- Top of page
- Terminology and Concepts for Classification of Seizures and Epilepsies
- Underlying type of cause (etiology)
- Diseases, syndromes, and epilepsies
- Dimensions for classifying epilepsies and organizing information
- An interim organization (“classification”) of the epilepsies
The International League Against Epilepsy (ILAE) Commission on Classification and Terminology has revised concepts, terminology, and approaches for classifying seizures and forms of epilepsy. Generalized and focal are redefined for seizures as occurring in and rapidly engaging bilaterally distributed networks (generalized) and within networks limited to one hemisphere and either discretely localized or more widely distributed (focal). Classification of generalized seizures is simplified. No natural classification for focal seizures exists; focal seizures should be described according to their manifestations (e.g., dyscognitive, focal motor). The concepts of generalized and focal do not apply to electroclinical syndromes. Genetic, structural–metabolic, and unknown represent modified concepts to replace idiopathic, symptomatic, and cryptogenic. Not all epilepsies are recognized as electroclinical syndromes. Organization of forms of epilepsy is first by specificity: electroclinical syndromes, nonsyndromic epilepsies with structural–metabolic causes, and epilepsies of unknown cause. Further organization within these divisions can be accomplished in a flexible manner depending on purpose. Natural classes (e.g., specific underlying cause, age at onset, associated seizure type), or pragmatic groupings (e.g., epileptic encephalopathies, self-limited electroclinical syndromes) may serve as the basis for organizing knowledge about recognized forms of epilepsy and facilitate identification of new forms.
The history of classification has rested largely upon astute observations and expert opinions. First published in 1960 and last updated officially in 1981 for seizures (Commission on Classification and Terminology of the International League Against Epilepsy [ILAE], 1981) and 1989 for epilepsies (Commission on Classification and Terminology of the International League Against Epilepsy, 1989), the ILAE classifications are based on concepts that, for the most part, predate modern neuroimaging, genomic technologies, and concepts in molecular biology. The original authors foresaw that changes to the classification would be needed as new information was acquired and as new investigative technologies were developed. This is no simple task. Attempts have been made to update the 1989 and 1981 documents (Engel, 2001, 2006); however, no new proposal has been forthcoming.
A primary motivation for revising the classification in the 2005–2009 Commission term and to continue revising it in the future is to bring epilepsy out of the shadows of expert opinion and assertion-dominated arguments so that the classification of the epilepsies fully reflects and profits from all of the other advances being made in basic and clinical neurosciences and so that those advances can be incorporated into clinical practice. In the following report we present the main findings and recommendations of the Commission’s deliberations during the 2005–2009 term accompanied by comments interleaved with the main text. The comments provide background, explanations, and justifications for these decisions and provide some insight into the variety of considerations that were addressed and why specific decisions were made.
Although changes have been made to terminology and concepts, we emphasize that no changes (other than to nomenclature) are being made to the list of epilepsy entities (“syndromes”) already recognized and updated in the 2006 Task force report (Engel, 2006). Furthermore, the revisions made to terminology and concepts in epilepsy do not have any tangible impact on how clinicians use the electroclinical syndromes that have been internationally recognized and that are applied to people with epilepsy around the world every day.
Comments: Classification and terminology as it relates to seizures:
The Commission accepted the ILAE definition of epileptic seizure (Fisher et al., 2005): “a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.” Therefore, the comments are limited to describing epileptic seizures and are not designed to assist the clinician in distinguishing epileptic seizures from nonepileptic events. This will be treated separately in a diagnostic manual.
The terms “focal” and “generalized” have been used to express a dichotomous classification for both seizures and the epilepsies. In fact in the late 1800s, Hughlings-Jackson wrote that focal discharging lesions caused both focal and generalized seizures (see York & Steinberg, 2009). For seizures, based on current electroclinical evidence, the Commission felt that it was still of some pragmatic utility to maintain the terminology, although it was generally acknowledged that these terms likely did not represent a clear dichotomy.
The conceptualization of generalized seizures as arising in and rapidly engaging bilaterally distributed networks was, in part, an attempt to address the apparently generalized nature of spasms in the context of a focal lesion. This could represent a paradigmatic breakthrough in thinking about manifestations versus underlying pathology. There was much lively discussion and at times bitter disagreement over how best to classify spasms, as generalized or focal or both. In the end, the considerable collective knowledge of spasms represented by the various Commission members was still not up to the task of resolving this issue precisely because of inadequate information. Spasms are thus left on their own.
