New Seizure and Epilepsy Classifications: Current and Future Perspectives

Kurupath  Radhakrishnan; Aparajita  Chatterjee

New Seizure and Epilepsy Classifications: Current and Future PerspectivesCHAPTER 1

Aparajita Chatterjee,

Kurupath Radhakrishnan

ABSTRACT

Classifications that are universally adopted and practiced provide a common language facilitating communication among clinicians, researchers, and students, and are therefore extremely useful. In the last few years, the International League Against Epilepsy (ILAE) has published new classification schemes for seizures and epilepsies in general, and a focused classification for seizures and epilepsy in the neonates. A new set of position papers have also been published this year, aimed to define the various epilepsy syndromes. In this review, we discuss in detail the current classifications of seizures and epilepsies, and their merits and shortcomings. We have also touched upon the classification of seizures and epilepsies in the neonates. These new classifications have allowed for the inclusion of some previously unclassifiable seizure types and epilepsies and have utilized more intuitive terminology. Nonetheless, they fall short in several aspects and have introduced new ambiguities, highlighting the need for incessant refinements and revisions. The rapid advances in genomics and brain connectomics will play pivotal roles in future classifications. The ultimate goal of classification systems in people with epilepsy should be to facilitate the practice of precision medicine by enabling the choice of personalized diagnostic and therapeutic strategies.

Keywords: Classification, Epilepsy, Etiology, Focal, Generalized, Seizures

“Learn from yesterday, live for today, hope for tomorrow.

The important thing is not to stop questioning.”

—Albert Einstein

INTRODUCTION

Classification has been commonly applied since antiquity by mankind to simplify approach to various aspects of life. It is something we deal with in everyday life and can range from the most basic to the most complex. To classify is to put like with like and separate the disparate from each other. One might wonder why we need these systems in the first place. Confucius in 6th century before Christian era (BCE) remarked “If names are not correct, language is not in accordance with the truth of things. If language is not in accordance with the truth of things, affairs cannot be carried on to success.”¹ Simply put, classification systems help us in conveying relevant information, which is far more than what individual entities otherwise would. Classification systems are invaluable in the field of epilepsy in order to communicate the diagnosis, prognosis, and possible therapeutic approaches to fellow clinicians and researchers, and also to people with epilepsy and their caregivers.

The diagnosis of epilepsy is primarily clinical, based on the detailed information gathered by history taking from the patient and from those who have witnessed the event. Investigations such as electroencephalogram (EEG), magnetic resonance imaging (MRI), and others can only support and further refine the clinical diagnosis but cannot be a substitute to history. We strongly recommend routine use the five axes diagnostic scheme proposed by the International League Against Epilepsy (ILAE)² (Fig. 1) in order to be comprehensive in our diagnostic approach and to minimize the misdiagnosis, and to facilitate classification of seizure type, epilepsy type, epilepsy syndrome, and its consequences on the patient's quality of life.

In this review, firstly, we will discuss the new classification systems proposed by the ILAE on seizures and epilepsies 2by tracing the evolution from the past to the present, and by underscoring why periodic changes in classification were necessitated. We will also briefly touch upon the new ILAE classifications on neonatal seizures and epilepsies. The review does not address the classification of epilepsy emergencies such as status epilepticus. Secondly, we shall debate on the merits and limitations of the present ILAE classifications. Lastly, we will speculate on how the present rapid advances in brain structural and functional imaging, connectomics, and genomics will give rise to future epilepsy classification systems aimed at achieving precision in the diagnosis and treatment.

The foundation slab to any classification is to have clear definitions of whatever is being classified. In Table 1, we have provided the current ILAE definitions for seizures, epilepsies and epilepsy syndromes, and other related terms.

EVOLUTION OF CLASSIFICATION: PAST TO PRESENT

Historical Perspectives

Man, from times immemorial, has been aware of different types of seizures and epilepsies. Well ahead of the Western civilization, our ancient Ayurveda (around 5,000 years BCE) recognized that seizures occur due to a disturbance in brain function or flow of “humors” to the brain.³

Fig. 1: The five axes diagnostic schemes for people with seizures and epilepsies.

TABLE 1 Definitions proposed by the International League Against Epilepsy.

