Chapter 558. Etiologies of Epilepsies

Understanding the etiology of a patient’s epilepsy may allow the physician to provide prognostic information and, most appropriately, manage the seizures. The classification system most widely used for the epilepsies is the International Classification of Epilepsies and Epileptic Syndromes set forth by the International League Against Epilepsy (ILAE) (see Chapter 557). Reflecting the importance of the cause underlying the epilepsy, this system delineates 3 primary categories of etiological classification: symptomatic, cryptogenic, and idiopathic.1 Symptomatic epilepsy refers to epilepsy that is a symptom of a known underlying cause, such as a structural brain lesion. Cryptogenic epilepsy, sometimes called “presumed symptomatic” epilepsy, occurs in children with other neurological abnormalities, suggesting that the symptoms are referable to an underlying etiology, albeit occult. Idiopathic epilepsy traditionally referred to epilepsy without discernable predisposing cause in otherwise normal children, but it has been increasingly evident that this category encompasses epilepsies with genetic underpinnings.

It is estimated that 20% to 40% of children presenting with epilepsy have an identifiable etiology that would place them in the symptomatic category.2 Nonetheless, the consideration of a possible underlying etiology dominates the initial evaluation of a child presenting with epilepsy. Many of the causes listed below are identifiable using magnetic resonance imaging (MRI). When MRI does not reveal an etiology for the epilepsy, further evaluation of potential genetic and metabolic causes should be undertaken. Table 558-1 lists some of the major diagnostic considerations that will motivate a thorough evaluation. Many of the individual conditions are discussed in other chapters.

Symptomatic epilepsy should be suspected in a child with epilepsy in the following conditions: (1) any child with new onset of localization-related (focal) epilepsy; (2) any child presenting with epilepsy with other neurological symptoms, such as developmental delay, or signs, such as hemiparesis; and (3) any child with a history or examination that leads to the suspicion of a specific etiology. Uncovering a specific etiology does not necessarily lead to a specific treatment based on the mechanisms of epileptogenesis of each condition, but this may provide prognostic information and allow the treating physician and family to focus on the treatment rather than on the cause of the epilepsy.

Acquired Neurological Conditions Leading to Symptomatic Epilepsy

Some of the causes of symptomatic epilepsy are neurological insults that may occur at any time in otherwise neurologically normal children. These etiologies include hypoxic-ischemic injury, head trauma, intracerebral hemorrhage, ischemic or thrombotic stroke, brain tumor, and central nervous system infection. Any of these conditions, particularly hypoxic-ischemic injury and infection, may arise prenatally or perinatally as well. In many cases, the history of the antecedent neurological condition is known at the time of presentation of unprovoked seizures. Acute symptomatic seizures may have been part of the initial presentation, but the epilepsy (defined as recurrent unprovoked seizures) typically occurs months or years later. On the other hand, the same condition may initially present with epilepsy, with neuroimaging performed as part of the evaluation for new onset epilepsy revealing a remote etiology. One such example is the previously asymptomatic in utero or perinatal stroke.3

Careful consideration of historical factors predisposing a child to such neurological conditions, as well as clues on the general and neurological examinations, may help elucidate a remote etiology. For example, perinatal depression would suggest neonatal hypoxic-ischemic encephalopathy, and congenital heart disease would raise the suspicion of stroke. Microcephaly might suggest a history of congenital infection.

Congenital or Genetic Abnormalities

An important cause of symptomatic epilepsy is congenital malformations of cortical development.4 These include small focal regions of cortical dysplasia, large hemispheric abnormalities, such as hemimegalencephaly, and widespread abnormalities, such as lissencephaly, subcortical band heterotopia, polymicrogyria, and periventricular heterotopia. These malformations are usually identifiable on 1.5 or 3 Tesla MRI. The age of presentation of seizures and the extent of cognitive and other neurological problems associated with these malformations are widely variable. They comprise about 40% of patients with medically intractable epilepsy.5

Neurocutaneous syndromes are frequently associated with epilepsy, and it may be the epilepsy that brings children with such conditions to medical evaluation and diagnosis. Notably, in tuberous sclerosis complex (TSC), up to 80% to 90% of affected individuals are reported to have epilepsy. Although there are a number of central nervous system manifestations of TSC, the cortical tubers have been shown to give rise to seizures.6 Neurofibromatosis type 1 is another neurocutaneous syndrome that predisposes to epilepsy, and macrocephaly, ocular findings, and dermatological findings may suggest this diagnosis. These and the other syndromes listed in Table 558-1 are included in Chapter 198.