The 1981 seizure document used the terms simple partial, complex partial, and partial seizures secondarily generalized (Commission, 1981). This terminology was imprecise, as the terms “simple” and “complex” were often misused or misunderstood. Moreover, the distinction based on impairment of consciousness or awareness, although of great pragmatic social importance (e.g., for driving), was impossible to define precisely (Gloor, 1986). The term “secondarily” generalized is poorly understood and inconsistently used. Currently, we have inadequate information to create a scientific classification within focal seizures. Instead, we recommend that focal seizure be described according to features that are the most useful for a given specific purpose. For example, in many circumstances such as the differential diagnosis of epileptic versus nonepileptic events or in presurgical evaluation it is often useful to describe the specific elemental features of seizures and their sequence of occurrence (Luders et al., 1993). Others may wish to recognize terms to describe degree of disability caused by the seizures. We encourage those interested to consult the Glossary of Ictal Semiology (Blume et al., 2001) for well-defined descriptive terms.
Comments: Terminology and concepts for underlying cause:
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. The term idiopathic was defined in the 1989 document: “There is no underlying cause other than a possible hereditary predisposition. Idiopathic epilepsies are defined by age-related onset, clinical and electrographic characteristics, and a presumed genetic etiology.” We now state a minimum threshold for presuming a form of epilepsy does in fact have a genetic basis. Undocumented assertions are not accepted. Examples of epilepsy syndromes that would be classified as genetic epilepsies include childhood absence epilepsy, autosomal dominant nocturnal frontal lobe epilepsy, and Dravet syndrome. Note that in the 1989 classification, Dravet syndrome was not classified as idiopathic epilepsy. Dravet is now considered as a genetic epilepsy.
The term “idiopathic” was also used to convey the idea of a highly pharmacoresponsive form of epilepsy. Many, although not all, of the traditional “idiopathic” epilepsies also spontaneously remit during a predictable age range (a separate quality or dimension) and were generally thought to be unaccompanied by other consequences or disabilities, although this is clearly not the case, as a variety of subtle cognitive and behavioral disorders are seen in association with these epilepsies.
The new terminology and concepts require that the concept of cause contain only one dimension and not be used to imply others. Cause is no longer equated with prognosis, and the implication that “idiopathic” confers the quality of “benign” is intentionally discarded. 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.
The term “symptomatic” is a truism; all epilepsy is symptomatic of something. It is often substituted for the concept of a poor prognosis. 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). Depending on the purposes, it will be necessary to subdivide these heterogeneous causes further starting with separate groups for structural and for metabolic. Within each of these subdivisions, further taxa will be elaborated (e.g., for malformations, gliomas, and mitochondrial disorders). Other ILAE Commissions and other groups around the world are tackling these very issues.
“Cryptogenic” was defined in 1989 as “presumed symptomatic,” apparently meaning “lesional.” It is, however, from among these “cryptogenic” epilepsies that genetic electroclinical syndromes such as autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) and autosomal dominant epilepsy with auditory features (ADEAF) have been discovered (Scheffer et al., 1995; Ottman et al., 1999). In replacing the term “Cryptogenic” with “unknown,” the Commission discarded the notion that a clinical hunch should be the basis of a scientific classification.
Examples of syndromes that would be classified as “of unknown cause” include epilepsy of infancy with migrating focal seizures and myoclonic epilepsy in infancy [formerly benign myoclonic epilepsy of infancy, (Engel, 2006)]. At the present time, it might be reasonable to include some of the traditional electroclinical syndromes previously classified as “idiopathic” in the unknown category as well. These include benign rolandic epilepsy (Vadlamudi et al., 2006), Panayiotopoulos syndrome, and benign occipital epilepsy of the Gastaut type (Taylor et al., 2008). It is likely that genetic factors are involved in these syndromes. Current evidence (e.g., low or absent concordance in siblings) does not suggest that genetic factors are paramount. This issue will be revisited if high quality evidence supporting the hypothesis of a genetic contribution comes to light.
As new genetic contributions to epilepsy are recognized, it may often be difficult to know how best to characterize them with respect to the preceding distinctions. For example, ARX, a homeobox gene, is associated with phenotypic heterogeneity including West syndrome and lissencephaly (Stromme et al., 2002). STXBP1 encodes a protein involved in synaptic vesicle release and is associated with Ohtahara syndrome (Saitsu et al., 2008). Both syndromes involve severe encephalopathic forms of epilepsy. In the first case, one might consider the ARX mutation in the structural/metabolic category. In the case of STXBP1, because of the function of the protein product, one might associate this with the concept of genetic epilepsy. No determination has been made in either case at this time. Instead the role of the specific genetic error should be recognized, but it is not necessary to pigeon-hole the cause of the disorder further unless there is an adequate basis for doing so. We advocate a focus on mechanisms. This focus should ultimately reveal the natural classes. The overly simplistic designation of “genetic” versus “structural-metabolic” will then be replaced by a more precise characterization of the underlying cause.
