CRITICAL REVIEW AND INVITED COMMENTARY
The new ILAE report on terminology and concepts for the organization of epilepsies: Critical review and contribution
Address correspondence to Chrysostomos P. Panayiotopoulos, Neurosciences Offices, West Wing, Third Floor, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, United Kingdom. E-mail: firstname.lastname@example.org
This critical review refers to the new report on terminology and concepts for the organization of epilepsies by the Commission of the International League Against Epilepsy (ILAE). It is unfortunate that most of the proposals in the Commission’s report are modified interpretations and nomenclature of previous ILAE classifications; new terms are not better than the old ones, and recent advances have not been incorporated. Hence, the new ILAE report met with considerable dissatisfaction from several expert epileptologists. The Commission abandoned (1) the disease-syndrome distinction, although “disease” is generally differentiated from “syndrome” in most medical texts as well as in the ILAE classification itself; (2) the distinction of “generalized” and “focal” for epileptic syndromes, despite maintaining this distinction for epileptic seizures and despite the fact that most epileptic syndromes manifest exclusively either with generalized or focal epileptic seizures; (4) the terms “idiopathic,”“symptomatic,” and “cryptogenic,” although these terms have been well defined in the previous ILAE classifications; reiterating their true meaning would be sufficient. Genetic epilepsy could be a new category and (5) the designation of “benign” epilepsies, despite the recommendations of experts at the Monreale workshop. In addition, the Commission proposed that “age at onset” be used as a primary dimension for organizing the epilepsies. However, (a) this runs counter to classification efforts of other diseases in medicine and neurology; (b) syndromes that are likely to be linked together on the basis of electroclinical (and often genetic) evidence are now separated and intermixed with a number of heterogeneous epilepsies; and (c) a considerable number of epileptic syndromes have a wide range of age at onset from childhood to adulthood. Furthermore, epilepsy syndromes were given by name only, without definition; thus we remain dependent on previous ILAE definitions, which are often broad and imprecise. The ILAE should commission consensus of opinion from experts in specific fields in order to define each syndrome. Areas of certainties and uncertainties and of agreements and disagreements should be identified and explained. This approach may be the only way toward achieving a scientifically sound and clinically meaningful organizational system for the epileptic seizures and the epilepsies—a process that would incorporate the tremendous advances in our field and would be accepted by the wider community of clinicians and scientists.
A major advance in modern epileptology has been the recognition of epileptic syndromes and diseases. This advance provides a firm foundation for short- and long-term therapeutic decisions, and enables natural history, inheritance, treatment efficacy, and prognosis of epilepsies to be studied scientifically. The benefits of syndromic diagnosis over seizure/symptom diagnosis (or an inclusive diagnosis such as “epilepsy”) far outweigh any morbidity from mistaken categorization that may arise in difficult cases. A syndromic diagnosis of patients with epilepsies is now a firm recommendation in all relevant formal guidelines.
The current International Classification of Epilepsies and Epileptic Syndromes (ICE) is the 1989 proposal approved by the International League Against Epilepsy (ILAE) General Assembly (Commission on Classification and Terminology of the International League Against Epilepsy, 1989). However, some parts of the 1989 ICE classifications are contentious and require further clarification. Newly recognized syndromes require attention, as do those patients whose clinical and electroencephalography (EEG) features do not fit neatly into any recognized category—perhaps representing new or “overlap” syndromes, or unusual or atypical forms of known syndromes or cases where clinical history is misleading.
Since 1997, the ILAE Commissions chaired by Jerome Engel (1997–2005) and Anne Berg (2005–2009) have undertaken the difficult task of incorporating recent major clinical, genetic, technologic, and scientific advances into a better and internationally uniform classification (Engel, 2001, 2006; Berg et al., 2010). Their initial aim was to construct a “new scientific classification from application of methods used in biology that determines separate species and natural classes for the organization of seizures and epilepsies: As the tree of life (for living organisms) or the periodic table of the elements is our vision” (Berg & Scheffer, 2011a). However, such a scientific classification proved elusive, with the most recent Commission recommendations focusing on “new terminology and concepts instead of proposing a new classification (in the sense of organization) of epilepsies” (Berg et al., 2010).
