` Department of Pediatrics, University of British Columbia, British Columbia s Children s Hospital, Vancouver, Canada

Transcription

1 The Organization of the Epilepsies: Report of the ILAE Commission on Classification and Terminology Ingrid E Scheffer *^#, Samuel F Berkovic *, Giuseppe Capovilla +, Mary B Connolly`, Laura Guilhoto -&, Edouard Hirsch, Solomon L Moshe %, Douglas Nordli =, Yue-Hua Sameer M Zuberi ~. * Department of Medicine, The University of Melbourne, Austin Health, Melbourne, Australia ^ Florey Institute of Neuroscience and Mental Health, Melbourne, Australia # Department of Paediatrics, The University of Melbourne, Royal Children s Hospital, Melbourne, Australia + Epilepsy Center, Child Neuropsychiatry Dept, C. Poma Hospital, Mantova, Italy ` Department of Pediatrics, University of British Columbia, British Columbia s Children s Hospital, Vancouver, Canada - Pediatrics Division, Hospital Universitário da Universidade de São Paulo, Brazil & Neurology Department, Hospital São Paulo, Universidade Federal de São Paulo, Brazil Strasbourg University, Fédération de Médecine Translationnelle de Strasbourg (FMTS), France % Albert Einstein College of Medicine, New York, USA = Ann & Robert H. Lurie Children s Hospital of Chicago Department of Pediatrics, Northwestern University Feinberg School of Department of Pediatrics, Peking University First Hospital, Beijing China ~ Paediatric Neurosciences Research Group, Royal Hospital for Sick Children, Glasgow, United Kingdom College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow, United Kingdom

2 Scheffer et al 2 Summary The classification of the epilepsies is a key clinical tool that impacts on every patient we see. As such, it is essential that it reflects current understanding of this complex group of diseases. In 2010, the first major overhaul of the classification in twenty-one years was proposed and introduced recent, wellaccepted concepts developed through major scientific advances in the field. Significantly, it presented an Organization rather than a Classification to denote that knowledge is still inadequate to have a fundamental framework on which to base a scientific classification. Here, we refine the Organization in response to feedback and suggest two non-hierarchical, complementary domains that overlap but provide different information. The first comprises electroclinical syndromes which remain essentially unchanged apart from updating the nomenclature. The second domain concerns etiology and has been expanded to include six non-exclusive categories that affect therapeutic approaches: genetic, structural, metabolic, immune, infectious and unknown. The etiology may fall into two or more categories. For the majority of patients, epilepsy evaluation should encompass both domains but one may be more important in determining clinical management for a specific patient. There still remains a significant group of patients who fall into the unclassified category, whose epilepsy cannot be diagnosed as a syndrome and the etiology is unknown. It is from this group that new entities will be recognized through further research. The concept behind the Organization is flexibility: you can organize it how you will, be that according to seizure type, EEG or imaging pattern. Today s Organization of the Epilepsies will be modified as knowledge increases, however, ongoing research, collaboration and management depends on clinicians and researchers speaking a common language. For all patients we should aim to use a diagnostic framework that includes identification of seizure types, syndrome and etiology. It is hoped that this Organization will serve as a basis for taking our care of patients and our understanding of the epilepsies forward in the years to come. Keywords: classification, etiology, organization, electroclinical syndromes, epilepsy