Comments: Reestablishing the concept of “electroclinical syndrome” and recognizing the precision or imprecision of diagnosis.
Electroclinical syndromes: The 1989 report used the terms “syndromes” and “epilepsies” almost interchangeably. The result was that the term “syndrome” took on a broad and very imprecise meaning to the point where very specific and highly recognizable entities (such as childhood absence epilepsy) and poorly differentiated and not well-described epilepsies (such as cryptogenic parietal lobe epilepsy) tended to be treated as though they represented the same level of diagnostic precision. The result was a veneer of equivalency bestowed upon all entities identified within that document.
An electroclinical syndrome, however, 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 (e.g., Scheffer et al., 1998, 2008; Guerrini et al., 2007; Ottman et al., 2008). 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. It would be inappropriate to refer to, for example, epilepsy with a frontal lobe focus and not otherwise specified as a “syndrome.” The currently recognized electroclinical syndromes are presented in the first part of Table 3 organized by typical age at onset, as this is one of the most distinctive and clinically salient dimensions for organizing these entities, but this is just an example of one way to organize them.
Table 3. Electroclinical syndromes and other epilepsies
|Electroclinical syndromes arranged by age at onseta|
| Neonatal period|
| Benign familial neonatal epilepsy (BFNE)|
| Early myoclonic encephalopathy (EME)|
| Ohtahara syndrome|
| Epilepsy of infancy with migrating focal seizures|
| West syndrome|
| Myoclonic epilepsy in infancy (MEI)|
| Benign infantile epilepsy|
| Benign familial infantile epilepsy|
| Dravet syndrome|
| Myoclonic encephalopathy in nonprogressive disorders|
| Febrile seizures plus (FS+) (can start in infancy)|
| Panayiotopoulos syndrome|
| Epilepsy with myoclonic atonic (previously astatic) seizures|
| Benign epilepsy with centrotemporal spikes (BECTS)|
| Autosomal-dominant nocturnal frontal lobe epilepsy (ADNFLE)|
| Late onset childhood occipital epilepsy (Gastaut type)|
| Epilepsy with myoclonic absences|
| Lennox-Gastaut syndrome|
| Epileptic encephalopathy with continuous spike-and-wave during sleep (CSWS)b|
| Landau-Kleffner syndrome (LKS)|
| Childhood absence epilepsy (CAE)|
| Adolescence – Adult|
| Juvenile absence epilepsy (JAE)|
| Juvenile myoclonic epilepsy (JME)|
| Epilepsy with generalized tonic–clonic seizures alone|
| Progressive myoclonus epilepsies (PME)|
| Autosomal dominant epilepsy with auditory features (ADEAF)|
| Other familial temporal lobe epilepsies|
| Less specific age relationship|
| Familial focal epilepsy with variable foci (childhood to adult)|
| Reflex epilepsies|
| Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE with HS)|
| Rasmussen syndrome|
| Gelastic seizures with hypothalamic hamartoma|
| Epilepsies that do not fit into any of these diagnostic categories can be distinguished first on the basis of the presence or absence of a known structural or metabolic condition (presumed cause) and then on the basis of the primary mode of seizure onset (generalized vs. focal)|
|Epilepsies attributed to and organized by structural-metabolic causes|
| Malformations of cortical development (hemimegalencephaly, heterotopias, etc.)|
| Neurocutaneous syndromes (tuberous sclerosis complex, Sturge-Weber, etc.)|
| Perinatal insults|
|Epilepsies of unknown cause|
|Conditions with epileptic seizures that are traditionally not diagnosed as a form of epilepsy per se|
| Benign neonatal seizures (BNS)|
| Febrile seizures (FS)|
Constellations: Whether these entities should be considered syndromes or nonsyndromic epilepsies was the subject of considerable disagreement. Ultimately, these conditions can and should be recognized based on their clinical features. What they are called as a group in no way detracts from their clinical importance.
Epilepsies associated with structural or metabolic conditions: Previously, many such epilepsies were grouped together as “symptomatic focal epilepsies” and distinguished on the basis of localization. We recommend less emphasis be given to localization and more to the underlying structural or metabolic cause. Terms such as “symptomatic temporal lobe epilepsy” are replaced by longer but more precise expressions such as “epilepsy with focal seizures secondary to cortical dysplasia in the temporal lobe.” Localization is not, based on current knowledge, the primary factor of importance for understanding the cause and prognosis of these epilepsies. Further organizations might consider type of lesion, age at onset, localization, seizure type, specific ictal and interictal EEG patterns, or other factors.