Because most of the proposals in the new ILAE report are simply modified interpretations and nomenclature of the previous ILAE classifications, they were met with considerable dissatisfaction: “The downside to changing terms is that the change may confuse the wider community (those not intimately involved with classification) and thus lessens the authority and credibility of an organization such as the ILAE” (Shorvon, 2011b). “The new ILAE system intentionally lacks any uniform, standardized organization or hierarchy for classifying epilepsy. This system basically amounts to a glossary database of descriptors and causes to pick and choose from” (Wong, 2011). (See also Wolf, 2010; Fisher, 2010; Shorvon, 2011a,b,c; Wolf, 2011).
The following comments reflect this writer’s perspective, and refer to terminology and concepts for the organization of epilepsies in the new ILAE report. A critical review on the nomenclature and organization of epileptic seizures has been published previously (Panayiotopoulos, 2011). My comments are presented as disagreements with a number of decisions and recommendations of the Commission:
The Commission Abandoned the Disease-Syndrome Distinction
In their recent report (Berg et al., 2010), the ILAE Commission decided “not to insist on the disease-syndrome distinction in referring to the epilepsies at this time.” However (1) “disease” is generally differentiated from “syndrome” in most medical books as well as in the ILAE classification itself (Appendix); and (2) the International Classification of Diseases (ICD) is the standard international diagnostic classification for general epidemiology, many health management purposes, and widespread clinical use. The 1989 ICE is clear on this point: “In contradistinction to a disease, a syndrome does not necessarily have a common etiology and prognosis. On the other hand, some of the epileptic disorders included in this ICE are diseases, and in others, currently considered syndromes, a common etiology may still be discovered. For the sake of convenience, all these disorders are included in one ICE” (Commission on Classification and Terminology of the International League Against Epilepsy, 1989).
The Commission Indicated that the Concepts of “Generalized” and “Focal” Were No Longer Applicable with Respect to Electroclinical Syndromes
Although generalized and focal seizures/syndromes certainly exhibit similarities in their pathophysiologic and/or genetic aspects, that overlap should not distract us from the fact that their differences are much greater than their similarities. It is by emphasizing their differences that therapeutic mistakes—such as prescribing carbamazepine in juvenile myoclonic epilepsy or juvenile absence epilepsy—have been minimized. The Commission, “based on current electroclinical evidence,” rightly maintains the terminology and the distinction between focal and generalized epileptic seizures. Therefore, their decision to discard the distinction of “generalized” and “focal” for epileptic syndromes [“The concepts of generalized and focal do not apply to electroclinical syndromes” (Berg et al., 2010)] is puzzling. Abandoning the term “generalized epileptic syndromes” creates the paradox that syndromes such as “epilepsy with generalized tonic–clonic seizures (GTCS) only” are not classified as generalized epilepsy, even though by name they manifest exclusively with “GTCS only.” The same objection applies for childhood absence epilepsy and other idiopathic generalized epilepsies (IGEs) that may manifest only with generalized seizures. Similarly, numerous focal epileptic syndromes such as hippocampal epilepsy or most of the familial (autosomal-dominant) focal epilepsies manifest solely with focal epileptic seizures.
The Commission Proposed New Terminology and Concepts for Underlying Cause
The new ILAE report proposes to abandon the terms “idiopathic,”“symptomatic,” and “cryptogenic” and replace them with “genetic,”“structural–metabolic,” and “unknown” as a means of categorizing underlying cause (Appendix). The reason provided is that “The terms idiopathic, symptomatic, and cryptogenic have taken on a variety of meanings and connotations laden with presumptions which, at times, conflate multiple concepts into a single word. This has resulted in considerable contradiction and confusion.”“For example,” the report states: “The term (idiopathic) is also used to convey the idea of a highly pharmaco-responsive form of epilepsy, idiopathic also implied benign and cause was equated with prognosis” (Berg et al., 2010). However, these terms have been well defined and clarified in the ICE classifications (Appendix), and there is nothing in these definitions to justify the Commission’ statements. Therefore, reiterating their true meaning would be sufficient.