Terminology	Definition	Reference
Epileptic seizure	Epileptic seizure is defined as a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain	8,9
Generalized seizure	Generalized seizures are those originating at some point within, and rapidly engaging, bilaterally distributed networks
Focal seizure	Focal seizures are those originating within networks limited to one hemisphere
Epilepsy	Epilepsy is a pathologic and enduring tendency to have recurrent seizures. It is diagnosed when an individual has one of the following: at least two unprovoked or reflex seizures >24 hours apart, or one unprovoked or reflex seizure and a probability of having another seizure similar to the general recurrence risk after two unprovoked seizures (≥60%) over the next 10 years, or an epilepsy syndrome	11
Epilepsy syndrome	Epilepsy syndrome is defined as a characteristic cluster of clinical and electroencephalogram (EEG) features, often supported by specific etiological findings (structural, genetic, metabolic, immune, and infectious). The diagnosis of a syndrome in an individual with epilepsy frequently carries prognostic and treatment implications. Syndromes often have age-dependent presentations and a range of specific comorbidities	14,17
Epilepsy resolved	Epilepsy is considered to be “resolved” for individuals who either had an age-dependent epilepsy syndrome but are now past the applicable age or those who have remained seizure-free for the last 10 years, with no use of antiseizure medications for the last 5 years	11
Drug-resistant epilepsy	Drug-resistant epilepsy is defined as failure of adequate trials of two tolerated and appropriately chosen and used antiepileptic drug schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom. A person is supposed to have achieved “sustained seizure freedom” when free of seizures for a minimum period of 12 months or for a period three times the previous longest seizure-free period, whichever is longer	15
Epileptic encephalopathy	Epileptic encephalopathy is defined as a condition in which epileptiform abnormalities are believed to contribute to the progressive disturbance in cerebral function	14
Developmental encephalopathy	Developmental encephalopathy is defined as a condition where there is just developmental impairment without frequent epileptic activity associated with regression or further slowing of development	14
Developmental and epileptic encephalopathy	Defined as a condition where both epileptic activity and preexisting developmental delay coexist, and contribute to further deterioration of cognitive development, most commonly due to underlying genetic mutation	14

3Ayurveda texts of those times have described classifications of seizures with clear descriptions of generalized tonic-clonic seizures, focal seizures with impaired awareness and secondarily generalized seizures.³ There was also an understanding that different causes for seizures and epilepsy existed, including post-traumatic epilepsy.³ A Babylonian tablet dating back to 1067–1046 BCE, contained descriptions about different types of seizures.⁴ Galenus proposed two different types of epilepsies—“idiopathic” epilepsy when the disorder was primarily due to a malfunctioning of the brain, and “sympathetic” when it was due to secondary causes affecting the brain. The word “sympathetic” was later replaced by “symptomatic”.⁴ The first modern classification of epileptic seizures was proposed by Henri Gastaut in 1964, and its use became popular in the 1970s.⁵

The ILAE modernized the classification on epileptic seizures for the first time in 1981, which was prompted by the availability of video electroencephalography (VEEG).⁶ The 1981 ILAE Seizure Classification used terms such as “simple partial”, “complex partial”, “generalized”, and “unclassifiable” that have been in use until recently.⁶ The ILAE Classification of the Epilepsies and Epilepsy Syndromes were updated in 1989.⁷ A revision of the existing systems of classifications was proposed in the early 21st century, which led to a series of extensive discussions culminating the present day ILAE definitions and classifications of epileptic seizures and epilepsies.^2,8–14 The ILAE Commission on Therapeutic Strategies provided a comprehensive definition of drug-resistant epilepsy in 2010.¹⁵ A new classification of neonatal seizures and epilepsy, which incorporated the directions given by the 2017 classification, was published in 2021.¹⁶ More recently, the Nosology and Definitions Task Force of the ILAE, has published a series of articles providing detailed definitions of epilepsy syndromes encompassing all age groups.^17–21 We have traced the chronological evolution of ILAE seizure and epilepsy classifications in Figure 2.

