Rudolph's Pediatrics, 22nd Ed.

CHAPTER 557. Epidemiology of Epilepsy, Seizure Classification, Epilepsy Syndromes

Mark H. Libenson and Ann M. Bergin

DEFINITIONS

SEIZURES

An epileptic seizure is a change in neurologic function (motor, sensory, experiential, or autonomic) that is associated with an abnormal synchronous discharge of cortical neurons. Usually that discharge can be recorded by routine electroencephalogram (EEG) using scalp electrodes, although occasionally, because the discharge’s location is on a surface distant from the scalp, it can only be recorded by surgically implanted electrodes. Although the term seizureis sometimes used to refer to any paroxysmal event, in this chapter seizure always refers to an epileptic seizure, driven by an abnormal neuronal discharge. A convulsion is an epileptic seizure that results in involuntary muscle contractions.

EPILEPSY

Epilepsy refers to a tendency to spontaneous, recurrent seizures usually defined by the experience of having had two or more unprovoked seizures. This definition excludes certain types of provoked seizures, such as seizures caused by fever during childhood (febrile seizures), seizures caused by a temporary metabolic derangement such as hypoglycemia or hyponatremia, or seizures that occur in the setting of an acute central nervous system (CNS) insult such as stroke, trauma, or meningitis. Seizures that occur exclusively during the newborn period are also traditionally excluded from the definition of epilepsy because the majority of these are considered provoked seizures.

EPIDEMIOLOGY

Across the human life span, the first year of life is associated with the highest incidence of epilepsy with approximately 80 to 120 new cases of epilepsy per 100,000 children per year.1,2 Thereafter, most studies show that the incidence rate for the remainder of the next 2 decades decreases to as little as half that rate, reaching a nadir during the third decade that does not begin to rise substantially until the age of 60 years. Incidence rates comparable to those seen in the first 10 years of life are not reached again until after age 70.1 Prevalence rates of epilepsy in industrialized countries generally range between 0.5% and 1% during childhood.3

The overall recurrence risk after a first unprovoked seizure in childhood is approximately 50%. This statistic is the basis for the decision made to defer antiepileptic drug treatment after a first seizure episode in many children. Etiologies of seizure are reviewed in Chapter 558.

SEIZURE TYPES AND SEIZURE SYNDROMES

The most widely used systems for categorizing seizure types and seizure syndromes (or epilepsy syndromes) have been promulgated by the International League Against Epilepsy (ILAE). Although currently under revision, the ILAE seizure classification of 1981 and the epilepsy syndrome classifications of 1985 and 1989 are the basis for the categorization systems in widest use today23,24,25 (eTables 557.1  and 557.2 ).

The term seizure type refers to the classification of an individual seizure event. Two key features of a seizure event are used to classify its seizure type: the seizure semiology (the patient’s subjective description of the experience of the seizure or the patient’s outwardly observable actions during the seizure) and any simultaneous EEG recording made during the event. The patient’s background history is not critical in diagnosing seizure type.

By contrast, the diagnosis of a patient’s seizure or epilepsy syndrome is based on a cluster of signs and symptoms customarily occurring together. These may include case history; age of seizure occurrence; seizure type or types; modes of seizure recurrence; neurological, psychological, and EEG findings; and the results of neuroimaging.24

SEIZURE TYPES

The ILAE classification of seizure types describes two broad groups: partial (focal) seizures and generalized seizures, with a smaller “unclassified” group that cannot be assigned easily to either category (see eTable 557.1 ). The process of assigning a seizure to either the partial or generalized category is the first step in seizure classification.

PARTIAL SEIZURES

The terms partial seizure and focal seizure can be used interchangeably. Because a seizure discharge can arise from nearly any location on the cortical surface, partial seizures have a wide range of potential clinical manifestations. Motor findings are particularly common and include clonic (jerking) movements, tonic (stiffening) contraction of muscle groups, or atonic change (loss of tone) in a muscle group. Sensory or special sensory manifestations may also occur, such as tingling or pain over a region of the body, auditory or olfactory hallucinations, or seeing brightly colored shapes. Psychic features such as the experience of a feeling of fear or déjà vu may also occur. Autonomic findings such as sweating, palpitations, flushing, excess salivation, or incontinence may accompany a seizure. These findings can occur singly or in combination. If the seizure discharge flows from its region of onset into different areas of cortex, the seizure manifestations will evolve accordingly.