Epilepsies of unknown cause: These epilepsies account for one-third or more of all epilepsy, are the most poorly understood, and represent perhaps the most fertile area for future research in imaging and genetics. For such research to be feasible, however, it will require that the simple characterization by localization of interictal focus (e.g., cryptogenic parietal lobe epilepsy) be replaced with a detailed characterization of all relevant features (see next section). Among these poorly differentiated epilepsies are likely to be additional genetic electroclinical syndromes (such as ADNFLE and ADEAF); however, they cannot be recognized until they are adequately characterized. This approach should also facilitate identification of nongenetic determinants of epilepsy.
Comments: Other dimensions for classifying epilepsies and organizing information:
The commission decided to discard the terms generalized and focal for modifying the epilepsies themselves. “Generalized” spasms arising from a focal lesion as occurs in West syndrome and focal seizures arising from a diffuse genetic disorder as occurs in Dravet syndrome were some of the prime examples of why and how these terms do not adequately reflect the processes underlying the epilepsies.
In addition to the traditional dimensions and features, each syndrome and each patient can be characterized according to a large number of other features, which are often routine parts of any patient’s evaluation and essential features in distinguishing among established syndromes. These include the cognitive and developmental antecedents and consequences, motor and sensory examinations, EEG features, provoking or triggering factors, and patterns of seizure occurrence with respect to sleep. There is also an important traditional cluster of syndromes that might be convenient to maintain, the “idiopathic generalized epilepsies;” however, we recommend that they be called the “genetic generalized epilepsies.”
Natural evolution: Epileptic Encephalopathy. The term “epileptic encephalopathy” can be used to characterize syndromes and also be applied to individuals. As a domain for clustering and describing syndromes, an epileptic encephalopathy is an electroclinical syndrome associated with a high probability of encephalopathic features that present or worsen after the onset of epilepsy. Separately but important to note, as a group, they tend to be pharmacoresistant, but this is another quality or dimension. Inclusion of a specific syndrome in the domain of “epileptic encephalopathy” does not imply that all individuals with these disorders will appear encephalopathic; however, the risk is often quite high. Diagnosing an individual as having an encephalopathic course requires demonstration of a failure to develop as expected relative to same-aged peers or to regress in abilities. Note that it is not necessary for an individual to have a syndrome identified as being one of the “epileptic encephalopathies” (e.g., West, Dravet) in order to have an encephalopathic course. Epileptic encephalopathy can present along a continuum of severity and may occur at any age. The phenomenon is most common and severe in infancy and early childhood, where global and profound cognitive impairment may occur. Adults, however, can also experience cognitive losses over time from uncontrolled seizures (Hermann et al., 2006). Whether these involve similar or different mechanisms as those early in development remains to be seen, but the phenomenon should be recognized.
“Epileptic encephalopathy” should be viewed as a concept and a description of what is observed clinically with the recognition that, we are rapidly approaching a clearer understanding of the effects of epilepsy on brain function and the potential for lasting deleterious impact in the developing brain. We must, however, recognize that the source of an apparent encephalopathy is usually unknown. It may be the product of the underlying cause, the result of epileptic process, or a combination of both.
The argument against the term,“Benign”: One of the new research Benchmarks of the National Institutes of Health for epilepsy research is to understand the various comorbidities of epilepsy including cognitive, behavioral, and psychiatric disorders as well as mortality (Kelly et al., 2009). There are international efforts underway to understand the mechanisms of sudden death and to educate patients and families of this risk and how it may be mitigated. Increasingly, basic science and clinical studies are illuminating the shared mechanisms between epilepsy and these various other disorders.
Self-limited: The terms “idiopathic” and “benign” captured important features of clinical relevance. We recommend that, instead of designating a group of syndromes as “benign,” we recognize the different qualities that make up the concept of benign and apply them specifically and consistently to individual forms of epilepsy. One of these features is predictable spontaneous remission. Instead of benign, we recommend the descriptive term “self-limited” to mean having a high likelihood of spontaneously remitting at a predictable age. If a better term is devised, that can be considered in the future.