Need for Classifications and their Revisions

Since classifying seizures and epilepsies is a daunting task which necessitates in-depth deliberations on the part of the panel of epileptologists deputed to complete the job, and requires intensive efforts to familiarize new terminologies to clinicians in their practice of epileptology, one must wonder why we need these classifications. Jerome Engel, while deliberating about the classification systems, aptly stated: “The classification provided a universal vocabulary that not only facilitated communication among clinicians, but also established a taxonomic foundation for performing quantitative clinical and basic research on epilepsy”.² For clinicians (general physicians, pediatricians, neurologists, epileptologists, and psychiatrists) and the patient's caregivers, the classifications enhance communication and discussion. From a research standpoint, having the classifications enables evaluation of the clinical courses of various epilepsy syndromes and in assembling a uniform cohort of patients to assess different pharmacological and nonpharmacological therapeutic strategies.

When we already have a user-friendly classification system in place, one might question the need to revise it periodically. The straightforward answers are that previous systems have had some major lacunae which needed to be remedied, and the advances which have happened in the field of epileptology in the recent years necessitated the revisions. With our mounting knowledge of genetics and inputs from neuroimaging, invasive EEG monitoring, brain connectomes, molecular biology, and new avenues in epilepsy therapeutics, need for an updated classification system which incorporated this newfound information became essential.

Fig. 2: Historical landmarks on the development of the International League Against Epilepsy (ILAE) seizure and epilepsy classifications.

4The new ILAE definitions and classifications, when compared to the older ones, utilize alternative terms and contain several important additions. In general, these changes have enhanced user-friendliness, transparency, and versatility of the classifications, and allowed for inclusion of previously unclassifiable seizure and epilepsy types.

THE NEW INTERNATIONAL LEAGUE AGAINST EPILEPSY SEIZURE CLASSIFICATION

Rationale of Seizure Classification

Seizures can be classified on the basis of different characteristics and in many different ways. Previous classifications were largely based on anatomy as temporal, frontal, parietal, occipital, diencephalic, or brainstem seizures. At present, epilepsy is considered a network disease.²² From a network perspective, seizures arise from a point or points in neocortical, thalamocortical, limbic, and brainstem networks, and their semiology depend upon the propagation along preferential networks. Accordingly, while generalized epileptic seizures are conceptualized as originating at some point within, and rapidly engaging bilaterally distributed networks, focal epileptic seizures are conceptualized as originating within networks limited to one hemisphere (Table 1). Although our understanding of seizure networks is evolving rapidly, it is not yet sufficient enough to serve as a singular basis for seizure classification. The ILAE Task Force chose to refer to their new seizure classification as an “operational”, since at present it is not possible to have a comprehensive scientific classification where all seizure types find a place.^12,13

Two Versions of the Seizure Classification

The new classification has a basic and expanded version, depending upon the needs and expertise of the individual using the classification (Figs. 3A and B).^12,13 While the basic version will serve the requirement of physicians, pediatricians, general neurologists, nurses, and healthcare workers, the expanded version will be essential for epileptologists and researchers.

The epileptic seizures are categorized according to onset into focal, generalized, unknown, or unclassifiable. The term “focal” replaced the old term “partial” as it was felt to be too ambiguous and often conveys different meanings such as part of a seizure and without losing consciousness. The term “generalized” has been retained unchanged from the old classifications.

Figs. 3A and B: The International League Against Epilepsy (ILAE) 2017 seizure classification. (A) Basic version; (B) Expanded version.

5A generalized onset seizure is one in which both the hemispheres are activated at the onset of the seizure according to the seizure semiology and EEG findings. “Unknown” onset refers to seizures where the onset is ambiguous, but other clinical manifestations are known. “Unclassified” remains as a category to start with, but a majority from this category will become classifiable with information added during follow-up visits by repeated history taking and review of smart phone recorded seizures. Focal seizures are classified as “aware” or “impaired awareness” seizures. These terms replace the older terminologies “simple” and “complex”, respectively. It should be emphasized that “impaired awareness” and “loss of consciousness” are not synonymous. If awareness is impaired at any time during a focal seizure, it should be classified as “focal seizure with impaired awareness”. In the basic version, the next step after consideration of the level of awareness for a focal seizure entails defining the onset as “motor” or “nonmotor”. Secondarily generalized seizures are now called “focal to bilateral tonic-clonic seizures”, in order to restrict “generalized” to seizures of generalized onset. When classifying generalized seizures, “aware” versus “impaired awareness” is omitted, since awareness is impaired in nearly all generalized seizures. Generalized motor seizures can further be classified as “tonic-clonic” or “other motor”. The nature of seizure onset is crucial, and a seizure whose onset was unwitnessed, followed by tonic-clonic activity should be labeled an “unknown onset to bilateral tonic-clonic seizure”.