Todd’s Phenomenon

The best known manifestation of Todd’s phenomenon is Todd’s paralysis. When a motor seizure involves only part of the body, the seizure episode may be followed by a transient weakness in the involved area. In children, this weakness usually promptly resolves, typically in less than 1 hour. When invoking Todd’s paralysis as an explanation for weakness after a presumed seizure episode, steady improvement and complete resolution of the weakness are expected.

Complex Partial Seizures

Partial seizures are further subdivided into simple partial seizures and complex partial seizures (CPS). A CPS is a partial seizure associated with diminished consciousness or responsiveness. CPSs may arise from any lobe of the brain, with the temporal lobe being the most common site of origin. Temporal lobe seizures classically begin with staring and unresponsiveness, possibly associated with automatic movements such as chewing or hand fumbling, although considerable variation is seen. CPS may or may not secondarily spread to motor areas to manifest tonic or clonic activity. Children are often, but not always, amnesic for CPS episodes. Especially when the seizure discharge involves both temporal lobes, it can be impossible for the brain to record new memories during the seizure. Seizure episodes associated with discharges that remain unilateral are more likely to be recalled by the patient.

Epileptic Auras

An epileptic aura is a subjective sensation that heralds the onset of a seizure. The range of sensations can be diverse, such as hearing a buzzing sound in the ears or experiencing a déjà vu phenomenon or a feeling of nausea immediately preceding a seizure. This initial, comparatively minor manifestation may then be followed by the more dramatic features of the seizure. Because the aura actually represents the onset of a clinical seizure, an epileptic aura can be considered a seizure. In some cases, the aura does not progress and represents the seizure in its entirety.

Automatisms

Automatisms are automatic behaviors that may be seen during a seizure event. Examples include fumbling of the hands, running the fingers through the hair, making humming sounds, or mechanically continuing an activity that was in progress at the time of seizure onset. Unlike most clinical features of a seizure, automatisms are not driven directly by a seizure discharge in the way that clonic jerking is driven by repetitive EEG spike-wave discharges. Rather, automatisms represent the release of automatic, preprogrammed behaviors. When cerebral cortex is functioning normally.

Partial Seizures with Secondary Generalization

A seizure discharge may start focally and subsequently spread to involve all brain areas (generalize). A classic example of a partial seizure that spreads is the Jacksonian march: a seizure that begins with clonic activity in one limb or the face and sequentially spreads to the remainder of the involved hemibody, finally involving both sides of the body with a bilaterally synchronous convulsion. Partial seizures that secondarily generalize are classified among the partial seizures rather than the generalized seizures, as partial seizures, whether or not they generalize, have the same list of possible causes.

GENERALIZED SEIZURES

The category of generalized seizures includes absence seizures, myoclonic seizures, clonic seizures, tonic seizures, generalized tonic-clonic (GTC) seizures, and atonic (astatic) seizures. All generalized seizures share the fact that the discharge that drives the seizure is seen in all cortical areas at seizure onset.

Absence Seizures

In their purest form, simple absence seizures consist of a pure stare typically lasting 3 to 15 seconds associated with complete unawareness of the environment, the minimum duration only limited by the challenge of documenting unresponsiveness for the very briefest episodes.

In addition to a pure stare, most absence seizures are associated with some combination of a low amplitude rhythmic blinking of the eyes, a mild deviation of the eyes (usually upward), or a mild slackening of the facial muscles. Absence seizures are accompanied by “classic” 3 Hz generalized spike-wave discharges (see eFig. 557.1 ). Typical absence seizures are almost never associated with a fall. Although the patient is usually completely unaware of the environment during absence seizures, occasional patients report partial awareness and the ability to hear during episodes. In the majority of cases, patients are unaware that absence seizures have occurred, the only clue being the subjective feeling that something has been missed in the observed sequence of events.

Atypical Absence Seizures

The essential features of atypical absence seizures are also staring and unresponsiveness; however, onset and termination of the seizure are less sharply demarcated than is seen with typical absence seizures. Changes in tone with slumping of the head or shoulders is more common. Atypical absence seizures tend to occur in the setting of cognitive impairment or mental retardation. The EEG correlate of atypical absence seizures is the “slow spike-wave discharge,” firing at 2.5 Hz or less in contrast to the 3 Hz (or faster) generalized spike-wave discharge associated with typical absence.