The new report proposes to include all cryptogenic and many idiopathic epilepsies in the category of ‘‘unknown cause’’ (Appendix). For example, the Commission proposes to include benign rolandic epilepsy, Panayiotopoulos syndrome, and childhood occipital epilepsy of Gastaut among syndromes of an “unknown cause” because “low or absent concordance in siblings does not suggest that genetic factors are involved in these syndromes.” However, as the Commission states elsewhere “it is likely that genetic factors are involved in these syndromes”—which suggests that they should be viewed as idiopathic rather than of unknown cause; indeed, recent evidence strongly supports significant genetic contributions for rolandic epilepsy (Strug et al., 2009). A practical consequence of abandoning the terms “idiopathic” (and “generalized”) is that we will not have a diagnostic category for a considerable number of patients with IGE (20–30%) who cannot be classified among the relevant ILAE-accepted syndromes of IGE (Panayiotopoulos, 2005).
Although it is true that “symptomatic” may not be the best term to characterize epilepsies currently labeled in this way, this term has now been well established and with further clarification of its meaning it may continue to serve its purpose. Furthermore, “the replacement of the term ‘symptomatic’ with ‘structural/metabolic’ seems…unjustified and unnecessary, and furthermore includes epilepsies that are neither structural (in the sense of having a normal macroscopic structure) or metabolic (in the sense of causing some measurable metabolic change); examples are numerous, and include some epilepsies due to autoimmune, inflammatory, synaptic, degenerative, toxic, or neurochemical changes” (Shorvon, 2011b).
Genetic epilepsies are the best “new” category to recognize and incorporate into a revised classification of epilepsies, in order to take advantage of the tremendous advances made in the field of genetics in recent years. However, this category should be in addition to “idiopathic,”“cryptogenic,” and “symptomatic” (Ferrie, 2010; Guerrini, 2010; Shorvon, 2011b). “Genetic” is not a substitute for “idiopathic” (Appendix). Some epilepsies can be immediately categorized as “genetic”—for example, the familial autosomal-dominant focal epilepsies have already been recognized as “genetic” by the ILAE Task Force (Engel, 2001, 2006). For other epilepsies, such as childhood absence epilepsy, juvenile myoclonic epilepsy, and rolandic epilepsy, we may have to wait for more concrete evidence to emerge. Until then, these epilepsies can be nested within their corresponding grouping of IGEs and benign childhood focal epilepsies.
The Commission Recommended Abandoning the Designation of “Benign” Epilepsies
According to Engel (2001), a benign epilepsy syndrome is characterized by “epileptic seizures that are easily treated or require no treatment and remit without sequelae.” The prefix “benign” in some epileptic syndromes serves to contrast these epileptic syndromes from the most severe forms such as “epileptic encephalopathies.”“Benign” in general medical terminology indicates conditions that are not recurrent or progressive, not malignant, have little or no detrimental consequences, are favorable for recovery, and are generally not life-threatening. The Commission decided to abandon the term “benign” because it “belies the growing understanding of the relationship between the epilepsies and a wide variety of brain disorders including cognitive, behavioral, and psychiatric illnesses as well as sudden death and suicide.” This decision contrasts with the recommendations of experts at the Monreale workshop (Vigevano et al., 2009). Instead of “benign,” the Commission has proposed more descriptive terms, such as “pharmacoresponsive.” However, “pharmacoresponsive,” may be problematic because: (1) at least one-third of children with benign epilepsies do not need pharmacologic treatment; and (2) patients with the same syndrome may be “pharmacoresponsive” or “pharmacoresistant.”
Children with rolandic seizures and related benign childhood syndromes may develop usually mild and reversible linguistic, cognitive, and behavioral abnormalities during the active phase of their disease. However, it is still unclear if/how much these abnormalities result from the effects of antiepileptic drugs, the impact of stigmatizing because of epilepsy, bias in selection of the most serious cases, or other factors. The developmental, social adaptation, and occupational history of adults with a previous history of such seizures were found normal in prospective studies of many years of follow-up (Panayiotopoulos et al., 2008).
