not to use the term “crypto- tiform discharges (PLEDs) against a slow low-voltage genic” in relation to any of the identified syndromes listed background on EEG. The myoclonic movements reflect here. severe brain damage caused by prolonged status epilepti- Now that it is becoming increasingly possible to inves- cus and may not be epileptic in nature. tigate the suppositions that form the basis of individual syndrome definitions, it is important that we use the best EPILEPSY available scientific evidence to construct clinical entities There are operational (16) and conceptual (18) defini- that are as homogeneous and biologically relevant as pos- tions of epilepsy endorsed by the ILAE. In general, the sible. The epilepsy syndromes approved by the General diagnosis of epilepsy implies a persistent epileptogenic Assembly in 2001, therefore, were evaluated according to abnormality of the brain that is able to spontaneously gen- the following criteria: erate paroxysmal activity. This is in contrast to a brain that • Epileptic seizure type(s): This includes seizure has an acute seizure as a natural response to a transient in- type(s) that i) must occur in order to diagnose a syn- sult or loss of homeostasis. The epilepsies and syndromes drome, ii) occur but are not necessary for diagnosis, listed here presume the existence of an intrinsic epilepto- and/or iii) would preclude a diagnosis of this syn- genic abnormality that is a property of the brain itself and drome. present between seizures, independent of any acute insult • Age of onset: Is there a distinctive range for age of or condition. This property may be responsible for seizures onset for taxonomic purposes and, if so, how strictly during a relatively short period of time (as in many of the should this range be applied for diagnostic purposes? age-dependent idiopathic epilepsies) or for many years or • Progressive nature (i.e., epileptic encephalopathy): even throughout an individual’s lifetime. Evidence that suggests or supports the notion that An epilepsy syndrome was defined in an earlier report there is an epilepsy-dependent neurodevelopmental of this Task Force (3) as “a complex of signs and symptoms or neurodegenerative process involved in the evolu- that define a unique epileptic condition. This must involve tion of the syndrome (as opposed to an underlying more than just a seizure type: thus frontal lobe seizures per metabolic, degenerative, or encephalitic process). se, for instance, do not constitute a syndrome.” Epilepsy • Interictal EEG: EEG findings that i) must be observed syndromes were distinguished from epileptic diseases, in order to diagnose the syndrome, ii) may be ob- which were defined as “a pathologic condition with a served in some cases; and iii) if observed, preclude single, specific, well-defined etiology.” Thus, the term diagnosis of the syndrome. PME would designate a syndrome, but Unverricht- • Associated interictal signs and symptoms (partic- Lundborg is a disease. Epilepsy syndromes may be symp- ularly neurological and neuropsychological status tomatic when they result from one or more identifi- and deficits). It is important to distinguish between able pathological disturbances in cerebral structure or deficits that are due to the cause of the epilepsy, those metabolism, or idiopathic when no such underlying dis- that are due to pharmacotherapy, and those that are turbance exists and the primary etiology is believed to be due to the epilepsy itself (epileptic encephalopathy). genetic. Unfortunately, this can be difficult and many epilep- Not all syndromes can be easily classified as either focal tic encephalopathies remain theoretical. or generalized or as either symptomatic or idiopathic, and • Pathophysiologic mechanisms, anatomical sub- there is no need to do so. These terms are used here with re- strates, and etiological categories: Permanent distur- spect to specific syndromes only when they have historical bances that characterize the syndrome (i.e., general- or clinical value. The term “cryptogenic” is avoided here ized brain damage vs. localized brain damage vs. no because of ambiguities in its definition and use. The term brain damage). Genetic diseases that cause epilepsy was introduced in the 1989 classification (12) to define and susceptibility genes can also be included. conditions where the cause of the disorder is “hidden or • Genetic basis: This consists of specific genetic mech- occult.” It is specifically stated that “cryptogenic epilep- anisms that have been implicated and differentiate a sies are presumed to be symptomatic, but the etiology is syndrome from all other syndromes, but do not con- not known.” The 1993 report of the ILAE Commission stitute diseases. on Epidemiology and Prognosis, however, stated that the group of cryptogenic epilepsies “includes patients who The epilepsy syndromes listed in Table 2 were individ- do not conform to the criteria for the symptomatic or idio- ually discussed by the Core Group and rated on a score of

