ILAE Classification of Epilepsies

Although many concepts described in the 1989 ILAE classification remain valid, it is clear that a review is needed to account for the scientific discoveries that in recent decades have changed the understanding of epilepsies, as well as the approach to their diagnosis. and management.

Epilepsy classification is the key clinical tool for evaluating an individual with seizures, and serves many purposes: providing a framework for understanding the type of seizure the patient is having, the other types of seizures that may occur in that individual, potential triggers and often their prognosis. It also reports on the risk of comorbidities, such as learning difficulties, intellectual disabilities, and psychiatric characteristics, and the risk of mortality due to sudden unexpected death from epilepsy (SIED). Additionally, it often guides the selection of antiepileptic therapies.

The ranking is based on the opinion of experts from around the world. While the desired endpoint is a scientific classification, the authors’ understanding is not advanced enough to construct a classification on a scientifically rigorous basis. So the current proposals are based on a combination of the latest scientific knowledge together with high-level expert opinion.

Before attempting to classify a seizure, the clinician must determine whether the paroxysmal event is in fact an epileptic seizure, with a myriad of differential diagnoses including convulsive syncope, parasomnias, movement disorders, and other nonepileptic events.  

One should begin by classifying the type of seizure and then the type of epilepsy of the patient and, in many cases, the diagnosis of a specific epilepsy syndrome can be made. Equally important is trying to identify the etiology of epilepsy at each step of the diagnostic pathway. The classification takes into account the results of various studies exploring the underlying etiology of epilepsy. Presented here is the first major Classification of Epilepsies since the last ILAE Classification ratified in 1989.

1. Type of seizure

The starting point for the classification of epilepsy is the type of seizure; It is assumed that the physician made a definitive diagnosis of an epileptic seizure, and that it is not required to distinguish it from non-epileptic events. Seizures may be focal, generalized, or unknown in onset. In some settings, seizure type classification may be the maximum level of diagnosis, as there may not be access to electroencephalogram (EEG), video, and imaging studies.

2. Type of epilepsy

The second level is the type of epilepsy and it is assumed that the patient has that diagnosis according to the 2014 definition. This level includes a new category of “Combined Generalized and Focal Epilepsy”, in addition to the well-established categories of Generalized Epilepsy and Focal Epilepsy . Also includes the "Unknown Type" category. Many epilepsies include several types of seizures.

For the diagnosis of Generalized Epilepsy, the patient typically shows generalized wave spike activity on the EEG. These patients may have a range of seizure types including absence, myoclonic, atonic, tonic, and tonic-clonic seizures. The diagnosis of generalized epilepsy is based on clinical criteria, and is supported by the finding of interictal EEG discharges. In a patient with generalized tonic-clonic seizures and a normal EEG, there must be supporting evidence to make a diagnosis of generalized epilepsy, such as myoclonic spasms or a family history.

Focal Epilepsies include unifocal and multifocal disorders, as well as seizures involving one hemisphere. They include a variety of seizure types such as focal conscious seizures, focal seizures with impaired consciousness, focal motor seizures, focal non-motor seizures, and focal to bilateral tonic-clonic seizures. Interictal EEG typically shows focal epileptiform discharges, but the diagnosis is made by clinical criteria, supported by EEG findings.

The new group of Combined Generalized and Focal Epilepsies exists since there are patients who have both generalized and focal seizures. The diagnosis is clinical, supported by EEG findings. Ictal recordings are useful, but not essential. Interictal EEG may show focal epileptiform and generalized spike-wave discharges, but epileptiform activity is not required for diagnosis. Common examples of both types of seizures are Dravet syndrome and Lennox-Gastaut syndrome.

The type of Epilepsy may also be the final level of diagnosis achievable, since the doctor cannot make a diagnosis of Epilepsy Syndrome.

The term “Unknown Type” is used to indicate that the patient has epilepsy, but the doctor cannot determine whether the type is focal or generalized because there is not enough information available, lack of access to the EEG, or uninformative studies. If the type of seizure is unknown, then the type of epilepsy may be unknown for similar reasons, although the two may not always be concordant.

3. Epilepsy syndrome

The third level is the diagnosis of Epilepsy Syndrome. It refers to a group of features that incorporate seizure types, and EEG and imaging features that tend to occur together. It often has age-dependent characteristics such as age of onset and remission, triggers, diurnal variation, and sometimes prognosis. It may also have distinctive comorbidities such as intellectual and psychiatric dysfunction, along with specific findings on EEG and imaging studies. It may have associated etiological and prognostic factors and treatment implications. There are many well-recognized syndromes, such as infant absence, West and Dravet syndromes, although it should be noted that there has never been a formal classification of syndromes by the ILAE.

