ILAE classification of seizures and epilepsy

INTRODUCTION — Epilepsy is defined as a disorder of the brain characterized by an enduring predisposition to epileptic seizures [1]. It is a heterogeneous condition characterized by multiple possible seizure types and syndromes, diverse etiologies, and variable prognoses. Accurate classification is essential for several reasons [2]:

●To provide a framework for understanding the type(s) of seizure(s) a patient has, other types that are more likely to occur, potential seizure triggers, and prognosis

●To inform the risk of comorbidities (eg, psychiatric, cognitive) and mortality, including sudden unexpected death in epilepsy

●To guide choice of optimal antiseizure medication and surgical therapies

Over the past several decades, significant advances in neuroimaging, genomic technologies, and molecular biology have improved the understanding of the pathogenesis of seizures and epilepsy [3]. The International League Against Epilepsy (ILAE) Commission on Classification and Terminology proposed substantial changes to the 1989 classification system in 2010 [4] and made further revisions in the position paper on ILAE Classification of the Epilepsies in 2017 [2,5,6]. The framework allows for diagnosis at three levels (seizure types, epilepsy types, and epilepsy syndromes), depending on information and resources that are available, and also addresses the broad concepts of etiology and associated comorbidities at all three levels (figure 1). In resource-poor settings with limited access to electroencephalography (EEG), neuroimaging, or specialized genetic and metabolic studies, or in situations in which limited history is present, the maximal level of diagnosis may be limited to seizure type only (level 1). Conversely, higher levels of diagnosis will likely be possible with more detailed history and greater availability of testing.

The most important concepts developed in the ILAE Classification of the Epilepsies are described here. The evaluation and diagnosis of seizures and epilepsy in children and adults are discussed separately. (See "Seizures and epilepsy in children: Clinical and laboratory diagnosis" and "Seizures and epilepsy in children: Classification, etiology, and clinical features" and "Epilepsy syndromes in children" and "Evaluation and management of the first seizure in adults" and "Seizures and epilepsy in older adults: Etiology, clinical presentation, and diagnosis".)

LEVEL 1: SEIZURE TYPE — Diagnosis at level 1 requires that the clinician identify that the patient has had an epileptic seizure rather than some other type of paroxysmal event, and then establish the type of seizure(s) (table 1) [2,5,6]. (See "Evaluation and management of the first seizure in adults", section on 'Differential diagnosis' and "Nonepileptic paroxysmal disorders in infancy" and "Nonepileptic paroxysmal disorders in children" and "Nonepileptic paroxysmal disorders in adolescents and adults".)

Seizure type is classified based on the initial manifestation of the seizure as generalized, focal, or unknown (if seizure onset is either missed or obscured) (table 1). Of note, the terms simple partial, complex partial, and secondarily generalized have been eliminated, since they were difficult to define pragmatically and were often used incorrectly.

Generalized seizures are further broken down into motor and nonmotor (absence) seizures. Focal seizures are further subdivided based on level of awareness (aware, impaired awareness, or unknown awareness). Additionally, focal seizures are subgrouped into motor and nonmotor seizures, based on signs and symptoms at onset. Additional descriptors for both generalized and focal seizures may be added based on specific motor or nonmotor symptoms. Focal seizures can also be more clearly described based on their elemental features (table 2).

The term "focal to bilateral tonic clonic" is used to describe a seizure that begins focally but then spreads to engage bilateral networks.

LEVEL 2: EPILEPSY BASED ON SEIZURE TYPE — The 1989 classification categorized epilepsies as either focal or generalized. The 2017 classification retains these terms, but acknowledges that not all epilepsies can be dichotomized into these two categories [2,5,6]. Thus, two additional categories have been added: generalized and focal epilepsy and unknown if generalized or focal epilepsy.

Generalized epilepsy — Epilepsy is considered generalized if the seizures originate at some point within, or rapidly engage bilaterally distributed networks, which can be subcortical or cortical structures and are frequently both. Generalized seizures do not need to necessarily include the entire cortex, however, and they may be asymmetric. Individuals with generalized epilepsy typically show generalized spike-wave or generalized paroxysmal fast activity on electroencephalogram (EEG). (See "Electroencephalography (EEG) in the diagnosis of seizures and epilepsy", section on 'EEG findings in patients with epilepsy'.)