Pharmacoresponsive: In syndromes designated as idiopathic, most cases tend to be pharmacoresponsive. Diagnosis of one of these syndromes allows, within a reasonable certainty, the prediction that the seizures will rapidly come under control with appropriate medication. As yet, we do not have perfect prediction, so some patients diagnosed with a particular syndrome may not be pharmacoresponsive; however, clinical prognostication was never an exact science. Labeling these syndromes as pharmacoresponsive may be more meaningful to clinicians and provide anticipatory guidance to families better than the term “idiopathic,” which requires explanation.
Of note, the inclusion of features that are descriptive of the natural evolution of a form of epilepsy is not, strictly speaking, based upon natural classes but rather on repeated observations and impressions. They are included for pragmatic purposes.
Age at onset: For grouping syndromes or individuals, age at onset categories are recommended as per standard use: neonate (<44 weeks of gestational age), infant (<1 year), child (1–12 years), adolescent (12–18 years), and adult (>18 years). For some purposes, it may be helpful to distinguish a category for elderly (>60 or >65). The age ranges are approximate and meant to be used only for convenience in describing already characterized forms of epilepsy. For individual patients, the exact age at onset or best approximation should be used, and greater precision for electroclinical syndromes is encouraged when possible.
Other features: Many other dimensions and features will ultimately be used in describing, classifying, and grouping the different forms of epilepsies and may prove to be more useful for organizing the epilepsies than those used in the 1989 Classification. We may ultimately classify by specific cause, for example, ion channelopathies and by specific ion channel genes, as is being done with prolonged QT syndrome (Johnsons et al., 2009). Alternatively, one could organize a subgroup of epilepsies by age at onset and association with specific types of cortical malformations (Lerner et al., 2009). Other dimensions would include but are not limited to detailed aspects of ictal and interictal EEG, structural neuroimaging findings, neurologic examination, and cognitive and psychiatric status.
A syndrome is characterized with respect to many factors. Knowing a given patient’s syndromic diagnosis, provides key information about that patient’s epilepsy, for example, likely age at onset, EEG patterns, likely responses to medications, and cognitive and developmental status. We can organize our information about these syndromes along the many dimensions by which they are characterized. The benefits of this approach for developing a diagnostic manual are considerable.
For epilepsies that do not fall into clear electroclinical syndromes and which are associated with structural–metabolic causes, the most natural and rational primary approach to organizing them seems to be by specific underlying cause or lesion. For epilepsies of unknown cause and predominately characterized by seizure onset, there is no natural class that validly sorts them into more homogeneous groups. The revised recommended approach explicitly acknowledges this. Forcing these partially or poorly characterized epilepsies into a system of classification for which they are not yet ready suggests greater knowledge than we currently have and impedes progress. Much greater effort should be invested in characterizing individual patients sufficiently to facilitate objective research into identifying previously unrecognized entities. This information can then be used as the basis for objective analyses to identify potential new “syndromes” (Berg & Blackstone, 2006). It will also greatly facilitate the use of the planned diagnostic manual, which will provide a guide with specific definitions and examples that will encourage clinicians to make the necessary, precise observations on all patients in order to make or exclude specific diagnoses.
Comments: Classification in the future:
The previous “classifications” of seizures and epilepsies were often treated as rigid doctrine. Epilepsy classification was dominated by expert opinion and assertion. Advances in all areas of investigation (epidemiology, electrophysiology, imaging, developmental neurobiology, genomics, computational neuroscience, and neurochemistry) have made it clear that such a simple and often autocratic approach does not do justice to the complexity of the underlying developmental and physiologic processes. Therefore, any classifications put forth by this Commission should be viewed as a guide to summarize our current understanding about seizures and epilepsies in a useful manner, one that is responsive to the needs to which it is put and flexible enough to incorporate new information as it develops.
Unfortunately, this remains an area where long-held beliefs and ignorance often clash with reason and evidence. For example, an overly melodramatic comment posted on the website stated that the Commission’s rejection of the term “benign” to characterize epilepsy was “… a stone of death to all of us, who have campaigned for year that on evidence, a significant number of patients and mainly children have some forms of epilepsies … that are entirely benign with little or no detrimental consequences as documented with long term prospective studies over the last 50 years (…). The main consequences … are psychosocial resulting from equating them with epilepsy.” Such emotional assertions actively ignore the last several years of very productive research in the neurosciences and represent the kind of arguments that are no longer acceptable.
In the future, the Classification of the Epilepsies will essentially be a database. The features discussed earlier and other essential pieces of information will form the basis for a diagnostic manual. In the interim, we encourage people to conceptualize a future classification as a flexible, multidimensional catalog of features for organizing information about different epilepsies (or seizures) as appropriate for purposes of drug development, clinical and basic research, and of course, clinical practice.