Myoclonic Seizures

Myoclonic seizures consist of a lightning-like or shock-like contraction of the muscles. Many myoclonic seizures are generalized, though focal myoclonus is also possible. Nonepileptic myoclonus also occurs and can be distinguished from epileptic myoclonus with simultaneous EEG recording.

Generalized Clonic Seizures, Tonic Seizures, and Tonic-Clonic Seizures

Generalized clonic seizures are characterized by repetitive, synchronous whole-body jerks. Clonic jerks tend to have a rhythmical quality. Generalized tonic seizures consist of a tonic stiffening of the whole body, most often in extension, though tonic flexion of some muscle groups may be seen in some examples.

The term generalized tonic-clonic (GTC) seizure specifically refers to the seizure sequence of whole-body tonic stiffening followed by whole-body clonic jerking. Unfortunately, this term is often misused to refer to any generalized convulsion, a use that is technically incorrect. During a GTC seizure, the EEG shows a train of generalized rapid spikes that slow in frequency to become individual spike-wave discharges, followed by slowing. The rapid spikes are associated with the phase of tonic stiffening. As the firing rate of the spikes slows, each spike discharge is able to generate a separate clonic jerk, accounting for the progression from tonic stiffening to clonic jerking that is seen in the GTC seizure.

Atonic Seizures

Atonic seizures consist of a sudden loss of tone, usually of the axial musculature. In its mildest form, an atonic seizure may manifest as a subtle slumping of the shoulders. More frequently, an atonic seizure may manifest as a head-drop spell during which the head falls forward on the body. The most dramatic version of the atonic seizure is the drop attack (astatic seizure) in which the patient collapses to the ground, possibly resulting in injury.

NEONATAL SEIZURES

The neonatal seizure classification system in most common use today was described by Volpe in 1989.28 This 1989 classification includes subtle seizures, clonic seizures (focal and multifocal), tonic seizures (focal and generalized), and myoclonic seizures (focal, multifocal, and generalized). The most important difference between this neonatal seizure classification and the general ILAE classification used for older children and adults is the presence of a “subtle seizure” category. Subtle seizures described in neonates include movements such as “swimming,” “boxing,” or “hooking” movements of the upper extremities; “bicycling” movements of the lower extremities; oro-bucco-lingual movements such as sucking or lip-smacking; eye-opening or complex eye movements; and pure apneas. Because such phenomena are usually not associated with abnormal EEG discharges, the epileptic nature of these “subtle seizure” behaviors has not been firmly established. Many of these behaviors may represent the unmasking of automatic reflex behaviors in the newborn which are released when the cerebral cortex is not functioning normally. Even though the large majority of apneas in newborns are not related to seizure activity, rarely an epileptic seizure may manifest as a pure apnea in a newborn.

EPILEPSY (SEIZURE) SYNDROMES

A patient’s epilepsy (seizure) syndrome is defined by the types of seizures experienced, age of onset, neurologic assessment, family history, progression of the disorder, and EEG patterns. Identification of a particular epilepsy syndrome will often suggest possible etiologies, a specific prognosis, and treatments to be tried or avoided30 (see eTable 556.2 ). Select epilepsy syndromes are discussed below, generally in order of age of onset.

EARLY MYOCLONIC ENCEPHALOPATHY AND EARLY INFANTILE EPILEPTIC ENCEPHALOPATHY

Early myoclonic epilepsy (EME) and early infantile epileptic encephalopathy (EIEE) are the two major catastrophic epilepsies of early infancy. Infants with EME present soon after birth with both fragmentary and massive myoclonic seizures. Other seizure types also occur. The magnetic resonance imaging (MRI) scan is typically normal, and a large fraction of these babies are eventually found to have a specific metabolic disorder: nonketotic hyperglycinemia (NKH). Infants with EME fail to make developmental progress, and the seizures tend to be refractory to treatment. The EEG shows an unremitting burst-suppression pattern that may continue unabated through childhood.