Many genetic syndromes include seizures and epilepsy as part of their phenotype, but a few bear specific mention in the setting of symptomatic epilepsy. Wolf-Hirschorn (4p monosomy) syndrome and ring chromosome 20 are both conditions that might be suggested by dysmorphic features and systemic abnormalities and can be diagnosed by karyotype. Fragile X syndrome, Angelman syndrome, and Rett syndrome also have specific features accompanying epilepsy and are discussed elsewhere in this text. Fragile X can sometimes be ascertained by karyotype, but if there is high suspicion for this condition, molecular testing must be performed. Specific molecular genetic testing is required to diagnose Angelman and Rett syndromes.

Another group of genetic disorders giving rise to symptomatic epilepsy are the progressive myoclonus epilepsies (PMEs). They present with the constellation of myoclonic and tonic-clonic seizures, myoclonus, ataxia, and progressive neurological decline. The prototypical PMEs include Unverricht-Lundborg disease, Lafora disease, sialidosis types I and II, neuronal ceroid lipofuscinosis, dentatorubral pallidoluysian atrophy, and myoclonic epilepsy with ragged red fibers. Unlike the symptomatic epilepsies mentioned thus far, these disorders are usually associated with generalized epileptiform abnormalities on EEG.

A wide range of inborn errors of metabolism can be associated with epilepsy, and examples are listed in Table 558-1.

Evaluation of the Patient with Suspected Symptomatic Epilepsy

The epilepsy associated with the symptomatic etiologies is most often localization-related or arising from focal areas of cortex. Electroencephalography (EEG) will often show focal abnormalities, including epileptiform spikes or focal slowing, though it may be normal. A notable exception occurs with generalized abnormalities seen with the PMEs. It is important to try to record the EEG in both the awake and asleep states because sleep may potentiate epileptiform focal abnormalities.

Especially if the history, physical examination, or EEG suggests a structural etiology for epilepsy, MRI should be performed first and as soon as is practical. If the MRI is normal, both a complete genetic as well as metabolic evaluation must be performed in a patient thought to have symptomatic epilepsy. If the examination suggests a specific genetic syndrome or if there are multiple dysmorphic features, evaluation with a karyotype and testing for specific conditions should be performed. If these evaluations are unrevealing of a diagnosis, chromosomal microarray analysis or other genome-wide screens for deletions and duplications may be indicated, and the clinician should consider consultation with a geneticist if there is continued strong suspicion of a genetic etiology. In the absence of a structural or genetic diagnosis and in the presence of symptoms suspicious for metabolic disorders (eg, history of developmental regression, history of unexplained coma), a screening metabolic evaluation should be performed.

The term cryptogenic has been the source of controversy and discussion, and there has been a lack of consistency in its use.7According to the ILAE classification, cryptogenic epilepsy refers to epilepsy that is presumed to be symptomatic but for which an etiology has not been found.1 This definition would apply to any patient suspected of having symptomatic epilepsy on the basis of concurrent developmental delay who has a normal MRI and unrevealing genetic and metabolic evaluation. Thus, once an exhaustive evaluation is complete, such a patient can be classified as having cryptogenic epilepsy. This appears to be the case in up to one third of children treated for localization-related epilepsy.7 It is expected that this group will slowly diminish in size with the advent of improving neuroimaging techniques and an expanding array of clinically available genetic testing, including comparative genomic hybridization studies to evaluate for microdeletions and duplications at higher resolution than a standard clinical karyotype.

The idiopathic epilepsies are thought to be the most common of the epilepsies, and they occur in children who have a normal developmental history, no risk factors for symptomatic epilepsy, normal neurological examination, and normal neuroimaging.8 Idiopathic epilepsy is a term that literally means epilepsy without cause. This term now refers, however, to epilepsy in individuals who are thought to have a form of genetic epilepsy, based on the type of epilepsy syndrome with which they have been diagnosed, a positive family history, or both.