3 Scheffer et al 3 The classification of the epilepsies is an evolving process for which the ultimate aim is to establish a clinically relevant, scientifically-based classification. The Organization of the Epilepsies, published in 2010, was the first major reconfiguration of the classification of the epilepsies following the seminal introduction of the concept of epilepsy syndromes in 1985 (Commission 1985; Commission 1989; Berg et al, 2010). The Organization focused on updating terminology in line with current understanding. The term Organization was used, rather than Classification, to acknowledge that epilepsies could be organized according to the element of interest in the absence of being able to construct a truly scientific framework. While many list epilepsies on the basis of age of seizure onset, the Organization allows epilepsies to be arranged by the parameter of choice such as a seizure type, EEG or imaging marker. Conversely, electroclinical syndromes are well established entities that are diagnosed daily in the clinic and remained unchanged in the new Organization apart from updated terminology (Berg et al, 2010). These changes to the Organization are in response to the need to modify the terminology and classification used in epilepsy to reflect the significant scientific advances that have improved our understanding of seizures and epilepsies. As stated so eloquently in 1964 by Henri Gastaut and colleagues with the first ILAE proposal for a classification of seizures all attempts at classification of seizures are hampered by our limited knowledge of the underlying pathological processes within the brain and that any classification must of necessity be a tentative one and will be subject to change with every advance in scientific understanding of epilepsy (Gastaut et al 1964). We have moved forward, yet almost fifty years later, the same caveats apply. Epilepsy classification will always be a work in progress but, as a forward thinking community, we need to ensure that current, well accepted concepts are employed in how we approach classification in the patients for whom we care. The reasoning behind the implementation of new recommended terms (such as self-limited and pharmacoresponsive to replace benign) and the cessation of using old terminology (such as catastrophic, malignant, idiopathic, symptomatic and cryptogenic) is delineated fully in Berg et al (2010). Here, we develop the Organization further to take into account the valuable and extensive feedback we have received from the global epilepsy community both through discussion and the literature. The Organization has been designed primarily for clinical practice and therefore cannot ideally serve all purposes. It is important to consider epilepsy diagnosis at several different categorical levels to distinguish the manifestations from the underlying cause. Seizures are a separate category to epilepsies, and epilepsies are a separate category to etiologies. In some cases, they will be closely related whereas, in others, a seizure type will be merely one of many seizure types that occur in an epilepsy syndrome which, in turn, may have many etiologies. Generalized seizures and focal seizures

4 Scheffer et al 4 In 2010, new definitions of generalized and focal seizures were introduced to reflect recent understanding of the networks involved: Generalized seizures originate at some point within, and rapidly engage, bilaterally distributed networks. Such bilateral networks can include cortical and subcortical structures, but do not necessarily include the entire cortex. Although individual seizure onsets can appear localized, the location and lateralization are not consistent from one seizure to another. Generalized seizures can be asymmetric. (Berg et al, 2010) Focal seizures originate within networks limited to one hemisphere, which may be discretely localized or more widely distributed. Focal seizures may originate in subcortical structures. For each seizure type, ictal onset is consistent from one seizure to another with preferential propagation patterns, which can involve the contralateral hemisphere. In some cases, however, there is more than one epileptogenic network, and more than one seizure type, but each individual seizure type has a consistent site of onset. Focal seizures do not fall into any recognized set of natural classes based on any current understanding of the mechanisms involved. (Berg et al, 2010) The number of types of generalized seizures has reduced from previous classifications as per Table 1 (Table 1 from Berg et al, 2010). The nomenclature denoting focal seizures has also changed to use words that have a clear and transparent meaning. For example, the term complex partial seizure has been replaced by focal seizure with impaired consciousness or awareness or responsiveness. While altered cognition does not always encompass loss of awareness, the term dyscognitive has been suggested as a shorthand alternative to impaired consciousness or responsiveness or awareness. This means that the term focal dyscognitive seizure can replace complex partial seizure. Where clinicians prefer, they can use the longer phraseology of impaired consciousness or responsiveness or awareness. Simple partial seizure is now focal seizure with retained consciousness or awareness and aura can be used for subjective sensations. Other new descriptors are documented in Table 2 (Table 2 from Berg et al, 2010). Generalized and focal epilepsies: not always a dichotomy In order to make an epilepsy diagnosis, in addition to a careful clinical evaluation, it is necessary to have access to EEG and MRI studies where appropriate. While the terms generalized epilepsy and focal epilepsy remain useful descriptors for many cases, there are, however, clinical settings in which a dichotomous approach is not supported by the electroclinical data. Therefore such an approach cannot form the basis of a biological classification. The electroclinical syndromes within the group of Genetic Generalized Epilepsies such as Childhood Absence Epilepsy, Juvenile Absence Epilepsy, Juvenile Myoclonic Epilepsy and Generalized Tonic-Clonic Seizures Alone refer to epilepsies with generalized seizures (Table 1) associated with generalized

