Workshop Report: Conceptual dichotomies in classifying epilepsies: Partial versus generalized and idiopathic versus symptomatic (April 18–20, 2008, Monreale, Italy)
2009; Wiley; Volume: 50; Issue: 6 Linguagem: Inglês
10.1111/j.1528-1167.2008.01950.x
ISSN1528-1167
AutoresGiuseppe Capovilla, Anne T. Berg, J. Helen Cross, Solomon L. Moshé, Federico Vigevano, Peter Wolf, G. Avanzini,
Tópico(s)Metabolism and Genetic Disorders
ResumoEpilepsiaVolume 50, Issue 6 p. 1645-1649 Free Access Workshop Report: Conceptual dichotomies in classifying epilepsies: Partial versus generalized and idiopathic versus symptomatic (April 18–20, 2008, Monreale, Italy) Giuseppe Capovilla, Giuseppe Capovilla Department of Child Neuropsychiatry, Epilepsy Center, "C. Poma Hospital", Mantova, ItalySearch for more papers by this authorAnne T. Berg, Anne T. Berg Department of Biology, Northern University, DeKalb, Illinois, U.S.A.Search for more papers by this authorJ. Helen Cross, J. Helen Cross University College London-Institute of Child Health, London, United KingdomSearch for more papers by this authorSolomon L. Moshe, Solomon L. Moshe The Saul R. Korey Department of Neurology, Department of Pediatrics, the Dominick P. Purpura Department of Neuroscience and the Laboratory of Development Epilepsy, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, U.S.A.Search for more papers by this authorFederico Vigevano, Federico Vigevano Department of Neurology, Ospedale Bambino Gesù, Rome, ItalySearch for more papers by this authorPeter Wolf, Peter Wolf Danish Epilepsy Centre, Dianalund, Copenhagen, DenmarkSearch for more papers by this authorGiuliano Avanzini, Giuliano Avanzini C. Besta Foundation Neurological Institute, Milan, ItalySearch for more papers by this author Giuseppe Capovilla, Giuseppe Capovilla Department of Child Neuropsychiatry, Epilepsy Center, "C. Poma Hospital", Mantova, ItalySearch for more papers by this authorAnne T. Berg, Anne T. Berg Department of Biology, Northern University, DeKalb, Illinois, U.S.A.Search for more papers by this authorJ. Helen Cross, J. Helen Cross University College London-Institute of Child Health, London, United KingdomSearch for more papers by this authorSolomon L. Moshe, Solomon L. Moshe The Saul R. Korey Department of Neurology, Department of Pediatrics, the Dominick P. Purpura Department of Neuroscience and the Laboratory of Development Epilepsy, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, U.S.A.Search for more papers by this authorFederico Vigevano, Federico Vigevano Department of Neurology, Ospedale Bambino Gesù, Rome, ItalySearch for more papers by this authorPeter Wolf, Peter Wolf Danish Epilepsy Centre, Dianalund, Copenhagen, DenmarkSearch for more papers by this authorGiuliano Avanzini, Giuliano Avanzini C. Besta Foundation Neurological Institute, Milan, ItalySearch for more papers by this author First published: 10 June 2009 https://doi.org/10.1111/j.1528-1167.2008.01950.xCitations: 36AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat The classification of epileptic syndromes and epilepsies (Commission on Classification and Terminology of the International League Against Epilepsy, 1985, 1989) is based on two main dichotomies: partial versus generalized (a distinction more relevant to seizures than to epilepsies) and idiopathic versus symptomatic (a distinction more relevant to epilepsies than to seizures). The concepts upon which these dichotomies are based are being challenged by the ongoing discussion of the classification (Engel, 2001, 2006). The present paper summarizes the results of the Workshop "Conceptual dichotomies: idiopathic versus symptomatic and partial versus generalized" held in Monreale (Italy) on April 18–20, 2008. Discussion sessions were devoted to partial versus generalized and to idiopathic versus symptomatic dichotomies. In addition, because it was recognized that the term "benign," which is used in the definition and name of some epilepsies, is somewhat ambiguous, a third discussion session was devoted to this concept. Partial versus Generalized Seizures and Epilepsies Avanzini G, Cross H (chairs), Beccaria F, Caraballo R, Dalla Bernardina B, Dulac O, van Emde Boas W, Fejerman N, Ozkara C, Striano S, Valenti MP, Wolf P The classification into generalized and partial (or focal) seizures dates back to Hughling Jackson but was officially recommended in the International League Against Epilepsy (ILAE) classification only in 1964 (Gastaut et al., 1964). The underlying pathophysiologic concept expressed by Jackson, and further elaborated by Penfield and Jasper, supported a clear-cut distinction between epilepsies caused by focal epileptogenic lesions versus "functional" epilepsies caused by a dysfunction of a diffusely projecting ("centrencephalic") system. The centrencephalic system could also be implicated in mechanisms responsible for "lesional" generalized epilepsies caused by diffuse brain damage. The emergence of the concept of benign focal epilepsies in the late fifties and early sixties (the prototype of which was Benign Epilepsy with Centro-Temporal Spikes: BECTS) introduced a novel view by establishing a new category of epilepsies attributed to a dysfunction affecting a localized cortical area in which no evidence of lesion was demonstrable. These localization-related epilepsies could not be attributed to an epileptic focus in an anatomic sense but rather to an age-related