Inherited Epilepsies

There are single gene disorders that give rise to idiopathic epilepsy. There are also idiopathic epilepsies with known genetic predisposition for which specific genes have yet to be implicated. Many of the idiopathic epilepsies comprise well-defined epilepsy syndromes, with characteristic age of onset, seizure types, and sometimes EEG features. The epilepsy syndromes typically inherited in a Mendelian fashion involve mutations in genes encoding sodium and potassium channels, a sodium-potassium ATPase, and subunits of the nicotinic acetylcholine receptor and the amino-butyric acid receptor. Table 558-2 provides a list of these epilepsy syndromes and their associated genes.8,9 These epilepsies are inherited in an autosomal-dominant fashion with incomplete penetrance, as is the case for the majority of familial epilepsies. A notable exception is the autosomal recessive inheritance seen in a form of familial rolandic epilepsy with paroxysmal exercise-induced dystonia and writer’s cramp. Note that the inherited epilepsies display genetic heterogeneity, in that mutations in multiple different genes can give rise to the same phenotypic condition, such as generalized epilepsy with febrile seizures plus (GEFS Plus), a familial syndrome in which family members may have simple febrile seizures, febrile seizures followed by afebrile generalized or localization-related seizures, or epilepsy without antecedent febrile seizures. There is also pleiotropy, as mutations in the same gene can cause distinct phenotypes in different individuals, such as SCN2A mutations causing either GEFS Plus or benign familial neonatal/infantile convulsions.

The familial idiopathic epilepsy syndromes have allowed the identification of the genes that give rise to epilepsy in some individuals with these disorders, but these genes account for only a minority of the individuals with idiopathic epilepsy. For example, the genes SCN1B, SCN1A, SCN2A, and GABARG2 account for only a small proportion of families and patients with the syndrome GEFS Plus.10 Other genes are likely involved in this familial syndrome as well as other epilepsy syndromes.

The most commonly occurring epilepsy syndromes for which an inherited genetic basis is established or presumed are the idiopathic generalized epilepsies: childhood absence epilepsy, juvenile absence epilepsy, and juvenile myoclonic epilepsy. A common localization-related epilepsy syndrome with inherited genetic basis is benign rolandic epilepsy, or benign childhood epilepsy with centrotemporal spikes. Although there are a few specific genes and genetic loci known to be associated with these epilepsy syndromes, in the majority of cases the inheritance does not seem to follow a simple Mendelian pattern.9 “Complex inheritance” is invoked and may include the effects of inheriting multiple alleles that contribute to an individual’s susceptibility to epilepsy. Families are described in which there are some individuals with absence epilepsy, some with juvenile myoclonic epilepsy, and some with generalized tonic-clonic seizures on awakening, suggesting that an underlying tendency toward generalized epilepsy may be one factor that is inherited.8 What other factors—whether inherited or noninherited—contribute to the expression of epilepsy within these families remains to be elucidated.

Sporadically Occurring Genetic Epilepsies

Within families with GEFS Plus but also sporadically, children may present with severe myoclonic epilepsy of infancy (SMEI), a generally severe form of epilepsy associated with typically hemiclonic febrile seizures presenting in the first year of life, later seizures that are medically intractable, and developmental regression. Mutations in the SCN1A and GABRG2 genes are responsible for this severe phenotype, but they more typically occur de novo rather than in an inherited pattern.9,10 Though closely related genetically to more benign phenotypes, SMEI might one day be classified as a symptomatic generalized epilepsy with genetic etiology.

The etiologies of childhood epilepsy are varied, ranging from dramatic congenital brain malformations to inherited predispositions toward relatively benign epilepsy syndromes. When treating a child with epilepsy, the physician must address the issue of etiology efficiently. The symptomatic and idiopathic epilepsies, and the cryptogenic epilepsies in the border zone between them, include a broad differential diagnosis that must be considered when evaluating the child with epilepsy. Keeping these possibilities in mind will allow the clinician to conduct a focused history and physical examination that will guide the evaluation for underlying etiologies.