5 Scheffer et al 5 epileptiform EEG patterns such as generalized spike wave activity (although focal fragmentation of spike wave patterns may be seen). In contrast, focal epilepsies refer to epilepsies with focal seizures (Table 2) with focal EEG findings (slowing, focal epileptiform discharges which may be unifocal or multifocal). Focal structural abnormalities are found in a significant proportion of cases. Distinguishing these two major categories has important implications for therapeutic management both in considering the type of antiepileptic drug to be prescribed and whether the patient may be an epilepsy surgery candidate. Caution is necessary in adopting a dichotomous approach as many patients may not fall into one group and therefore an understanding of the underlying process and etiology needs to be taken into account. For example a patient with tuberous sclerosis complex may present with a generalized epileptiform EEG pattern such as slow spike wave discharges yet may have a surgically remediable focal lesion. In such situations, it is essential to consider the underlying process and aetiology and not the generalized or focal electro-clinical categorization as the final determinant of therapeutic approaches. There are also patients who cannot be categorized into one group, typically because of overlapping features with both generalized and focal seizures, or generalized and focal epileptiform abnormalities on scalp EEG. In such instances, it is not appropriate to classify patients as having either generalized or focal epilepsy but to acknowledge that they have a more complex phenotype. This is the case for many of the epileptic encephalopathies such as Dravet, West and Lennox-Gastaut syndromes and many of the patients previously regarded as having Symptomatic Generalized Epilepsies (see below). Approaches to epilepsy diagnosis In a person with epilepsy, there are two diagnostic approaches that deserve consideration and provide different information that is not hierarchical and serves different purposes. The domains are electroclinical syndromes and etiologies; these domains overlap but provide complementary information. The domains offer different types of specificity in diagnosis and differ in which is the most important to apply to a particular patient. For each patient, we should aim to diagnose seizure type(s), electroclinical syndrome and etiology where possible. The domains offer different insights. The electroclinical syndrome describes a specific presentation that often has heterogeneous etiologies. Electroclinical syndromes may evolve over time from one age-related syndrome to another, for example, Childhood Absence Epilepsy may evolve to Juvenile Myoclonic Epilepsy. In contrast, a specific etiology may present with phenotypic heterogeneity yet respond to a targeted therapy. Ideally we need to aim for both levels of understanding for each patient. (A) Electroclinical syndromes

6 Scheffer et al 6 An electroclinical syndrome is defined by age of onset, seizure types, EEG patterns, imaging features and co-morbidities such as intellectual impairment (Commission 1985; Commission 1989; Berg et al 2010). The electroclinical syndromes are distinctive clinical entities and carry treatment and prognostic implications. They have not altered from previous classifications of the epilepsies (apart from some minor adjustments in their nomenclature in line with the Organization). There are many well established syndromes which are important in daily practice and remain unchanged. Examples include Childhood Absence Epilepsy, Childhood Epilepsy with Centro-Temporal Spikes and Juvenile Myoclonic Epilepsy. Diagnosis of an epilepsy syndrome often determines the selection of antiepileptic therapies and prognosis. Examples of well accepted electroclinical syndromes are listed in Table 3 but it should be emphasized that this is not an official list of all suggested syndromes in the literature (Table 3 from Berg et al, 2010). Note that the term self limited has been used to replace benign where possible to reflect our understanding that even the milder epilepsy syndromes may be associated with psychosocial and cognitive co-morbidities. The electroclinical syndromes include a range of epileptic encephalopathies such as Lennox-Gastaut syndrome and Landau-Kleffner syndrome. The term epileptic encephalopathy embodies the notion that frequent or near continuous epileptiform activity causes ongoing impairment in cognitive and behavioral function beyond that attributed to the underlying etiology alone. An epileptic encephalopathy can occur at any age but many begin in infancy and childhood. Electroclinical syndromes may be associated with heterogeneous etiologies. An example is West syndrome which may occur in the setting of hypoxic-ischemic encephalopathy, a malformation of cortical development, tuberous sclerosis complex, a genetic mutation in a range of genes such as ARX or STXBP1, or where the etiology is unknown. (B) Etiologically based diagnoses The 2010 Organization divided the etiological categories into three genetic, structural/metabolic and unknown. This was partly devised to assist with the transition from the outdated terminology of idiopathic, symptomatic and cryptogenic in the 1985 and 1989 Classifications. With the use of the new categories, it has become clear that it would make sense to expand these into six groups. It is important to note that these categories are not independent and a patient s etiology will often fit into two or more categories. Categories have been designated based on whether they would lead to major management decisions involving investigations, specific treatments or genetic counseling. It is acknowledged that this is an area of rapid change from a scientific point of view. We suggest the following etiological categories:

7 Scheffer et al 7 (1) Genetic (2) Structural (3) Metabolic (4) Immune (5) Infectious (6) Unknown Further categories will be introduced with advances in knowledge as new etiologies emerge. A specific category does not rule out the influence of other factors. For example, environmental factors are highly likely to contribute to the expression of seizures in a person with a genetic epilepsy. (1) Genetic The etiology is deemed genetic where genetic factors play a major role in the causation of the individual s epilepsy. The concept of genetic relates to where the epilepsy is, to the best of our knowledge, the direct result of a known or presumed genetic defect and where seizures are the core symptom of the disorder. In most cases, the underlying genes are not yet known. Epilepsies are determined to be genetic based on clinical genetic studies such as twin and familial aggregation studies. A good example is the group of the idiopathic generalized epilepsies where there are numerous family and twin studies supporting a genetic etiology. The name idiopathic generalized epilepsies has been updated to reflect the knowledge that clinical genetic studies demonstrate a genetic basis and is now referred to as the genetic generalized epilepsies (GGE). Having a genetic etiology does not, of course, preclude an environmental contribution. The Genetic Generalized Epilepsies account for one third of all epilepsies and often follow complex inheritance, where they have a polygenic basis with environmental factors possibly playing a role. Genetic variants identified in epilepsies with complex inheritance are often regarded as susceptibility variants. They may be inherited but alone are insufficient to cause epilepsy (Helbig et al 2009; Dibbens et al 2009). In this setting, there is often no family history of seizures as other family members do not have enough epilepsy genetic variants to be affected. Conversely, other epilepsy syndromes have a monogenic etiology where a single mutation is causative. The best known example is Dravet syndrome in which about 80% of patients have an abnormality of SCN1A. Recently many genes have been identified that cause epileptic encephalopathies due to de novo mutations (Carvill et al 2013; EPI4K 2013). With the identification of each new genetic epileptic encephalopathy, a phenotypic spectrum emerges and serves as the basis for diagnosis and targeted therapeutic approaches. It is important to emphasize that genetic is not the same as inherited as de novo mutations are increasingly identified, especially in the severe epilepsies. Examples include the increasingly large subgroup of epileptic encephalopathies