The expanded classification (Fig. 3B) builds on the basic classification by enlarging the “motor” and “nonmotor” categories under all three types of seizure onsets (focal, generalized, and unknown). A focal motor seizure is classified by first determining whether awareness is impaired during any part of the seizure, thereby rendering it a focal impaired awareness seizure. The next level of classifier derives from the first sign or symptom of the seizure, even if not the ultimately most prominent sign or symptom, because the first symptom marks the seizure focus or network. After seizure categorization, expanded classification allows use of additional terms, either from the seizure classification, or from a suggested list of seizure descriptors (Table 2). We have summarized in Table 3 the major changes built-in to the new ILAE seizure classification when compared to previous classifications.

THE NEW INTERNATIONAL LEAGUE AGAINST EPILEPSY CLASSIFICATION

The ILAE position paper by Scheffer and colleagues provided a new classification of the epilepsies with a major thrust on the etiology at each step of the diagnostic process.¹⁴ After classification of seizure type, the clinician should aim to identify the patient's epilepsy type and where possible, the epilepsy syndrome.

TABLE 2 Common descriptors of behaviors during and after seizures.

Cognitive Acalculia Aphasia Déjà vu Jamais vu Attention impairment Dysphasia Memory impairment Neglect	Automatisms Aggression Eye blinking Head nodding Manual Orofacial Pedaling Pelvic thrusting Perseveration Vocalization
Emotional or affective Anxiety Anger/agitation Laughing (gelastic) Crying (dacrystic) Fear Pleasure Paranoia	Motor Dysarthria Dystonia Fencer's posture figure-of-4 Jacksonian march Incoordination Paresis Versive
Autonomic Asystole Bradycardia Flushing Gastrointestinal Nausea Pallor Palpitations Piloerection Respiratory changes	Sensory Auditory Gustatory Hot or cold sensations Olfactory Somatosensory Vestibular Visual
Laterality Left Right Bilateral

TABLE 3 Summary of the major changes in terminologies and descriptions from 1981 to 2017 International League Against Epilepsy (ILAE) seizure classifications.

Change from “partial” to “focal” seizures
Seizure types can be either focal, generalized, or of unknown onset
Seizures of unknown onset may have features that can still be classified
Awareness is used as a classifier of focal seizures
The terms dyscognitive, simple partial, complex partial, psychic, and secondarily generalized have been removed from the current classification
New focal seizure types include automatisms, autonomic, behavior arrest, cognitive, emotional, hyperkinetic, sensory, and focal to bilateral tonic–clonic seizures (previously secondarily generalized seizures)
Atonic, clonic, epileptic spasms, myoclonic, and tonic seizures can be either focal or generalized
New generalized seizure types include absence with eyelid myoclonia, myoclonic absence, myoclonic–tonic–clonic, myoclonic–atonic, and epileptic spasms
Recurrent unprovoked epileptic seizures (epilepsy) were redefined as a “disease” and not a “disorder”

Fig. 4: The International League Against Epilepsy (ILAE) 2017 classification of epilepsies.

Patients who do not meet criteria for epilepsy, for example those with a single seizure, should be classified as to a seizure type, but classification should stop there. The epilepsy classification is broader in scope than the seizure classification, and considers the possibility of having multiple seizure types, and incorporates information about the overall clinical picture, genetics, laboratory tests, prognoses, and comorbidities. Hence, the epilepsy classification provides additional information that is critical in guiding the patient's management.

We have illustrated the 2017 ILAE epilepsy classification in Figure 4. Epilepsies are categorized into focal, generalized, combined generalized and focal, and unknown types. To position a patient into one of these categories, the first step remains the accurate classification of the seizure type(s), and then use all the additional information available to classify into one of the epilepsy subcategories. The new group of “combined generalized and focal epilepsy” has been devised because there are epilepsy syndromes such as Dravet syndrome and Lennox–Gastaut Syndrome, in which both generalized and focal seizures often coexist.