> Idiopathic generalized epilepsies: Within this group is the recognized subgroup of idiopathic generalized epilepsies (IGEs). IGEs encompass four well-established syndromes: Infantile Absence Epilepsy, Juvenile Absence Epilepsy, Juvenile Myoclonic Epilepsy, and Generalized Tonic-clonic Seizures alone.

It is more meaningful to refer to this group as Genetic Generalized Epilepsies (GGEs), when there is sufficient evidence for this classification, which is drawn from a meticulous clinical investigation of the inheritance of these syndromes in twin and family studies, even when they are not identified. specific genetic mutations.

> Self-limited focal epilepsies: There are several self-limited focal epilepsies, which typically begin in childhood. The most common is self-limited epilepsy with centrotemporal spikes, previously called “benign epilepsy with centrotemporal spikes.” Others in this large group are self-limited occipital epilepsies of childhood. Other self-limited epilepsies of the frontal, temporal and parietal lobes were also described, some with onset in adolescence and even in adulthood.

Often the first investigation carried out involves neuroimaging, ideally magnetic resonance imaging (MRI). This allows us to see if there is a structural etiology. The five additional etiological groups are genetic, infectious, metabolic and immunological, and unknown. Epilepsy can be classified into more than one etiological category; Etiologies are not hierarchical and their importance may depend on the circumstance.

1. Structural etiology: Refers to structural abnormalities visible on neuroimaging where electro-clinical evaluation together with imaging findings lead to the inference that the imaging abnormality is the probable cause of the seizures. Structural etiologies such as stroke, trauma and infection can be acquired, or genetic etiologies such as many malformations of cortical development can be acquired. Identification of a subtle structural lesion requires appropriate MRI studies with epilepsy-specific protocols.

There are well-recognized associations within epilepsies with structural etiology. These include the relatively common 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 patient images are carefully examined for the specific structural abnormality. This highlights the need to consider surgery if the patient fails medical therapy.

The underlying basis for a structural abnormality may be genetic, acquired, or both. For example, polymicrogyria can 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. When a structural etiology has a well-defined genetic basis, such as tuberous sclerosis complex, caused by mutations in the TSC1 and TSC2 genes that encode hamartin and tuberin respectively, both structural and genetic etiological terms can be used.

2. Genetic etiology: This concept results directly from a known or suspected genetic mutation in which seizures are a central symptom of the disorder. Epilepsies with genetic etiology are quite diverse and, in most cases, the underlying genes are unknown.

The inference of a genetic etiology can be based only on a family history of an autosomal dominant disorder. Furthermore, it may arise from clinical research of populations with the same syndrome. A molecular basis may be identified and involve a single gene or a numerical variant of the main effect. Most genes show phenotypic heterogeneity and most syndromes reveal genetic heterogeneity.

When epilepsy follows a complex inheritance, involving multiple genes with or without an environmental contribution, susceptibility variants can be identified that contribute to causality, but are insufficient on their own to cause epilepsy. In this setting, there may be no family history of seizures as other family members do not have enough epilepsy genetic variants to be affected.

It is important to note that genetic does not equal inherited . An increasing number of de novo mutations were identified in both severe and mild epilepsies; Furthermore, patients may be mosaic for a mutation. This means they have two populations of cells, one with the mutation and the other without it. Mosaicism can affect the severity of epilepsy, with lower rates of mosaicism resulting in milder epilepsy severity.

A genetic etiology does not exclude an environmental contribution. It is well accepted that environmental factors contribute to seizure disorders, such as sleep deprivation, stress, and illness.  

3. Infectious etiology: This is the most common etiology, and results directly from a known infection in which seizures are a central symptom of the disorder. Common examples in specific regions include neurocysticercosis, tuberculosis, HIV, cerebral malaria, subacute sclerosing panencephalitis, cerebral toxoplasmosis, and congenital infections such as Zika virus and cytomegalovirus. These infections sometimes have a structural correlate. Infectious etiology carries specific treatment implications.

4. Metabolic etiology: The concept of metabolic epilepsy is that it results directly from a known or suspected metabolic disorder in which seizures are a central symptom of the disorder. Metabolic causes refer to a well-defined metabolic defect with manifestations or biochemical changes in the body, such as porphyria, uremia, aminoacidopathies or pyridoxine-dependent seizures. In many cases, metabolic disorders will have a genetic defect. Identification of metabolic causes is extremely important because of the implications for treatment specification and potential prevention of intellectual disability.