8 Scheffer et al 8 with a genetic basis, Dravet syndrome and, more recently, the milder, selflimited, pharmacoresponsive epilepsies (Claes et al 2001; Weckhuysen et al 2012; Depienne et al 2009; Arsov et al 2012; Scheffer et al 2012; Carvill et al 2013). Importantly, a monogenic etiology may cause a spectrum of mild to severe epilepsies, such as SCN1A mutations which are associated with Dravet syndrome and Genetic Epilepsy with Febrile Seizures Plus (GEFS+), and may have implications for treatment (Brunklaus et al 2013). Understanding the phenotypic spectrum associated with mutations of a specific gene is critical information as the finding of a mutation in a specific gene may not, on its own, enable prediction of the outcome. Interpretation of its significance needs to be considered in the context of the electroclinical presentation. Thus, to date, the majority of genes show phenotypic heterogeneity and the majority of syndromes reveal genetic heterogeneity. (2) Structural A structural etiology refers to abnormalities visible on structural neuroimaging where the electro-clinical assessment together with the imaging findings lead to a reasonable inference that the imaging abnormality is the likely cause of the patient s seizures. From a conceptual standpoint, a structural etiology means that there is a distinct structural lesion that is associated with a substantially increased likelihood of developing epilepsy. Common structural causes of epilepsy include malformations of cortical development such as focal cortical dysplasia, trauma, and hypoxic-ischemic damage. Identification of a subtle structural lesion requires appropriate MRI studies using specific epilepsy protocols (Gaillard et al 2009). There are well recognized associations within the group of epilepsies with a structural etiology. These include the relatively frequent finding of mesial temporal lobe seizures with hippocampal sclerosis. Other key associations include gelastic seizures with hypothalamic hamartoma, Rasmussen syndrome, and hemiconvulsion-hemiplegia-epilepsy. Recognition of these associations is important to ensure that the patient s imaging is carefully examined for a specific structural abnormality. This in turn highlights the need for consideration for epilepsy surgery should the patient fail medical therapy. The underlying basis for a structural abnormality may be genetic or acquired or both. For example, polymicrogyria may be secondary to mutations in genes such as GPR56, or acquired, secondary to intrauterine cytomegalovirus infection. Acquired structural causes include hypoxic-ischemic encephalopathy, trauma, infection and stroke. Where a structural etiology has a well-defined genetic basis such as tuberous sclerosis complex, which is caused by mutations in the genes tuberin or hamartin, both terms, structural and genetic can be used. (3) Metabolic

9 Scheffer et al 9 A range of metabolic disorders is associated with epilepsy. This area is expanding and a greater understanding of the phenotypic spectrum emerging. Metabolic causes refer to a well delineated metabolic defect with manifestations or biochemical changes throughout the body such as porphyria, uremia, aminoacidopathies or pyridoxine dependent seizures. In many cases, metabolic disorders will have a genetic defect so the combined terminology metabolicgenetic could be used in describing their etiology. It is likely that the vast majority of metabolic epilepsies will have a genetic basis but some may be acquired such as cerebral folate deficiency. The identification of specific metabolic causes of epilepsy is extremely important due to implications for specific therapies and potential prevention of intellectual impairment. (4) Immune A range of immune epilepsies has been recently recognized with characteristic presentations in both adults and children. An immune etiology can be conceptualized as where there is evidence of autoimmune-mediated central nervous system inflammation. Diagnosis of these autoimmune encephalitides is rapidly increasing, particularly with greater access to antibody testing. Examples include anti-nmda receptor encephalitis and anti-lgi1 encephalitis (Lancaster and Dalmau 2012). With the emergence of these entities, this etiological subgroup deserves a specific category particularly given the treatment implications with targeted immunotherapies. (5) Infectious The commonest etiology worldwide is infectious. An infectious etiology refers to a patient with epilepsy, rather than with seizures occurring in the setting of acute infection such as meningitis or encephalitis. This includes tuberculosis, HIV, cerebral malaria, neurocysticercosis, subacute sclerosing panencephalitis and cerebral toxoplasmosis. These infections sometimes have a structural correlate. An infectious etiology carries specific treatment implications. (6) Unknown There remain many patients with epilepsy for whom the cause is not known. In this category it is not possible to make a specific diagnosis apart from the basic electroclinical semiology such as frontal lobe epilepsy. The extent to which a cause can be found depends on the extent of the evaluation available to the patient. This differs across different health care settings and countries and hopefully will improve over time in resource poor countries. Application of multiple etiologies to one patient Each etiology is not meant to be discrete and any one cause could be viewed as making a contribution to other etiologies. Similarly, the etiology may not determine the presentation. For example, glucose transporter 1 (GLUT1) deficiency is a metabolic-genetic etiology that has a wide range of clinical presentations including epilepsy with myoclonic-atonic seizures, absence