hyperexcitable condition of a given cortical region, most frequently sensorimotor and visual, with no detectable structural alteration. Accordingly, in the ILAE classification of epileptic seizures of 1981 (Commission on Classification and Terminology of the International League Against Epilepsy, 1981), partial seizures are defined as those in which the first clinical and electroencephalography (EEG) changes indicate initial activation of a system of neurons limited to part of one cerebral hemisphere. The choice of the term "system" of neurons instead of "group" or "population" of neurons is interesting, as it defines the focus according to a unifying functional criterion distinct from topography. The ILAE classification of epilepsies and epileptic syndromes of 1985 (Commission on Classification and Terminology of the International League Against Epilepsy, 1985) formalized the existence of idiopathic partial epilepsies, adopting the two main dichotomies: epilepsies with partial versus generalized seizures, and symptomatic versus idiopathic epilepsies. After long debate, the ILAE Commission decided to group idiopathic and symptomatic partial epilepsies under the new heading of localization-related epilepsies with the alternative terms focal, local, partial being reported in parenthesis. The reason for this preference was the recognition that for many epileptologists the term focal applies to a well-defined constant epileptic focus and not to the situations where focality of onset is variable. In the various classifications, care was taken in defining the concept of "generalized" seizures and epilepsies. A so-called "generalized" seizure may not be implied by involvement of both hemispheres (this could apply to secondary generalized seizures), both sides of the body (this could apply to motor seizures on one side with contralateral diffusion (or a frontal tonic seizure)), or loss of awareness, as this requires only extension toward some frontal regions. The concept of a generalized seizure relates to events for which no side can be identified from the onset; these seizures, in fact, involve both cortical and subcortical circuits, in both hemispheres from the onset. Indeed, the "generalized" concept is in many instances necessarily defined by EEG (except, of course, for a tonic–clonic seizure in the adult that most often does not require ictal recording). Sources of confusion with focal seizures may stem from an asymmetric involvement of the brain, although the overall involvement is widely distributed and no focus of onset can be identified. Confusion may also lie in that the electroclinical manifestation may change according to the degree of maturation of the brain. Seizures, in the very young, may appear to have focal manifestations, although the whole brain is involved—or indeed more frequently, the reverse. Clear focality becomes unclear when involvement is distributed over a wider area than a localized brain region. Further confusion is generated through use of the term "secondarily generalized." This term has a very specific meaning, and refers to the subsequent spread of a seizure—whether slow or rapid, and whether from focal onset or from a more widespread circuit. Finally, it should be noted that although in the introduction to the 1985 epilepsy classification document the two main categories are defined as "epilepsies with localization related seizures" and "epilepsies with generalized seizures," in the following table they are simply named "localization related epilepsies" and "generalized epilepsies." These headings are arguable, as the categories of focal (and synonyms) and generalized apply properly to seizures but not to epilepsies (e.g., some epileptic syndromes may present with both focal and generalized seizures). In some cases, however, the type of seizure (e.g., focal seizures of BECTS) is so characteristic of a given type of epilepsy that a diagnosis of type of seizures coincides with that of the epilepsy. Partial seizures and epilepsies In the Monreale workshop, the recognition of a substantial difference between seizures due to a fixed focus whose boundaries do not necessarily respect the functional organization of the cortex and seizures due to a discharge involving one (or more) functionally defined brain system(s), was the starting point of the discussion. Much evidence suggests that BECTS is caused by an age-related condition of hyperexcitability of the somatosensory or somatomotor system and could, therefore, be defined as a "system epilepsy." The alternative definition of "regional epilepsy" was discussed, but it was not considered satisfactory, as it does not bring out clearly the criterion of functional definition. Moreover, it was felt that "regional" evokes the idea of a cortical area, whereas evidence drawn from sleep studies demonstrate a highly significant correlation between BECTS interictal discharges and the EEG sigma band (which include sleep spindles), suggesting that systemic thalamocortical mechanisms may play a role in BECTS. In conclusion the new term of "system epilepsy" is proposed, which includes epilepsies with focal seizures depending on an age-related epileptic susceptibility of a given cerebral system (on either side of the brain). In these epilepsies, whose prototype is BECTS, there is no evidence of structural abnormality; they typically recover spontaneously after adolescence. Generalized