An “epilepsy type” is a separate designation than an epilepsy syndrome, and the two should not be confused. Epilepsy syndromes refer to clusters of features such as seizure type(s), age of onset, family history, EEG and MRI findings, age-dependent attributes, seizure triggers, optimum therapy, long-term outcome and comorbidities and impact of epilepsy on the patient's quality of life. Ultimately, the identification of epilepsy and epileptic syndromes is essentially like solving a jigsaw puzzle and stands on the foundation of an accurate description and identification of seizure type(s), along with other features listed above (Fig. 5). An epilepsy syndromic diagnosis provides more sophisticated information than does an epilepsy type diagnosis. While there are many well recognized syndromes the ILAE has at present formally classified, new syndromes are regularly being added, and these might be a part or even the basis of future classifications.

Fig. 5: Approach to epilepsy syndromic diagnosis: Solving the jigsaw puzzle.

(ASM: antiseizure medicine; EEG: electroencephalogram; MRI: magnetic resonance imaging)

ETIOLOGICAL CLASSIFICATION OF EPILEPSIES

The six etiologic categories defined by ILAE Task Force focus on those with management implications; they are not hierarchical and more than one etiology might coexist in an individual patient (Fig. 4).7

Structural: A structural etiology can be concluded when a finding on neuroimaging is reasonably inferred to be the cause of the patient's seizures based on concordant clinical and EEG findings.²³ An imaging abnormality with discordant seizure semiology and EEG findings is likely unrelated to the patient's epilepsy and would not be considered relevant when determining the etiology.
Genetic: When a specific disease-causing gene variant or copy number variant, which is believed to be pathogenic for epilepsy, is documented in a person with epilepsy, a genetic etiology can be concluded. Additionally, having relevant positive family history and concordant features (seizure semiology and EEG) even without the molecular genetic result is sufficient for ascribing genetic etiology. Genetic disease-causing variants often arise de novo and may not be inherited, so a family history of epilepsy is frequently absent, despite the patient having a genetic cause for their epilepsy.²⁴
Infectious: Even though an infectious etiology can be surmised in a patient with epilepsy associated with an infectious disease, an acute infection and seizures does not constitute epilepsy as the seizures are provoked (and no epilepsy classification should be applied). Examples of infectious etiologies include neurocysticercosis, human immunodeficiency virus infection, cytomegalovirus infection, and cerebral toxoplasmosis, which are often associated with structural lesions and hence could be classified under both.
Metabolic: Refers to a patient with epilepsy in whom a metabolic derangement is the cause for enduring predisposition to seizures. Someone with a transient metabolic disturbance resulting in acute symptomatic seizures would not qualify as their seizures are provoked. Many of the metabolic epilepsies are genetic in etiology, such as pyridoxine-dependent seizures and cerebral folate deficiency.
Immune: Refers to epilepsies where an autoimmune disease is the cause of new-onset epilepsy. Autoimmune encephalitis and epilepsy have been linked to both neuronal cell surface and intracellular antibodies. Because of immense therapeutic implications, autoimmune etiology should be suspected and investigated in patients with recent onset seizures and epilepsies that are poorly responsive to antiseizure medicines.²⁵
Unknown: This category is reserved for patients whose etiology remains unclear, despite extensive investigations.

CLASSIFICATION OF NEONATAL SEIZURES AND EPILEPSIES

A detailed discussion on the new classification of neonatal seizures and epilepsies is beyond the scope of this review. Seizures are the most common neurological emergency in the neonatal period, and in contrast to those in infancy and childhood, are often provoked by an acute cause. Neonatal seizures may be electrographic only without any clinical accompaniments. Hence, neonatal seizures do not fit easily into classification schemes for seizures and epilepsies primarily developed for older children and adults. A Neonatal Seizures Task Force established by the ILAE to develop a modification of the 2017 ILAE classification of seizures and epilepsies, designed a neonatal classification framework underscoring the role of EEG in the diagnosis of neonatal seizures.¹⁶ The seizure type is determined by the predominant clinical phenomenology. As many neonatal seizures may have no overt clinical features, electrographic seizures are also included in the proposed classification. However, clinical events without an EEG correlate are not included. Because nearly all the seizures in the neonatal period have been shown to have a focal onset, a division into focal and generalized was considered to be unnecessary. Seizures can have a motor (automatisms, clonic, epileptic spasms, myoclonic, and tonic), nonmotor (autonomic and behavior arrest), or sequential presentations. The ILAE framework of neonatal seizure and epilepsy classification is depicted in Figure 6. The definitions of epileptic encephalopathy, developmental encephalopathy, and their combinations are provided in Table 1.