Focal epilepsy — The term focal has replaced partial to describe epilepsy associated with seizures that are inferred from clinical or EEG data to originate in networks limited to one hemisphere [2,4-6]. Focal seizures may arise from either subcortical structures or neocortex. Most individuals with focal epilepsy show focal or multifocal discharges on interictal EEG.

Generalized and focal epilepsy — This term should be used for epilepsies that have both generalized and focal seizures. This category includes several epilepsy syndromes, particularly those with onset in early childhood, such as Dravet syndrome or Lennox-Gastaut syndrome, but may also be relevant for epilepsies associated with diffuse or focal structural, genetic, or metabolic etiologies. The interictal EEG may show both generalized and focal/multifocal discharges, or epileptiform discharges may be absent. (See "Dravet syndrome: Genetics, clinical features, and diagnosis" and "Lennox-Gastaut syndrome".)

Unknown if generalized or focal epilepsy — This term is used for epilepsies with seizures in which it cannot be clearly determined whether onset is focal or generalized. A key example is epileptic spasms, which may appear generalized despite being caused by a focal lesion. The term unknown should also be used in an individual who presents with a generalized tonic-clonic seizure and normal examination but whose EEG and neuroimaging is either noninformative or unavailable.

LEVEL 3: EPILEPSY SYNDROME — An epilepsy syndrome represents a complex of clinical features, signs and symptoms that together define a distinctive, recognizable clinical seizure disorder [2,5,6]. Some syndromes are highly correlated with a single specific etiology (eg, severe loss of function SCN1A variants in Dravet syndrome), whereas others may be due to a broad range of causes (eg, infantile spasms syndrome or Lennox-Gastaut syndrome).

Many syndromes can be identified based on age at onset, seizure type(s), electroencephalogram (EEG) characteristics, etiology, and associated comorbidities (figure 2 and table 3). The ILAE website EpilepsyDiagnosis.org is a resource for the diagnosis of epilepsy syndromes and contains parameters for diagnosis, as well as videos of specific seizure types and images of characteristic EEG findings.

Epilepsy syndromes are divided into epilepsy type (focal, generalized, or focal and generalized) with a separate category for syndromes with developmental and epileptic encephalopathy or with progressive neurological deterioration.

●Neonatal – In the neonatal period, recognized epilepsy syndromes (table 4) include (see "Overview of neonatal epilepsy syndromes"):

•Self-limited familial and nonfamilial neonatal epilepsy

•Early infantile developmental and epileptic encephalopathy, which encompasses syndromes formerly known as early myoclonic encephalopathy and Ohtahara syndrome

●Infancy – Epilepsy syndromes of infancy (table 4) include (see "Epilepsy syndromes in children"):

•Focal epilepsy syndromes:

-Self-limited familial and nonfamilial neonatal and infantile epilepsy

-Self-limited familial and nonfamilial infantile epilepsy

•Generalized epilepsy syndromes:

-Myoclonic epilepsy in infancy

•Focal and generalized epilepsy syndromes:

-Genetic epilepsy with febrile seizures plus

•Syndromes with developmental and epileptic encephalopathies:

-Epilepsy of infancy with migrating focal seizures

-Infantile spasms syndrome

-Dravet syndrome

-Gelastic seizures with hypothalamic hamartoma

●Childhood – Epilepsy syndromes of childhood include (see "Epilepsy syndromes in children"):

•Focal epilepsy syndromes:

-Self-limited epilepsy with autonomic seizures (SeLEAS), formerly known as Panayiotopoulos syndrome

-Self-limited epilepsy with centrotemporal spikes (SeLECTS), formerly known as benign epilepsy with centrotemporal spikes

-Childhood occipital visual epilepsy – formerly known as late-onset childhood occipital epilepsy (Gastaut type)

•Generalized epilepsy syndromes:

-Childhood absence epilepsy

-Epilepsy with myoclonic absences

-Epilepsy with eyelid myoclonia (formerly known as Jeavons syndrome)

•Focal and generalized epilepsy syndromes:

-Photosensitive occipital lobe epilepsy

•Syndromes with developmental and epileptic encephalopathies:

-Epilepsy with myoclonic-atonic seizures (EMAtS), formerly known as Doose syndrome or myoclonic-atonic epilepsy

-Lennox-Gastaut syndrome

-Developmental and epileptic encephalopathy with spike-wave activation in sleep (DEE-SWAS), which encompasses the former syndromes of epileptic encephalopathy with continuous spike-and-wave during sleep (CSWS) and Landau-Kleffner syndrome