seizures and epilepsies The term "generalized" implies that the onset seems to involve both sides of the brain. However so-called generalized seizures can be either symmetrical or asymmetrical. They can consist of cognitive or motor seizures; tonic, atonic, clonic, tonic–clonic, myoclonic seizures; or spasms. Each of these seizure types involves a distinct hyperexcitable circuitry that in most instances does not comprise the whole brain. As a result of maturation, circuits involved may even differ with age. The concept of "systems," referring to structures and pathways involved by the ictal event, was introduced (Wolf, 2006). Clearly, the systems or circuits involved in absence seizures, tonic seizures, tonic–clonic seizures, massive myoclonus, and epileptic spasms are not the same. Recent experiments in rodent models of absence epilepsy, the prototype of generalized idiopathic epilepsies, have shown that spike-wave discharges start in the parietal region of one side and rapidly invade the thalamocortical systems of both sides (Meeren et al., 2002; Polack et al., 2007). Thus the concept of "system epilepsy" may apply to generalized epilepsies as well as to the above-defined focal ones. The workshop group agreed that this concept may provide an interesting basis for testable hypotheses that may significantly advance our understanding of the pathogenesis of epilepsies. Such system epilepsies could occur as a result of widespread cortical/subcortical hyperexcitability and that activation of the circuit may have widespread, multifocal or focal origin; depending on the type of circuit involved, and on the modality of its activation, focal or generalized phenomenology may occur. Idiopathic–Symptomatic–Cryptogenic: Nature of the Underlying Cause Berg A (Chair), Lerche H, Moshé S, Striano P, Zara F. The discussion of the terms used in describing underlying causes of epilepsy reflected a general appreciation for the fact that the concepts aligned with the terms idiopathic, symptomatic, and cryptogenic are still of fundamental value, although somewhat imprecise given what is known today. The terms themselves have, however, come to have specific meanings or connotations which were, in today's context, found to be inadequate or misleading. For example, it was noted that all epilepsy may be symptomatic of something and that idiopathic should not imply benign. Consequently, rather than reject the concepts, time was spent on defining them more precisely, and without the use of the specific terms idiopathic, symptomatic, and cryptogenic. Ultimately we would hope to find terms that precisely convey the concepts we have defined. (1) "Type 1" epilepsy is epilepsy in which the seizures are a core—and sometimes the only apparent—symptom of the disorder. These seizures are, as currently understood, the direct result of a known or presumed genetic defect. The knowledge regarding the genetic contributions may derive from specific genetic studies that have been well replicated and even become the basis of diagnostic tests (e.g., SCN1A and Dravet syndrome), or the central role of a genetic component may be presumed based on analyses of appropriately designed family studies. Designation of the fundamental nature of the disorder as being genetic does not exclude the possibility that environmental factors (outside the individual) may contribute to the expression of disease. At the present time, there is virtually no knowledge to support specific environmental influences as causes of or contributors to these forms of epilepsy. Our current understanding of these disorders, based on the available evidence, is that they are genetically determined. Examples of epilepsy syndromes that would be classified as type 1 include: childhood absence epilepsy, autosomal dominant nocturnal frontal lobe epilepsy, and Dravet syndrome. Type 1 replaces the term "idiopathic." Other terms that were considered were: "primary" (a term that represents a return to much older terminology, and that was met with considerable debate),"direct," genetic,""fundamental," essential," and "original." Until an accurate and precise word or phrase can be identified, the workshop group recommended that this first concept simply be labeled "Type 1." (2) "Type 2" epilepsy refers to epilepsies that occur in conjunction with a distinct condition or disease that has been demonstrated (in appropriately designed studies) to be associated with a substantially increased risk of developing epilepsy. "Type 2" replaces the term "symptomatic." When the association is very strong, a causal association between the factor and epilepsy is reasonably justified. When the factor increases the risk by only 2- or 3-fold, attribution is much less certain. Similarly to "type 1" epilepsies, there may be genetic factors that modify the risk of developing epilepsy in response to a type 2 cause. At the present time, no clear data regarding genetic modifying factors are available that can be used meaningfully in assigning causation. Other terms that were considered include "secondary" (met with considerable debate), "derivative," and "subsidiary.""Type 2" should be used for now, until an accurate and precise word or phrase can be found. (3) "Type 3" epilepsy indicates that the nature of the underlying cause is as yet unknown. It may have a fundamental genetic defect at its core (type 1) or it may be the consequence of a