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TABLE 2. Epilepsy syndromes by age of onset and related INFANCY conditions Migrating Partial Seizures of Infancy: (3) This has Neonatal period been sufficiently described by several independent inves- Benign familial neonatal seizures (BFNS) tigators to merit recognition as a syndrome. Early myoclonic encephalopathy (EME) West Syndrome: (3) This is a clearly defined syndrome Infancy based on specific clinical features and age of onset. Migrating partial seizures of infancy Myoclonic Epilepsy in Infancy (MEI): (3) Because West syndrome this is not benign in some infants, the word “benign” Myoclonic epilepsy in infancy (MEI) Benign infantile seizures was removed from the name. It was initially introduced to Dravet syndrome distinguish it from Severe myoclonic epilepsy in infancy Myoclonic encephalopathy in nonprogressive disorders (SMEI), which is now called Dravet syndrome. Seizures Childhood Early onset benign childhood occipital epilepsy may occasionally be reflex (i.e., touch). (Panayiotopoulos type) Benign Infantile Seizures: (3). Whereas BFNS and Be- Epilepsy with myoclonic astatic seizures nign (nonfamilial) neonatal seizures clearly represent two Benign childhood epilepsy with centrotemporal spikes (BCECTS) Late onset childhood occipital epilepsy (Gastaut type) distinct syndromes because of differences in seizure type Epilepsy with myoclonic absences and age of onset, the familial and nonfamilial forms of Be- Lennox-Gastaut syndrome (LGS) nign infantile seizures are identical except for the family Epileptic encephalopathy with continuous spike-and-wave during sleep (CSWS) including Landau-Kleffner syndrome (LKS) history. Consequently, the sporadic form cannot be con- Childhood absence epilepsy (CAE) sidered a separate syndrome, and both should be combined Adolescence into a single syndrome, unless subsequent information in- Juvenile absence epilepsy (JAE) Juvenile myoclonic epilepsy (JME) dicates otherwise. Progressive myoclonus epilepsies (PME) Dravet Syndrome: (3) Because many of these children Less Specific Age Relationship do not have myoclonic components to their characteris- Autosomal-dominant nocturnal (ADNFLE) Familial temporal lobe epilepsies tic seizures in infancy, it cannot be called SMEI, and we Mesial with hippocampal should retain the eponym. sclerosis (MTLE with HS) Myoclonic Encephalopathy in Nonprogressive Disor- Rasmussen syndrome Gelastic seizures with hypothalamic hamartoma ders: (3) There is sufficient evidence to support this as Special epilepsy conditions a syndrome. It is important as a form of epileptic en- Symptomatic focal epilepsies not otherwise specified cephalopathy. Epilepsy with generalized tonic-clonic seizures only Reflex epilepsies Febrile seizures plus (FS+) CHILDHOOD Familial focal epilepsy with variable foci Early Onset Benign Childhood Occipital Epilepsy Conditions with epileptic seizures that do not require a diagnosis of epilepsy (Panayiotopoulos Type): (3) The consistency of localiza- Benign neonatal seizures (BNS) tion remains controversial in this syndrome. Febrile seizures (FS) Epilepsy with Myoclonic Astatic Seizures: (3) This syndrome is now well defined but the course is variable. 1Ð3 (3 being the most clearly and reproducibly defined) re- Many are epileptic encephalopathies. garding the certainty with which the group believed each Benign Childhood Epilepsy with Centrotemporal syndrome represented a unique diagnostic entity. These Spikes (BCECTS): (3) This condition also is not always be- ratings are informal and should be considered very pre- nign, although nonbenign forms occur in only a small per- liminary pending the development of firm criteria. Crite- centage of patients, and may represent related conditions. ria for syndrome identification continue to be improved Late Onset Childhood Occipital Epilepsy (Gastaut and the syndromes are being reanalyzed in more detail. Type): (1) There was concern because this condition is This process could involve an evidence-based approach rare and there has been a paucity of recent confirmatory requiring formal review and systematic evaluation of the reports. More data are needed. published literature. Epilepsy with Myoclonic Absences: (2) This syndrome needs further study in the context of the work to be done Epilepsy Syndromes and Related Conditions on myoclonic seizures. NEONATAL PERIOD LennoxÐGastaut Syndrome (LGS): (3) This syndrome Benign Familial Neonatal Seizures (BFNS): (3) This is clearly defined by clinical and EEG features and by age may be a disease and not a syndrome. of onset. Early Myoclonic Encephalopathy (EME): (3) Al- Epileptic Encephalopathy with Continuous Spike- though this may be different from Ohtahara syndrome, and-Wave During Sleep (CSWS) Including Landau- the clinical distinction can be difficult. Kleffner Syndrome (LKS): (3) It was decided that there is Ohtahara Syndrome: (3) See above. insufficient evidence for mechanistic differences between