10 Scheffer et al 10 epilepsies beginning from infancy to young adult life, focal epilepsies and genetic generalized epilepsies. Knowing the etiology in this setting is important and may inform treatment (e.g. the ketogenic diet for GLUT1 deficiency) but does not enable the clinician to predict how the patient will present in terms of electroclinical semiology. Over time patients will undoubtedly move between etiological categories as knowledge grows. (C) Unclassified epilepsies For a third of epilepsies, the specific diagnosis in terms of syndrome or etiology remains unknown. There may be electroclinical features that allow localization, such as temporal lobe seizures, but the patient does not have a recognized electroclinical syndrome nor is their etiology known. It is here that more specific phenotyping or time to observe the evolution of the patient s epilepsy may lead to the emergence of subgroups for which an etiological diagnosis can be found. For example, genes are just emerging that cause non-lesional temporal lobe epilepsy in sporadic cases and account for a subset of common focal epilepsy of previously unknown etiology (Dibbens et al, 2013). Research approaches looking at molecular and acquired determinants promise to elucidate new etiologies. Future directions in epilepsy classification The classification of such a complex group of diseases as the epilepsies will remain challenging. While it is unlikely to ever be perfect, ongoing refinement is essential as it forms our primary clinical tool in the assessment of patients with epilepsy. In every case, the clinician should consider seizure type(s), epilepsy syndrome and etiology. The focus of the new organization is primarily on clinical practice but it also needs to be relevant, practical and useful as a basis for clinical and translational research so that we can advance our understanding of epilepsy in the years ahead. Our goal must be to improve the plight of individuals with epilepsy around the world.

11 Scheffer et al 11 Acknowledgments The Commission is grateful to the Classification Taskforce comprising Kate Riney, Lynette G Sadleir, Christian Korff, Elaine Wirrell, Yoshimi Sogawa, Stephan Schuele, Andrew Lux and Jeffrey Buchhalter, for their input to this document and for their work with members of the Commission in developing the online Diagnostic Manual (see url:). References Arsov T, Mullen SA, Rogers S, Phillips AM, Katherine M Lawrence KM, Damiano JA, Goldberg-Stern H, Afawi Z, Kivity S, Trager C, Petrou S, Berkovic SF, Scheffer IE. GLUT1-deficiency in the idiopathic generalised epilepsies. Ann Neurol (in press 2012) Berg AT., Berkovic, S. F., Brodie, M. J., Buchhalter, J., Cross, J. H., van Emde Boas, W., Engel, J., et al. (2010). Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, Epilepsia, 51(4), doi: /j x Blume, W. T., Lüders, H. O., Mizrahi, E., Tassinari, C., van Emde Boas, W., & Engel, J. (2001). Glossary of descriptive terminology for ictal semiology: report of the ILAE task force on classification and terminology. Epilepsia, 42(9), Brunklaus A, Dorris L, Ellis R, Reavey E, Lee E, Forbes G, Appleton R, Cross JH, Ferrie C, Hughes I, Jollands A, King MD, Livingston J, Lynch B, Philip S, Scheffer IE, Williams R, Zuberi SM. (2013) The clinical utility of an SCN1A genetic diagnosis in infantile-onset epilepsy. Developmental Medicine & Child Neurology. 55: Carvill, GL, Heavin SB, Yendle SC, McMahon JM, O Roak BJ, Cook J, Khan A, O Dorschner M, Weaver M, Calvert S, Malone S, Wallace G, Stanley T, Bye AME, Bleasel A, Howell KB, Kivity S, Mackay MT, Rodriguez-Casero V, Webster R, Korczyn A, Afawi Z, Zelnick N, Lerman-Sagie T, Lev D, Møller RS, Gill D, Andrade DM, Freeman JL, Sadleir LG, Shendure J, Berkovic SF, Scheffer IE, Mefford HC. Targeted resequencing in epileptic encephalopathies identifies recurrent de novo mutations in CHD2 and SYNGAP1. Nat Genet May 26. doi: /ng [Epub ahead of print] Claes, L., Del-Favero, J., Ceulemans, B., Lagae, L., Van Broeckhoven, C., & De Jonghe, P. (2001). De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. American journal of human genetics, 68(6), doi: / Commission on Classification and Terminology of the International League against Epilepsy. Proposal for classification of epilepsies and epileptic syndromes. Epilepsia. 1985;26:268-78