separate disorder or condition not yet recognized (type 2). "Type 3" replaces the term "cryptogenic." Unlike "cryptogenic," which has at times been linked to the presumption of an underlying symptom ("type 2"), "type 3" indicates neutrality regarding the nature of the underlying cause. Examples of syndromes that would be classified as type 3 include migrating partial seizures of infancy and myoclonic epilepsy in infancy. To replace the term "cryptogenic," the term "unknown" met with some enthusiasm. (4) A fourth group, "Type 4," was also recognized for the purpose of classifying causes for certain electro-clinical syndromes which, as they are currently recognized, would reasonably be considered to be of mixed origins. West syndrome is a prime example as it may occur in direct association with a genetic defect (e.g., ARX or TSC mutation), in association with a separate neurological condition or insult (tuberous sclerosis, cortical malformation, intraventricular hemorrhage), or be of unknown origin. However, most electroclinical syndromes, as we understand them appear to fall into only one main category. Further considerations To date, no study of the underlying causes of epilepsy has yielded a complete understanding of the full causal pathway and pathophysiology, from initial precipitating factor to seizures and epilepsy. As a result, any classification of the nature of the underlying causes of epilepsy is based on our best, but ultimately very imperfect, understanding of the pathophysiology. In considering the type 1 versus type 2 distinction, it is worth noting that other workers in the field have struggled with this same dilemma; nothing is purely genetic and nothing is purely environmentally or otherwise induced. Lennox (1941) noted in this regard that "… in almost all patients both hereditary (essential) and acquired (symptomatic) causes combine. In order to start a blaze there must be both combustible material and a match. In individual cases the relative importance of the two may be very different. A spark will light a pile of powder but only a hot fire will kindle green wood." The type 1–type 2 distinction is intended to recognize the cause with the greatest explanatory power or importance. Electroclinical syndromes versus other epilepsies Many people with epilepsy cannot be diagnosed as having a specific electroclinical syndrome. In characterizing the cause for the individual patient who does not clearly meet the criteria for one of the electroclinical syndromes, "type 1" would generally not be appropriate as it implies that the form of epilepsy has been demonstrated to have a genetic basis and the patient has been diagnosed with that particular form of epilepsy. For the individual, then, if a type 2 cause is diagnosed (e.g., a stroke, traumatic brain injury, or encephalitis), the patient would be diagnosed as having a form of "type 2" epilepsy. If no type 2 cause can be diagnosed, then the patient's epilepsy would be considered as type 3 or unknown, with no presumptions as to whether it is actually type 1 or type 2. Revisiting the Concept of Benign Vigevano F (Chair), Capovilla G, Genton P, Gobbi G, Hirsch H, Specchio N The word "benign" literally means "to do good" or "gifted of natural goodness." The term has been widely used in the medical literature to define clinical entities in which the prognosis has a favorable outcome, otherwise not dangerous or likely to cause death. These disorders are clearly opposed to similar entities, which have "malignant" evolution, or unfavorable outcome. The meaning of the term may change within the medical branch in which it is applied. The 1989 classification (Commission on Classification and Terminology of the International League Against Epilepsy, 1989) proposal included epileptic syndromes that qualified as benign (e. g., Benign Childhood Epilepsy with Centro-Temporal Spikes), but the meaning of the term was not specified or clarified. The 2001 classification scheme (Engel, 2001) defined a "benign epilepsy syndrome" as "a syndrome characterized by epileptic seizures that are easily treated or require no treatment, and remit without sequelae." This definition pointed out four concepts: (1) easy to treat, (2) seizure remission, (3) no sequelae, (4) treatment not always necessary. Those concepts were not further clarified; for example, the meaning of the terms "no sequelae" and "seizure remission" was not clearly established. The 2001 classification scheme lists seven entities that contain the term "benign": 1 Benign familial neonatal seizures (BFNS) 2 Benign myoclonic epilepsy of infancy (BMEI) 3 Benign familial infantile seizures (BFIS) 4 Benign infantile seizures (Nonfamilial) (BIS) 5 Early onset benign childhood occipital epilepsy (Panayiotopoulos type) 6 Benign childhood epilepsy with centro-temporal spikes (BECTS) 7 Benign neonatal seizures (BNS) Recently (Engel, 2006), the term "benign" has been withdrawn from benign myoclonic epilepsy in infancy, because a cognitive delay may sometimes occur. Historically, there are two further entities—JME (juvenile myoclonic epilepsy) and late-onset childhood occipital epilepsy (Gastaut type)—that had been labeled "benign." However, in these syndromes, pharmacodependency is frequent. If we analyze the present classification, it is clear that the term "benign" is used exclusively in age-dependent (onset in paediatric age) idiopathic epilepsy syndromes