5. Immune etiology: This concept results directly from an immune disorder in which seizures are a central symptom, with evidence of autoimmune-mediated inflammation of the central nervous system. Diagnosis of autoimmune encephalitis is increasing rapidly, particularly with increased access to antibody testing. With the appearance of these entities, this etiological subgroup deserves a specific category, particularly due to the implications of treatment with targeted immunotherapies.

6. Unknown etiology: It means that the cause of epilepsy is still unknown. It is not possible to make a specific diagnosis apart from basic electro-clinical semiology such as frontal lobe epilepsy.

> Comorbidities: There is increasing awareness that many epilepsies are associated with comorbidities such as learning, psychological and behavioral problems. These vary in type and severity, from subtle learning difficulties to intellectual disabilities, psychiatric characteristics such as autism spectrum disorders and depression, and psychosocial problems. In more severe epilepsies, a complex range of comorbidities may be seen, including motor deficits such as cerebral palsy or gait impairment, movement disorders, scoliosis, sleep and gastrointestinal disorders.

The term “epileptic encephalopathy” is used when the epileptic activity itself contributes to severe cognitive and behavioral deficits above and beyond what might be expected from the underlying pathology alone (e.g., cortical malformation). Global or selective deficiencies may worsen over time.  

The concept of epileptic encephalopathy may be applicable to epilepsies of all ages and should be used more widely than just for severe epilepsies with childhood onset. Many epilepsy syndromes associated with encephalopathy have a genetic origin, such as West syndrome and continuous spike-and-wave epileptic encephalopathy during sleep (CSWS). Likewise, such syndromes may have an acquired cause such as hypoxic-ischemic encephalopathy or cerebrovascular accident, or may be associated with a malformation of cortical development of genetic or acquired etiology.

The concept of epileptic encephalopathy can also be applied to single-gene disorders, such as CDKL5 encephalopathy and CHD2 encephalopathy. Epileptiform activity can cause regression in an individual with normal development or preexisting developmental delay. A key component of the concept is that improving epileptiform activity may have the potential to ameliorate the developmental consequences of the disorder.

Many of these serious genetic disorders also have developmental consequences that arise directly from the effect of the genetic mutation, in addition to the effect of frequent epileptic activity, and which may manifest as delay, stagnation, or regression of pre-existing development, with onset of seizures or with prolonged seizures. In others, developmental slowing may occur in the context of normal development, with slowing emerging before the presence of frequent epileptic activity on the EEG.

Therefore, it is suggested to use the term “epileptic and developmental encephalopathy” when appropriate and can be applied to people of any age. This allows the use of one or both descriptors: developmental encephalopathy when there is only developmental impairment without activity frequent epilepsy associated with regression or further slowing of development; epileptic encephalopathy when there is no pre-existing developmental delay and the genetic mutation is not thought to cause slowing in its own right; and developmental and epileptic encephalopathy where both factors play a role. Often not It can be unraveled whether the epileptic or developmental component is the most important contributor.

In many cases, when a large-effect genetic mutation is identified, the terms “developmental and epileptic encephalopathy” can be summarized using the name of the underlying condition. For example, they can now be called by their gene name along with the word encephalopathy, such as “STXBP1 encephalopathy” or “KCNQ2 encephalopathy.” This is particularly important when referring to a genetic disease where genes are associated with both severe and self-limiting drug-responsive epilepsies, such as KCNQ2 or SCN2A. So the term “encephalopathy” can be used to denote the severe form of the disease associated with developmental impairment.

With increasing recognition of the impact of these comorbidities on an individual’s life, there has been considerable concern that the term "benign" underestimates this burden particularly in milder epilepsy syndromes such as benign epilepsy with centrotemporal spikes (BECTS) and childhood absence epilepsy (CAE).

Therefore, the term "benign," as a descriptor of epilepsy, is replaced by the terms "self-limited" and "drug-sensitive," each replacing different components of the meaning of benign. “Self-limited” refers to the probable spontaneous resolution of a syndrome. “Drug-sensitive” means that the epilepsy syndrome is likely to be controlled with appropriate antiepileptic treatment. However, it is important to recognize that there will be individuals with these syndromes who are not drug-sensitive. As noted above, there is no formal classification of ILAE syndromes. The terms “malignant” and “catastrophic” will no longer be used; They will be eliminated due to their serious and devastating connotations.

It is expected that this new Classification of Epilepsies will help diagnosis, understanding the etiology, and the use of therapies aimed at the patient’s disease. With the advent of significant advances in the understanding of the neurobiology of seizures and epileptic diseases, major paradigm shifts will emerge in the concepts underlying classification.