EIEE, also known as Ohtahara syndrome, appears to be a “lesional” epilepsy syndrome and is often associated with an abnormal MRI scan. Tonic seizures are more prominent in EIEE as compared to EME. MRI abnormalities associated with this syndrome can include cerebral malformations or cerebral injuries, including those that may occur in babies with hypoxic-ischemic encephalopathy. Therefore, EIEE occurs as an epileptic syndrome that is believed to be symptomatic of a preexisting abnormality, be it a cerebral malformation or some type of brain injury, though recently a few cases have been associated with genetic abnormalities.31,32 Compared to EME, EIEE is more likely to evolve to West syndrome or the Lennox-Gastaut syndrome (see below).

PYRIDOXINE-DEPENDENT SEIZURES

The syndrome of pyridoxine-dependent seizures is extremely rare in its pure form. In the classic presentation of this disorder, a newborn is found to have refractory seizures associated with a persistent burst-suppression pattern on EEG. Administration of pyridoxine, sometimes in high doses, abruptly breaks the EEG pattern and brings about a prompt termination of the seizure activity. Without continued supplementation with pyridoxine, the seizures will relapse.

BENIGN NEONATAL CONVULSIONS (BNC) AND BENIGN FAMILIAL NEONATAL CONVULSIONS (BFNC)

The syndrome of benign neonatal convulsions (BNC) is also referred to as fifth day fits, a reminder that the fifth day of life is the most common age of onset of this syndrome. Because a benign long-term course is a key element of the syndrome, the diagnosis must often be made in retrospect. Affected babies usually appear normal at birth and have been discharged home from the hospital uneventfully. The seizures begin in the first week of life with 90% of babies presenting between the fourth and sixth days of life. The seizures usually resolve during the first year of life, most often by 2 months of age, with continuing normal development. There is no antecedent history of a difficult delivery or birth injury, and neuroimaging is normal. A positive family history of seizures is usually absent.

The syndrome of benign familial neonatal convulsions (BFNC) has many elements in common with the BNC syndrome. In BFNC, however, there is a positive family history for seizures in the newborn period and seizure onset is somewhat earlier, typically on the second or third day of life, usually resolving by the second month, but sometimes later. Unlike BNC, BFNC may be associated with a later incidence of epilepsy as high as 10% to 15%. A large proportion of affected babies have a mutation in the KCNQ2 or KCNQ3 potassium channel genes.  The typical seizure BFNC is the clonic seizure, preceded by tonic stiffening and apnea in some.33

INFANTILE SPASMS AND WEST SYNDROME

The term infantile spasms refers to a specific seizure type; the term “West syndrome” denotes an age-dependent epilepsy syndrome that includes the triad of infantile spasms, an EEG pattern of hypsarrhythmia, and abnormal neurodevelopment. Infantile spasms may express as flexor spasms, extensor spasms, or mixed (asymmetrical) spasms. Flexor spasms, the most common form, consist of a brief tonic contraction in flexion of the body on the hips, flexion of the head on the neck, and tensing of the shoulders, sometimes in abduction (also referred to as “jackknife seizures” or “Salaam seizures”). The flexed posture is maintained for approximately 1 second, followed by relaxation. The spasms tend to occur in clusters lasting several minutes, often after awakening from sleep. Milder variants of spasms can be seen, including relatively subtle bobbing of the head. The tensing posture assumed during infantile spasms can mimic gastrointestinal discomfort or episodes of colic.

West syndrome usually begins between the ages of 3 and 18 months. In many, the seizures resolve spontaneously but are often later replaced by other seizure types, such as focal seizures or the Lennox-Gastaut syndrome. Only a relatively small minority of patients are intellectually normal after West syndrome. The finding of hypsarrhythmia or one of its variants on EEG, a high-voltage, chaotic pattern that may only appear in sleep, is important to the diagnosis of West syndrome.

BENIGN PARTIAL EPILEPSIES

The benign partial epilepsies of childhood are a group of epilepsy syndromes associated with normal neurodevelopmental status, normal neuroimaging, a favorable long-term outcome, and a specific age range of occurrence. These disorders are believed to be genetically transmitted and are often associated with distinctive EEG patterns. The most important of these disorders is benign childhood epilepsy with centrotemporal spikes (BCECTS).

BCECTS or benign rolandic epilepsy is one of the most common forms of childhood epilepsy. Rolandic seizures are usually seen between the ages of 5 and 13 years and almost always disappear by the age of 16 years.35 Two specific seizure types are seen in BCECTS. The first is a partial seizure usually occurring in the morning which includes speech arrest and hemifacial clonic spasms or a pulling of the face to one side. The second seizure type is a generalized convulsion that occurs out of sleep.