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LKS and CSWS to warrant considering them separate syn- iologic disturbance, if known, and the location of the le- dromes. It is unknown whether these conditions are idio- sion(s), if they do not fit into a described syndrome. pathic, symptomatic, or both. Epilepsy with Generalized TonicÐClonic Seizures only Childhood Absence Epilepsy (CAE): (3) Further de- is not a syndrome, and the Core Group was unable to liberation and research will be needed to clarify the dis- agree on any syndrome with this feature: The consistent tinction between this syndrome and JAE, and to define diurnal pattern of seizures in some patients needs further the relationship of this syndrome to the other idiopathic investigation. Whether epilepsy with generalized tonicÐ generalized epilepsies such as JME. clonic seizures on awakening exists as a distinct entity is unclear. ADOLESCENCE Reflex Epilepsies: Although Idiopathic photosensitive Juvenile Absence Epilepsy (JAE): (3) See above. occipital lobe epilepsy (2), Primary reading epilepsy (3) Juvenile Myoclonic Epilepsy (JME): (3) See above. and Hot water epilepsy in infants (2) are syndromes, it is Progressive Myoclonus Epilepsies (PME): (3) This unclear whether other reflex epilepsies constitute unique group is different from the others in that it consists en- syndromes. tirely of specific diseases, and might be considered under Febrile Seizures Plus (FS+): This is a condition that diseases with epilepsy rather than epilepsy syndromes. is part of the familial syndrome known as GEFS+. The However, because it is a very helpful concept for diag- latter is broader than a single generalized syndrome and nostic purposes when it is not possible to reach a more may be a useful category for future classifications. specific diagnosis, it is still included in this list. Familial Focal Epilepsy with Variable Foci: (3) This syndrome cannot be diagnosed in a single individual. LESS SPECIFIC AGE RELATIONSHIP Recognition depends on the occurrence within a family of Autosomal-Dominant Nocturnal Frontal Lobe individuals with different seizure patterns (commonly Epilepsy (ADNFLE): (3) All affected family members temporal or nocturnal frontal); each individual has a single have nocturnal frontal lobe seizures. In some families, seizure pattern. mutations in neuronal nicotinic acetylcholine receptor genes are found, but in many families the genetic etiology CONDITIONS WITH EPILEPTIC SEIZURES THAT DO is unknown. NOT REQUIRE A DIAGNOSIS OF EPILEPSY Familial Temporal Lobe Epilepsies: (3) There are a The reasons for not considering some syndromes to be number of forms that are being defined. Division into epilepsy seem to be more political than scientific. Two lateral and mesial temporal types based on the predom- syndromes exist in this group. inant seizure semiology is useful. The lateral temporal Benign Neonatal Seizures (BNS): (2) These are self- type (also known as Autosomal-dominant partial epilepsy limited events without sequelae. with auditory features) is associated with mutations in the Febrile Seizures (FS): (3) Classically, the seizures that LGI1 gene in about half the families. The mesial group constitute this condition consist of two forms: simple and is heterogenous within and between families in terms of complex; however, many different types undoubtedly ex- epilepsy severity, association with febrile seizures and ist. This condition may eventually be understood to en- presence of hippocampal sclerosis. compass many different entities. Mesial Temporal Lobe Epilepsy with Hippocampal The Core Group is not prepared to recommend a new Sclerosis (MTLE with HS): (2) This condition probably classification of epilepsies and epilepsy syndromes to re- consists of more than one syndrome, and it is not certain place the current classification (12); however, it was de- whether features of patients with HS clearly differentiate cided that a number of axes would be much more accurate them