Fig. 6: The International League Against Epilepsy (ILAE) 2021 classification of neonatal seizures and epilepsies.

(HIE: hypoxic-ischemic encephalopathy)

CRITIQUE OF THE NEW INTERNATIONAL LEAGUE AGAINST EPILEPSY CLASSIFICATIONS

Even though the new ILAE definitions and classifications have helped in clearing up some of the ambiguities of the older classifications, as listed here, there are quite a few areas the new classifications have either failed to resolve the existing inadequacies or have introduced new disagreements.²⁶

Lack of objectivity of some of the newly introduced terms: Some of the new terms may lead to the wrong interpretation and cause confusion among the users of the new classifications. One such term is “awareness” which is highly subjective by definition and difficult to 8verify. The term “behavioral arrest” is also subjective and could be confused with absence seizures, especially atypical absence seizures.
Ambiguity with the concept of consciousness: The term “consciousness” has been replaced by “awareness” in the new classification in an attempt to simplify terminologies. However, impaired consciousness and impaired awareness are not synonymous.²⁷ Impaired consciousness level could indicate the severity of the patients' seizures, especially with respect to activities such as driving, which the term awareness cannot provide. In a survey, more than three-fourths of the respondents agreed that the term consciousness was better than awareness, and therefore should be retained in seizure and epilepsy classifications.²⁸ Additionally, patients with sensory-motor deficits and aphasia or amnesia may have unresponsiveness, which may be mistaken for impaired awareness, but consciousness may not be affected.
Inadequate coverage of preictal and postictal semiology: Preictal and postictal semiological features during the evolution and resolution of the seizures were left out in the new classification. For example, classic auras such as complex visual hallucinations, rising epigastric sensations, déjà vu, or choking sensations in the throat can all help to localize from where in the cortex the seizures are likely to be arising from.
Scanty emphasis on comorbidities: Comorbidities such as anxiety, depression, and cognitive and behavioral disturbances are highly prevalent in people with epilepsy, and they contribute to their poor quality of life. Formulating guidelines for the diagnosis of comorbidities would not only improve the current understanding of the pathophysiology of epilepsy, but also in the management.
Failure to adequately define some important terminologies: Descriptors and identifiers with regard to provoked and unprovoked seizures are inadequately defined in the new classification. Seizures that occur following acute brain insults such as central nervous system infections, cerebrovascular diseases, head injury, and metabolic derangements are referred to as provoked, whereas unprovoked seizures occur spontaneously. Emphasizing this concept would not only encourage cost-effective diagnostic evaluation, but also in preventing unnecessary long-term use of antiseizure drugs.

INTERNATIONAL LEAGUE AGAINST EPILEPSY POSITION PAPERS ON EPILEPSY SYNDROMES

Although epilepsy syndromes had been recognized as distinct electroclinical entities long before the first ILAE Classification of Epilepsies and Epilepsy Syndromes was proposed in 1985, there was no formally accepted ILAE classification of epilepsy syndromes. A series of ILAE position papers from the ILAE Nosology and Definitions Task Force provide definitions of epilepsy syndromes across different age spectrum.^17–21 A detailed discussion of these epileptic syndromes is beyond the scope of this review, nonetheless we have summarized the salient features in Table 4.

TABLE 4 Recommendations of the International League Against Epilepsy (ILAE) task force on epilepsy syndrome diagnosis.