The Commission Proposed that “Age at Onset” Be Used as a Primary Dimension for Organizing the Epilepsies
The two recent ILAE reports introduce age at onset as the primary, “most distinctive and clinically salient dimensions for organizing” the epilepsies (Engel, 2006; Berg et al., 2010). This deviation from previous classification of epilepsy syndromes (Commission on Classification and Terminology of the International League Against Epilepsy, 1989; Engel, 2001) also runs counter to classification efforts of other diseases in medicine and neurology, most of which are not organized according to the age at onset (see for example, myopathies, neuropathies and even progressive myoclonic epilepsies). The result of this new dimension can be seen in Table 3 of the ILAE report (Berg et al., 2010); syndromes which are likely to be linked together on the basis of electroclinical (and often genetic) evidence (epilepsy with myoclonic absences, childhood absence epilepsy, juvenile myoclonic epilepsy) are now separated and intermixed with a number of heterogeneous epilepsies (Lennox-Gastaut syndrome, Landau-Kleffner syndrome, and so on). The uncertainties of organization of syndromes by age at onset become apparent by comparing the Berg et al. (2010) Table 3 with that of the ILAE Task Force of 2006 (Engel, 2006). Syndromes previous listed in childhood and/or of less specific age relationships are now moved to adolescence (now also expanded to include adulthood).
Age at onset is too broad a criterion to accept as the primary organizational factor in any classification. Some electroclinical syndromes have a small range of age at onset, whereas in others this expands for many decades.
Epilepsy Syndromes Are Given by Name Only without Defining Them
The 1989 ICE classification provided a brief definition for the recognized syndromes, which was based on the existing evidence. It was expected that the new classification would revise and correct these definitions, rather than list them by name only (Berg et al., 2010). Otherwise we remain dependent with the previous 1989 ICE definitions, which are often broad and imprecise.
Still Needed—A Proposal to Achieve a Truly Modernized Classification
It appears that the new ILAE report (Berg et al., 2010) does not fulfill its intent to “incorporate the tremendous advances in the neurosciences that have taken place in the last decade and that continue to occur” (Berg & Scheffer, 2011b). In my view, it is preferable to continue using the previous ILAE classifications, despite their significant imperfections, with certain modifications until we achieve our targets: “A number of concept categories that were recognized and updated in the 2001 and 2006 Task force reports (Engel, 2001, 2006) have been reinforced over time, and are a solid reference point for the clinician” (Guerrini, 2010). As suggested in my previous Commentary (Panayiotopoulos, 2011), the ILAE should commission consensus from experts in specific fields in order to define each syndrome and to avoid the previous ambiguities of the 1989 classification (Commission on Classification and Terminology of the International League Against Epilepsy, 1989). Areas of certainties and uncertainties and of agreements and disagreements should be identified and explained. This approach may be the only way to achieve a scientifically sound and clinically meaningful organizational system for the epileptic seizures and the epilepsies—a process that would incorporate the tremendous advances in our field and would be accepted by the wider community of clinicians and scientists.
I have no conflicts of interest to disclose.
I confirm that I have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
Appendix – Key Definitions as Per the ILAE Proposals
Epilepsy disease and epileptic syndrome
“An epileptic syndrome is an epileptic disorder characterised by a cluster of signs and symptoms customarily occurring together; these include such items as the type of seizure, etiology, anatomy, precipitating factors, age of onset, severity, chronicity, diurnal and circadian cycling, and sometimes prognosis. However, in contradistinction to a disease, a syndrome does not necessarily have a common etiology and prognosis. On the other hand, some of the epileptic disorders included in this ICE are diseases, and in others, currently considered syndromes, a common etiology may still be discovered. For the sake of convenience, all these disorders are included in one ICE” (Commission on Classification and Terminology of the International League Against Epilepsy, 1989).
“Epilepsy syndrome: A complex of signs and symptoms that define a unique epilepsy condition. This must involve more than just the seizure type; thus, for instance, frontal lobe seizures per se do not constitute a syndrome” (Engel, 2001).
“Epilepsy disease: A pathological condition with a single, specific, well-defined etiology. Thus, progressive myoclonus epilepsy is a syndrome, but Unverricht–Lundborg is a disease” (Engel, 2001).
“Epilepsy syndrome, more precisely “electroclinical syndrome,” is a complex of clinical features, signs and symptoms that together define a distinctive, recognizable clinical disorder. These often become the focus of treatment trials as well as of genetic, neuropsychological, and neuroimaging investigations. Use of the term “syndrome,” and more precisely “electroclinical syndrome,” will be restricted to a group of clinical entities that are reliably identified by a cluster of electroclinical and developmental characteristics. These are largely but not exclusively genetic in origin, and tend to have a strong relationship to developmental aspects of the brain. These are distinctive disorders identifiable on the basis of a typical age onset, specific EEG characteristics, seizure types, and often other features which, when taken together, permit a specific diagnosis. The diagnosis in turn often has implications for treatment, management, and prognosis. The term for these entities is “Electroclinical Syndromes.” While ultimately common usage will likely shorten the term again to “syndrome” alone, this is still specifically defined to mean entities that can be considered electroclinical syndromes. It would be inappropriate to refer to, for example, epilepsy with a frontal lobe focus and not otherwise specified as a “syndrome” (Berg et al., 2010).