from those with other mesial temporal lesions. and useful than the current dichotomies of idiopathic ver- Rasmussen Syndrome: (3) There continues to be a sus symptomatic, and localization-related versus general- question as to whether this is best characterized as a syn- ized. When adequate data are obtained regarding the ac- drome or a disease; that is, whether there may be multiple cepted epilepsy syndromes, multivariate approaches could etiologies for this inflammatory process. be used to construct an organization of syndromes, with Gelastic Seizures with Hypothalamic Hamartoma: (3) This may be a disease and not a syndrome. TABLE 3. Categories that might be considered in future classification systems SPECIAL EPILEPSY CONDITIONS Symptomatic Focal Epilepsies not Otherwise Speci- Autosomal dominant epilepsies Epileptic encephalopathies fied: Disorders due to epileptogenic lesions that are local- GEFS+ ized, diffuse but limited to one hemisphere, or multifocal Idiopathic generalized epilepsies do not constitute syndromes per se, but can be defined Idiopathic focal epilepsies Reflex epilepsies according to the seizure type, the underlying pathophys-

Epilepsia, Vol. 47, No. 9, 2006 1568 J. ENGEL the recognition that some syndromes may be represented 7. Engel, J Jr. Reply to “Of cabbages and kings: some considerations in more than one grouping, while other syndromes may fit on classifications, diagnostic schemes, semiology, and concepts.” Epilepsia 2003;44:4Ð6. in none of the groupings. The syndromes have been listed 8. L¬uders H, Najm I, Wyllie E. Reply to “Of cabbages and kings: some here by age only, in lieu of a more detailed approach to considerations on classifications, diagnostic schemes, semiology, syndrome classification or categorization. Possible cat- and concepts.” Epilepsia 2003;44:6Ð8. 9. Berg AT, Blackstone NW. Of cabbages and kings: perspectives on egorizations would involve the recognition that clusters classification from the field of systematics. Epilepsia 2003;44:8Ð12. of syndromes have certain commonalities. Considerations 10. Avanzini G. Of cabbages and kings: do we really need a systematic in this regard could include the items listed in Table 3. classification of epilepsies? Epilepsia 2003;44:12Ð3. 11. Commission on Classification and Terminology of the International We caution, however, that these should not be interpreted League Against Epilepsy. Proposal for revised clinical and elec- as a new classification but, rather, suggestions for future troencephalographic classification of epileptic seizures. Epilepsia work to develop a new classification or modify the current 1981;22:489Ð501. 12. Commission on Classification and Terminology of the Interna- one. tional League Against Epilepsy. Proposal for revised classifica- tion of epilepsies and epileptic syndromes. Epilepsia 1989;30:389Ð REFERENCES 99. 13. Gastaut H. Clinical and electroencephalographical classification of 1. Ax P. Multicellular animals: a new approach to the phylogenetic epileptic seizures. Epilepsia 1970;11:102Ð13. order of nature. Berlin: Springer-Verlag, 1996, pp. 9Ð21. 14. Wasterlain CG, Treiman DM, Eds. Status epilepticus: mechanisms 2. Engel J Jr. Classifications of the International League Against and management. Boston: MIT Press (2006). Epilepsy: time for reappraisal. Epilepsia 1998;39:1014Ð7. 15. of America’s Working Group on Status 3. Engel J Jr. A proposed diagnostic scheme for people with epilep- Epilepticus. Treatment of convulsive status epilepticus. JAMA tic seizures and with epilepsy: report of the ILAE Task Force on 1993;270:854Ð9. Classification and Terminology. Epilepsia 2001;42:796Ð803. 16. Commission on Epidemiology and Prognosis, International League 4. Blume WT, L¬uders HO, Mizrahi E, et al. Glossary of descriptive Against Epilepsy. Guidelines for epidemiologic studies on epilepsy. terminology for ictal semiology: report of the ILAE Task Force on Epilepsia 1993;34:592Ð6. Classification and Terminology. Epilepsia 2001;42:1212Ð8. 17. Lowenstein D, Bleck T, Macdonald RL. It’s time to revise the defi- 5. Fisher RF. Editor’s introduction: cabbages and kings in the classifi- nition of status epilepticus. Epilepsia 1999;40:120Ð122. cation of seizures and the epilepsies. Epilepsia 2003;44:1. 18. Fisher RS, van Emde Boas W, Blume W, et al. Epileptic seizures and 6. Wolf P. Of cabbages and kings: some considerations on classifi- epilepsy. Definitions proposed by the International League against cations, diagnostic schemes, semiology, and concepts. Epilepsia Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). 2003;44:1Ð4. Epilepsia 2005;46:470Ð2.

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