Identification of epilepsy syndromes are helpful as they help to guide therapy and prognosticate¹⁷
For each epilepsy syndrome diagnosis, there is a well-defined electroclinical picture characterized by seizure type(s), typical age at onset, developmental course, comorbidities, possible antecedents, examination findings, electroencephalogram (EEG) findings, and other investigations (imaging, genetic, metabolic, infectious, and immunological results). There are also mandatory and exclusionary criteria, and alerts for each syndrome, as some patients may have atypical features, which require careful clinical correlation prior to making a syndrome diagnosis¹⁷
Just involving the same part of an epileptogenic network is not enough for classification as epilepsy syndromes¹⁷
The new term “etiology-specific epilepsy syndromes” has been proposed to describe syndromes in which there is a specific etiology for the epilepsy that is associated with a clearly defined, relatively uniform, and distinct clinical phenotype in most affected individuals (clinical presentation, seizure types, comorbidities, and natural history, and at times, response to specific therapies), as well as consistent EEG, neuroimaging, and/or genetic results¹⁷
Classification of epilepsy syndromes is on the basis of age of onset and type of epilepsy¹⁷
On the basis of the age of onset, there are neonatal and infantile onset, childhood onset, and variable age at onset, as well as idiopathic generalized epilepsies (IGEs)
A syndrome has a “variable age” of onset if it can begin both in those aged ≤18 years and in those aged ≥19 years (both pediatric and adult patients)^17–20
Epilepsy syndromes are further subdivided (in each age group) into generalized, focal, or generalized and focal, based on seizure type(s), along with a separate category for syndromes with developmental and/or epileptic encephalopathy (DEE) and syndromes with progressive neurological deterioration¹⁷
Epilepsy syndromes in neonates and infants are divided into two groups: Self-limited epilepsy syndromes and DEEs, with a separate category for etiology-specific syndromes^17,18
Syndromes with onset in childhood are divided into three categories: Self-limited focal epilepsies, generalized epilepsies, and DEEs¹⁹

Syndromes with variable onset can be broadly divided into generalized, focal, and combined generalized and focal epilepsy syndromes. Some syndromes can be associated with developmental and/or epileptic encephalopathy in children or with progressive neurological deterioration if they begin later in life²⁰
The term “genetic generalized epilepsies (GGEs)” is to be used for the broad group of epilepsies with generalized seizure types and generalized spike-wave, based on a presumed genetic etiology. They include the IGEs and others which may have developmental encephalopathy, epileptic encephalopathy, both, or neither. IGE includes four syndromes: Childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, and epilepsy with generalized tonic–clonic seizures alone. The second group includes syndromes such myoclonic absence epilepsy, epilepsy with eyelid myoclonia, and others²¹

FUTURE PERSPECTIVES

A comprehensive characterization of epilepsy requires, in addition to seizure semiology, incorporation of other dimensions involving the brain area and brain networks, cause of the seizures, associated comorbidities, and consequences of seizures. Even though the latest emphasis by ILAE on the identification and definition of epilepsy syndromes is a step in the right direction, the present three-dimensional ILAE classifications systems fall short in the multidimensional approach. A different classification system for epilepsy was proposed by Lüders et al.,²⁹ which incorporated the clinical semiology, epileptogenic zone, etiology, and comorbidities and is referred to as the four-dimensional epilepsy classification system. Loddenkemper et al.³⁰ recommended a five-dimensional classification system which included, in addition to the above mentioned four-dimensions, seizure burden, which impacts the quality of life, as the fifth-dimension. The rapid advances in the delineation of structural, functional, and effective brain connectivity and genomics will have tremendous impact on future classifications of seizures and epilepsies. The ultimate objective of epilepsy classification should be to individualize diagnostic and therapeutic strategies, thereby promoting the practice of precision medicine.

CASE SCENARIOS

We have provided three case scenarios in the Text Box 1 to illustrate the application of the new seizure and epilepsy classification systems.

ACKNOWLEDGMENT

The authors wish to thank Mr Magith Thampi, PhD scholar, Department of Neurology, Kasturba Medical College, Manipal, Karnataka, for his help in designing the figures.

TEXT BOX 1 : CASE SCENARIOS

CASE SCENARIO 1

An 18-year-old male, with no significant perinatal or family history, normal growth and development, presented with complaints of two paroxysmal events during the last 1 month. He reported no aura, and was not aware at the onset of the event. These were characterized by uprolling of the eyes, with bilateral upper and lower limb jerking, frothing at the mouth and tongue bite. Examination was normal. On probing, he also reported dropping objects held in hands due to sudden jerking since the past 3 years, more in the mornings. The electroencephalogram (EEG) showed frontally dominant high amplitude 4–4.5 Hz generalized spike-wave and spike-multiple spike discharges with a normal background. The brain MRI was normal.