“Disease versus syndrome: Although there is reason to distinguish the concepts of disease and syndrome, these terms are not consistently used in medicine. Ultimately, it was decided not to insist on the disease-syndrome distinction in referring to the epilepsies at this time, although either or both terms may be used depending on the context and custom” (Berg et al., 2010).
Constellations: In addition to the electroclinical syndromes with strong developmental and genetic components to them, there are a number of entities that are not exactly electroclinical syndromes in the same sense but which represent clinically distinctive constellations on the basis of specific lesions or other causes. These are diagnostically meaningful forms of epilepsy and may have implications for clinical treatment, particularly surgery. These include mesial temporal lobe epilepsy (with hippocampal sclerosis), hypothalamic hamartoma with gelastic seizures, epilepsy with hemiconvulsion and hemiplegia, and Rasmussen ‘‘syndrome.’’ Age at presentation is not a defining feature in these disorders, as we understand them; however, they are sufficiently distinctive to be recognized as relatively specific diagnostic entities. Whether or not they are considered ‘‘electroclinical syndromes’’ now or in the future is less important than that they be recognized by clinicians who are treating patients (Berg et al., 2010).
Definitions of etiological classification
“Idiopathic epilepsies are defined by age-related onset, clinical and electroencephalographic characteristics, and a presumed genetic etiology. There is no underlying cause other than a possible hereditary predisposition. Idiopathic epilepsies and syndromes are described as disorders “not preceded or occasioned by another,” according to the Oxford English Dictionary” (Commission on Classification and Terminology of the International League Against Epilepsy, 1989).
“Idiopathic epilepsy syndrome: A syndrome that is only epilepsy, with no underlying structural brain lesion or other neurological signs or symptoms. These are presumed to be genetic and are usually age dependent” (Engel, 2001).
“Cryptogenic epilepsies are presumed to be symptomatic, but the etiology is not known. The term cryptogenic refers to a disorder whose cause is hidden or occult. The cryptogenic epilepsies are also age related but often do not have well-defined electroclinical characteristics” (Commission on Classification and Terminology of the International League Against Epilepsy, 1989).
“Probably symptomatic epilepsy syndrome: This is synonymous with, but preferred to, the term ‘cryptogenic,’ used for defining syndromes that are believed to be symptomatic but no etiology has been identified” (Engel, 2001).
“Symptomatic epilepsies and syndromes are considered the consequence of a known or suspected disorder of the central nervous system” (Commission on Classification and Terminology of the International League Against Epilepsy, 1989).
“Symptomatic epilepsy syndrome: A syndrome in which the epileptic seizures are the result of one or more identifiable structural lesions of the brain” (Engel, 2001).
Structural/metabolic epilepsies: includes epilepsies secondary to specific structural or metabolic lesions or conditions but which do not, given our current understanding, fit a specific electroclinical pattern, although that may change in the future. Therefore, these entities represent a lower level of specificity than the two previous groups. The term ‘‘structural and metabolic’’ is intended to highlight that there is a separate disorder the relationship of which to epilepsy is not as direct. The grouping of structural and metabolic disorders together is only to distinguish this concept from that of genetic (i.e., genetic vs. all else) (Berg et al., 2010).
Epilepsies of unknown cause: Those epilepsies, which in the past were termed ‘‘cryptogenic,’’ will now be referred to as being of ‘‘unknown’’ cause (Berg et al., 2010).
Genetic epilepsy:“The concept of genetic epilepsy is that the epilepsy is, as best as understood, the direct result of a known or presumed genetic defect(s) in which seizures are the core symptom of the disorder. The knowledge regarding the genetic contributions may derive from specific molecular 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 rely on evidence from 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.... It is possible that the genetic defect may have other effects in addition to the seizures but, as best we can tell, these other effects are not interposed between the genetic effect and the seizures” (Berg et al., 2010).