-Hemiconvulsion-hemiplegia-epilepsy syndrome (HHE)

-Febrile infection–related epilepsy syndrome (FIRES)

●Adolescence, adulthood, or variable age – Epilepsy syndromes that begin in adolescence, adulthood, or at variable ages include:

•Focal epilepsy syndromes:

-Sleep-related hypermotor epilepsy

-Epilepsy with auditory features

-Familial focal epilepsy with variable foci (FFEVF)

-Mesial temporal lobe epilepsy with hippocampal sclerosis

•Generalized epilepsy syndromes:

-Juvenile absence epilepsy

-Juvenile myoclonic epilepsy

-Generalized tonic-clonic seizures alone

•Focal and generalized epilepsy syndromes:

-Epilepsy with reading-induced seizures (ERIS)

•Syndromes with developmental and epileptic encephalopathies or with progressive neurological deterioration:

-Rasmussen syndrome

-Progressive myoclonic epilepsy

Specific epilepsy syndromes are more commonly identified in children and adolescents than in adults. The diagnosis can provide specific information on natural history, associated comorbidities, particularly intellectual disability and psychiatric features, and management. (See "Overview of neonatal epilepsy syndromes" and "Epilepsy syndromes in children".)

OTHER CLASSIFICATION VARIABLES

Etiology — Etiologic classification and terminology has evolved over the years. The 2017 ILAE Classification of the Epilepsies recognizes six etiologic categories: genetic, structural, metabolic, immune, infectious, and unknown [2,5,6]. The terms idiopathic, symptomatic, and cryptogenic were eliminated as of the 2010 revision [4]. Etiology of epilepsy should be considered at all three levels of diagnosis.

Some etiologies are best described by a combination of categories. For example, tuberous sclerosis would be described as a genetic-structural etiology, and Leigh syndrome as a genetic-metabolic etiology.

Genetic — A genetic etiology is defined when epilepsy is the direct result of a known or presumed genetic defect and seizures are the core symptom of the disorder [4]. A genetic etiology is most frequently based on family aggregation and twin studies; only a minority of patients have a known pathogenic genetic variant, but this is changing rapidly with advances in molecular technologies.

This category includes the syndromes of the idiopathic generalized epilepsies, a subgroup of the genetic generalized epilepsies [7]. Examples include childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, and generalized tonic-clonic seizures alone, in which there is strong evidence from both family and twin studies of a heritable etiology. These conditions are caused by the summed final effect of multiple gene abnormalities and variations, which increase susceptibility to seizures (polygenic), often with additional environmental contributions (complex). In these syndromes, cognition is usually normal and seizure control is most often favorable. (See "Childhood absence epilepsy" and "Juvenile myoclonic epilepsy".)

Other genetic causes may be associated with intellectual disability and poor prognosis for seizure control, including Dravet syndrome, PCDH19-related epilepsy, and Down syndrome. (See "Epilepsy syndromes in children" and "Dravet syndrome: Genetics, clinical features, and diagnosis".)

Structural — Distinct structural causes may be associated with a substantially increased risk of developing epilepsy. Structural etiologies may be congenital (eg, cortical dysplasia, tuberous sclerosis) or acquired (eg, stroke, trauma, infection, immune-based).

Metabolic — A metabolic etiology is defined when a patient has a documented metabolic condition that is associated with a substantially increased risk of developing epilepsy. Examples include glucose transporter deficiency, creatine deficiency syndromes, and mitochondrial cytopathies. Many of these conditions are also detected using genetic studies.

Immune — Distinct immune mediated etiologies are defined as those in which there is evidence of central nervous system inflammation that results in epilepsy. Examples of immune etiologies include Rasmussen encephalitis, anti-N-methyl-D-aspartate (NMDA) receptor encephalitis. (See "Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis".)

Infectious — Central nervous system infection may result in both acute symptomatic seizures as well as epilepsy. Infections are one of the most important causes of epilepsy worldwide. Examples of infectious etiologies of epilepsy include HIV, neurocysticercosis, malaria, and tuberculosis.

Unknown — The term unknown has replaced the term cryptogenic, and simply means that the nature of the underlying cause is not currently known. All types of epilepsies with normal imaging and no documented genetic, metabolic, immune or infectious etiology are included in this category.