12 Scheffer et al 12 Commission on Classification and Terminology of the International League Against Epilepsy. (1989) Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 30: Depienne, C., Bouteiller, D., Keren, B., Cheuret, E., Poirier, K., Trouillard, O., Benyahia, B., et al. (2009). Sporadic infantile epileptic encephalopathy caused by mutations in PCDH19 resembles Dravet syndrome but mainly affects females. PLoS Genetics, 5(2), e doi: /journal.pgen Dibbens, L. M., Mullen, S., Helbig, I., Mefford, H. C., Bayly, M. A., Bellows, S., et al. (2009). Familial and sporadic 15q13.3 microdeletions in idiopathic generalized epilepsy: precedent for disorders with complex inheritance. Human Molecular Genetics, 18(19), doi: /hmg/ddp311 Dibbens LM, de Vries B, Donatello S, Heron SE, Hodgson BL, Chintawar S, Crompton DE, Hughes JN, Bellows ST, Klein KM, Callenbach PMC, Corbett MA, Gardner AE, Kivity S, Iona X, Regan BM, Weller CM, Crimmins D, O Brien T, Guerrero-López R, Mulley JC, Dubeau F, Licchetta L, Bisulli F, Cossette P, Thomas PQ, Gecz J, Serratosa J, Brouwer OF, Andermann F, Andermann E, van den Maagdenberg A MJM, Pandolfo M, Berkovic SF, Scheffer IE. Mutations in DEPDC5 cause Familial Focal Epilepsy with Variable Foci. Nat Genet 2013;45: Epub 2013 Mar 31. Epi4K Consortium. De novo mutations in epileptic encephalopathies. Nature ;501: doi: /nature Epub 2013 Aug 11. Gaillard WD, Cross JH, Duncan JS, Stefan H, Theodore WH; Task Force on Practice Parameter Imaging Guidelines for International League Against Epilepsy, Commission for Diagnostics. Epilepsy imaging study guideline criteria: commentary on diagnostic testing study guidelines and practice parameters. Epilepsia Sep;52(9): doi: /j x. Epub 2011 Jul 8. Gastaut, H., Caveness, W. F., Landolt, W., Lorentz de Haas, A. M., McNaughton, F. L., Magnus, O., Merlis, J. K., et al. (1964). A proposed international classification of epileptic seizures. Epilepsia, 5, Helbig, I., Mefford, H. C., Sharp, A. J., Guipponi, M., Fichera, M., Franke, A., et al. (2009). 15q13.3 microdeletions increase risk of idiopathic generalized epilepsy. Nature Genetics, 41(2), doi: /ng.292 Lancaster E, Dalmau J. Neuronal autoantigens--pathogenesis, associated disorders and antibody testing. Nat Rev Neurol Jun 19;8(7): doi: /nrneurol Review. Scheffer, I. E., Turner, S. J., Dibbens, L. M., Bayly, M. A., (null), Hodgson, B., et al. (2008). Epilepsy and mental retardation limited to females: an under-recognized disorder. Brain 131(Pt 4), doi: /brain/awm338 Scheffer IE, Grinton BE, Heron SE, Kivity S, Afawi Z, Iona X, Goldberg-Stern H, Andrews I, Guerrini R, Marini C, Sadleir LG, Berkovic SF, Dibbens LM. PRRT2