Step 1: From the history, the semiology suggests a generalized motor tonic-clonic seizure.

Additionally, he has myoclonic jerks.

Step 2: EEG findings support a generalized epilepsy.

Step 3: Classic EEG findings, with the characteristic age of onset and a background of myoclonic and generalized epilepsy, points to a likely diagnosis of genetic generalized epilepsy. The most likely diagnosis here is an idiopathic generalized epilepsy (IGE), possibly juvenile myoclonic epilepsy.

Identification of the epileptic syndrome will help guiding therapy (first-line therapy with sodium valproate) and prognostication (likely to need pharmacotherapy for a longer duration). IGEs are usually associated with a normal development and cognition, but may be associated with behavioral issues.

CASE SCENARIO 2

A 24-year-old female, with history of multiple episodes of typical febrile seizures, presents with new-onset paroxysmal events since the past 6 months. These are characterized by a rising epigastric sensation, followed by a behavioral arrest. Patient is noted to have repeated lip smacking movements with picking at clothes with the left hand, while abnormal posturing is noted in the right hand. She is unable to speak during and for about 10 minutes after the events. Frequency of events is 5–6 per month. In two of these events, patient had subsequently developed head and eye deviation to the right, followed by initial right and then left tonic-clonic movements and loss of consciousness. The EEG showed left anterior temporal sharp waves with left temporal intermittent rhythmic delta activity (TIRDA). The MRI brain showed left mesial temporal sclerosis (MTS) with hippocampal atrophy.

Step 1: Semiology suggests a focal nonmotor onset (behavioral arrest) seizure with impaired awareness. The focal seizure became bilateral tonic-clonic in a few of the events.

Step 2: Epilepsy is clearly focal in nature, with the etiology being structural (left MTS). The classical history, with typical EEG and MRI features will help make a diagnosis of mesial temporal epilepsy with hippocampal sclerosis.

Step 3: Identification of the proper syndrome is aided by taking in to account all the preictal, ictal, and postictal features of the seizure, along with the past history of febrile seizures and characteristic EEG and MRI features. This is very useful in guiding therapy as it is known that MTS is often medically refractory and such patients should be referred for presurgical evaluation as soon as they fail a trial of appropriately chosen antiseizure medications.10

CASE SCENARIO 3

A two and a half-year-old boy is brought with history of paroxysmal events from 7 months of age and subsequent regression in neurological development. Birth and developmental history were unremarkable till 7 months of age, when child had a prolonged event during a febrile episode. This was characterized by continuous jerking of the right side of the body lasting for nearly 30 minutes. Subsequent events all occurred during febrile episodes, and were characterized by similar hemiclonic and sometimes bilateral tonic-clonic jerking of limbs which would subside often only with intravenous medications. For the first 1 year after the first seizure, child had no afebrile episodes, and interictal EEG was normal, along with MRI brain. However, child was noted to be initially not gaining new milestones, followed by regression and loss of previously acquired milestones. Subsequently, child started having afebrile seizures, some of which were characterized by prolonged flexion of the trunk and posturing of all four limbs, others by sudden jerking of limbs, or sudden falls without loss of consciousness.

EEG done at this time showed an abnormal background, with absent normal sleep structures, and multifocal and generalized epileptiform discharges.

Genetic testing for SCN1A was positive.

Step 1: The initial seizures here were focal motor-onset hemiclonic seizures. Subsequently, child has developed tonic, myoclonic, and atonic seizures.

Step 2: This would be classified as a “combined generalized and focal epilepsy syndrome”, with a genetic etiology.

Prolonged hemiclonic febrile seizures, with neuroregression, and later polymorphic seizures and abnormal EEG should alert the possibility of Dravet syndrome, where both the SCN1A mutation and the seizures contribute the cognitive deterioration. Identification of the epilepsy syndrome helped in rationalization of therapy and prognostication.

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Chapter Notes

New Seizure and Epilepsy Classifications: Current and Future PerspectivesCHAPTER 1

ABSTRACT

TEXT BOX 1 : CASE SCENARIOS