This category should also be used for disorders previously classified as idiopathic focal epilepsy, including self-limited epilepsy with centrotemporal spikes and self-limited epilepsy with autonomic seizures; in such disorders, there may be some genetic contribution to the epilepsy, but current evidence does not suggest that genetic factors are paramount. Generalized epilepsies that do not fit into one of the generalized genetic epilepsy syndromes, and for which there is insufficient evidence to support a heritable cause, should also be classified as unknown.

Epilepsies of unknown cause are common, accounting for approximately one-third of all cases. In this heterogeneous group of disorders, it is particularly important to collect further information on other relevant features, including cognitive and developmental antecedents and consequences, abnormalities on neurological examination, electroencephalography (EEG) features, provoking or triggering factors, natural history, age at onset, and other features.

Comorbidities — All epilepsies, at any level of the diagnostic framework, can have associated cognitive, psychological, and behavioral comorbidities, which may impact quality of life even more profoundly than the seizures. (See "Comorbidities and complications of epilepsy in adults" and "Seizures and epilepsy in children: Initial treatment and monitoring", section on 'Psychiatric and behavioral health screening'.)

Identification of specific etiologies and syndromes may assist in prediction of type and severity of comorbidity. As an example, infantile spasms syndrome predicts significantly greater risk of intellectual disability and autism spectrum disorder, and girls with pathogenic PCDH19 variants are also at high risk of behavioral problems and autism spectrum disorder. (See "Infantile epileptic spasms syndrome: Clinical features and diagnosis" and "Dravet syndrome: Genetics, clinical features, and diagnosis", section on 'Differential diagnosis'.)

OTHER TERMINOLOGY — The term epileptic encephalopathy applies to epilepsies with encephalopathic features that may present or worsen after onset of epilepsy [4]. This means that ongoing epileptic activity adversely impacts cognition and behavior, above and beyond what can be ascribed to the underlying etiology, if one is present (eg, cortical dysplasia).

Inherent to this concept is that amelioration of epileptiform activity has the potential to improve the developmental consequences of the disorder. However, many etiologies for epileptic encephalopathies also result in cognitive slowing and regression, independent of epilepsy (developmental encephalopathy), and it can be challenging to determine the degree to which developmental impact is caused by frequent seizures and epileptiform discharges versus the underlying etiology.

The 2017 proposal suggests broadening of this terminology to include both developmental and/or epileptic encephalopathy, to emphasize that both the underlying etiology and the epileptic process may independently impact development [2,5,6]. Acceptable terms include epileptic encephalopathy, developmental encephalopathy, or developmental epileptic encephalopathy. The term "gene name" encephalopathy (eg, KCNQ2 encephalopathy) can be used when a genetic pathogenic variant of major effect is identified.

The terms benign, malignant, and catastrophic have been used in the past to describe the natural history of epilepsy. The 2010 proposal suggested replacing the term benign with more descriptive terms, such as self-limited (for epilepsies in which spontaneous remission is likely) and pharmacoresponsive (for those in which there is high likelihood of rapid control with medication) [4]. Pharmacoresistent is the preferred term to replace malignant or catastrophic.

SUMMARY

●Significant advances in neuroimaging, genomic technologies, and molecular biology have highlighted the need for an evolving system of classification and terminology for seizures and epilepsy. The International League Against Epilepsy (ILAE) classification system is widely used and has been updated most recently in 2010 and 2017, with several key changes from prior versions. The ILAE classification allows for diagnosis at three levels (see 'Introduction' above):

•Seizure types

•Epilepsy types

•Epilepsy syndromes

●The diagnosis of seizure requires that the clinician identify that the patient has had an epileptic seizure as opposed to some other type of paroxysmal event, and then establish the type of seizure(s) (table 1). The four major seizure types are generalized, focal, unknown, and unclassified. (See 'Level 1: Seizure type' above.)

●Epilepsies can be subdivided into generalized, focal, generalized and focal, and unknown (figure 1). The latter includes epileptic spasms, for which current knowledge is inadequate to determine whether onset is focal or generalized. (See 'Level 2: Epilepsy based on seizure type' above.)

●An epilepsy syndrome represents a distinct clinical entity, defined as a complex of clinical features, signs and symptoms that together define a distinctive, recognizable clinical disorder (table 3). (See 'Level 3: Epilepsy syndrome' above.)

●The 2017 ILAE classification recognizes six etiologic categories: genetic, structural, metabolic, immune, infectious, and unknown. (See 'Etiology' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Christian M Korff, MD, who contributed to an earlier version of this topic review.