13 Scheffer et al 13 phenotypic spectrum includes sporadic and fever-related infantile seizures. Neurology 2012 Oct 17 (Epub ahead of print). Weckhuysen, S., Mandelstam, S., Suls, A., Audenaert, D., Deconinck, T., Claes, L. R. F., Deprez, L., et al. (2012). KCNQ2 encephalopathy: Emerging phenotype of a neonatal epileptic encephalopathy. Annals of Neurology, 71(1), doi: /ana.22644

14 Scheffer et al 14 Table 1. Classification of seizures # Generalized seizures Tonic-clonic (in any combination) Absence Typical Atypical Absence with special features Myoclonic absence Eyelid myoclonia Myoclonic Myoclonic Myoclonic-atonic Myoclonic-tonic Clonic Tonic Atonic Focal seizures Epileptic spasms # Seizures that cannot be clearly diagnosed into one of the preceding categories should be considered unclassified until further information allows their accurate diagnosis. This is not considered a classification category, however.

15 Scheffer et al 15 Table 2. Descriptors of focal seizures according to degree of impairment during seizure* Without impairment of consciousness or awareness With observable motor or autonomic components Focal motor and autonomic can be used Involving subjective sensory or psychic phenomena only aura can also be used Replaces term simple partial seizure With impairment of consciousness or awareness Dyscognitive can also be used. It is understood that dyscognitive may not always mean altered awareness but it is used here to denote altered consciousness or awareness which may be response tested Replaces term complex partial seizure Evolving to a bilateral convulsive^ seizure May include tonic, clonic or tonic and clonic components in any order Replaces term secondarily generalized seizure *For more definitions of descriptors, see Blume et al 2001 ^Although the term convulsive was considered lay in the Glossary (Blume et al 2001), its use is endorsed here as it has been used throughout medicine and translates well across many languages

16 Scheffer et al 16 Table 3. Examples of electroclinical syndromes and other epilepsies arranged according to (modified from Berg et al 2010)* Neonatal period #Self-limited neonatal seizures #Self-limited familial neonatal epilepsy Early myoclonic encephalopathy (EME) Ohtahara syndrome Infancy (onset under 2 years) Childhood Febrile seizures Febrile seizures plus Epilepsy of infancy with migrating focal seizures West syndrome Myoclonic epilepsy in infancy (MEI) #Self-limited infantile epilepsy #Self-limited familial infantile epilepsy Dravet syndrome Myoclonic encephalopathy in non-progressive disorders Febrile seizures Febrile seizures plus (FS+) Early onset childhood occipital epilepsy (Panayiotopoulos type) Epilepsy with myoclonic atonic (previously astatic) seizures #Self-limited epilepsy with centrotemporal spikes (ECTS) Autosomal-dominant nocturnal frontal lobe epilepsy (ADNFLE) Late onset childhood occipital epilepsy (Gastaut type) Childhood Absence Epilepsy (CAE)

17 Scheffer et al 17 Epilepsy with myoclonic absences Lennox-Gastaut syndrome Epileptic encephalopathy with continuous spike-and-wave during sleep (CSWS) Landau-Kleffner syndrome (LKS) Adolescence Adult Juvenile absence epilepsy (JAE) Juvenile myoclonic epilepsy (JME) Epilepsy with generalized tonic clonic seizures alone (GTCA) Autosomal dominant epilepsy with auditory features (ADEAF) Other familial temporal lobe epilepsies Familial epilepsy syndromes Familial focal epilepsy with variable foci (FFEVF) Genetic epilepsy with febrile seizures plus arrangement of electoclinical syndromes does not reflect etiology. Age of onset is one of many ways in which syndromes can be organized. *These are examples of epilepsy syndromes and not a complete list of syndromes. Inclusion does not denote ILAE endorsement of specific syndromes. # The term self-limited replaces benign.