in which there is reliable seizure remission. Data published in the literature show that a variable percentage of patients with syndromes considered "benign," such as BECTS and CAE, can be drug-resistant, despite the long-term favorable outcome with an age-dependent seizure remission that is characteristic of most patients with these conditions. Recent studies using neuropsychological evaluations have demonstrated that in some "benign" syndromes, a spectrum of neuropsychological sequelae can be present. These sequelae could be related to the disease per se, or could be a consequence of antiepileptic treatment or psychosocial factors. Favorable outcome can also be observed in nonidiopathic cases, in both paediatric and adult ages (e.g., in stroke-related epilepsy in the elderly). All the working group members agreed that the term "benign" should be kept, because it is used widely in medicine and is easy to understand. The main goal in using the term "benign" is to try to give early (at seizure onset or after a short follow-up) reliable information on the prognosis of the disease, information that can be reassuring and decrease anxiety for patients and caregivers. It is also important to communicate to caregivers, and to the public at large, the fact that epilepsy is not necessarily a severe and debilitating condition, and the word "benign" is the best way to convey this message. The a priori knowledge of a "benign" evolution allows adequate management, and avoids over-treatment as well as unnecessary procedures and restrictions. We, therefore, believe that it is highly important to establish when epilepsy can be defined as "benign"; if a revised definition is accepted, a second step will include its application to individual syndromes and entities. On the one hand, if we use the term "benign" in a restrictive sense, very few epilepsy syndromes should be included. On the other hand, we are aware that the most patients affected by other forms of epilepsy that are not classically considered as benign lead a "normal" life. Consequently we recommend that the term benign be reserved in defining age-related conditions that remit without sequelae. The concept of "benign" cannot, however, be excluded from other epilepsy syndromes. We believe that the definition of a benign epilepsy should include the following features: 1 Disappearance of seizures, which can be age-related and spontaneous, but can also be attained with medication. Above all, this feature must be a reliable characteristic, occurring in almost all cases. 2 No sequelae, which must be considered with attention to cognitive development, and also to overall quality of life and to fulfilment of expectations. 3 Diagnosis at onset, whereby clinical and/or EEG criteria, sometimes associated with neuroimaging, should permit definition of a "benign" evolution. This diagnosis should be possible at the very onset of the disease or after a short period of follow-up, allowing for the completion of diagnostic procedures and therapeutic management using adequate drugs. 4 Treatment not always necessary, which implies that the evolution of the disorder, in particular in age-dependent entities, may be considered benign regardless of treatment. Considering the preceding elements, we propose the following definition: "An epilepsy can be considered benign when characterized by clinical and/or EEG features that predict, with low risk of error, at onset or soon after, remission of seizures (with or without treatment) and without significant, permanent impact on the patient's potential." Following this definition we propose that the following entities be considered as "benign": Benign non-familial neonatal seizures Benign familial neonatal seizures Benign familial neonatal-infantile seizures (in progress) Benign familial infantile seizures Benign nonfamilial infantile seizures Benign infantile focal epilepsy with midline spikes and waves during sleep (in progress) Early onset benign childhood occipital epilepsy (Panayiotopoulos type) Late-onset childhood occipital epilepsy (Gastaut type) Benign epilepsy with centrotemporal spikes Benign myoclonic epilepsy in infancy Childhood absence epilepsy (pure type) Idiopathic generalized epilepsy with variable phenotypes: 1 Juvenile absence epilepsy 2 Juvenile myoclonic epilepsy 3 Epilepsies with generalized tonic–clonic seizures only Other epileptic conditions and situations not mentioned in the preceding, that do not necessarily fulfill the criteria that allow the diagnosis of an epileptic syndrome, may also have the characteristics of a benign epilepsy. Acknowledgments The support of EISAI s.r.l. through an unrestricted educational grant is gratefully acknowledged. We also thank Dr. Giuseppe Stranci for his contribution to the discussion. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Disclosure: We declare that all the authors have no conflict of interest in connection with this paper. References Commission on Classification and Terminology of the International League Against Epilepsy. (1981) Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia 22: 489– 501. Wiley Online LibraryPubMedWeb of Science®Google Scholar Commission on Classification and Terminology of the International League Against Epilepsy. (1985) Proposal for classification of epilepsies and epileptic syndromes. Epilepsia 26: 268– 278. 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