It is rare for the seizures of BCECTS to persist after the teenage years, and of all seizure syndromes, BCECTS is the most likely to spontaneously remit. The diagnosis of BCECTS is confirmed in children with the appropriate history by the presence of distinctive centrotemporal spikes in the EEG, although identical spikes are also found in the EEGs of many asymptomatic children.

Two types of BCEOP are recognized: a more common, early onset variety (also referred to as Panayiotopoulos type) and a late-onset form (referred to as Gastaut type). In the early onset form of BCEOP, seizures begin between the ages of 3 and 6 years. The typical seizures of early onset BCEOP include autonomic symptoms such as pallor, sweating, and irritability which may evolve to vomiting, eye deviation, and loss of consciousness and culminate in convulsions (either hemiclonic or generalized clonic). Nocturnal seizures are more common than daytime seizures.

The late-onset form of BCEOP is considerably (5-fold) less common than the early-onset form with mean age of onset at 8 years of age. In contrast to the early-onset form, seizures are much more frequent, tend to occur in the daytime, and visual phenomena with elementary or (more rarely) complex visual hallucinations are common. Blindness may occur as either an ictal or postictal phenomenon. Headache and, more rarely, nausea and vomiting can be associated seizure symptoms. Both the early and late forms of BCEOP may show a distinctive pattern of occipital spikes that suppress with eye opening, the fixation-off effect, though the finding is not diagnostic of either syndrome.

PRIMARY GENERALIZED EPILEPSIES

The primary generalized epilepsies are a group of genetic epilepsy syndromes characterized by generalized seizures and generalized spike-wave discharges in the EEG. Most of these idiopathic syndromes occur in cognitively normal children and are caused by disorders of ion channels (“channelopathies”) or errors in synaptic receptors.

CHILDHOOD AND JUVENILE ABSENCE EPILEPSY

The absence seizures of childhood absence epilepsy (CAE or pyknolepsy) usually begin between 4 and 8 years of age. Children with CAE typically have as many as 100 to 200 of these brief absence seizures per day. A large fraction of children eventually grow out of the tendency to have absence seizures during the teenage years, with 90% remitting by the age of 20 years. Families and patients should be made aware of the estimated 40% to 50% lifetime risk of generalized convulsions in children with CAE, even in those in whom the absence seizures remit spontaneously.

In JAE, the absence seizures begin in the early teenage years and, compared to CAE, JAE patients are more likely to experience GTC seizures; there is an important overlap between JAE and juvenile myoclonic epilepsy (described below). In JAE, the absence seizures tend to be much less frequent (eg, once or twice per week) but of longer duration, with spells lasting 20 seconds not uncommon in the JAE group.

JUVENILE MYOCLONIC EPILEPSY AND EPILEPSY WITH GENERALIZED TONIC-CLONIC (GTC) SEIZURES ON AWAKENING

Three seizure types may be seen in juvenile myoclonic epilepsy (JME): myoclonic seizures (required for the formal diagnosis), GTC seizures, and absence seizures (in approximately one quarter). On average, the myoclonic jerks begin at 12 years of age, and the GTC seizures begin at 13 years of age. The morning myoclonic jerks may initially escape medical attention until the more dramatic GTC seizures occur. In epilepsy with GTC seizure on awakening the morning seizures are similar to those that occur in juvenile myoclonic epilepsy. This syndrome may represent the subset of juvenile myoclonic epilepsy without myoclonic or absence seizures.

LENNOX-GASTAUT SYNDROME

The Lennox-Gastaut syndrome (LGS) consists of a triad of mixed seizures, a slow spike-wave pattern on EEG (firing at 2.5 Hz or less), and cognitive dysfunction, all beginning in early childhood. Seizure types seen in LGS include atypical absence seizures, atonic seizures, tonic seizures (especially occurring during sleep), and myoclonic seizures. The seizures of LGS are often refractory to treatment.

ACQUIRED EPILEPTIC APHASIA

The Landau-Kleffner syndrome (LKS)40 or acquired epileptic aphasia is a childhood epilepsy syndrome that probably exists somewhere on the spectrum that includes BCECTS and epilepsy with CSWS. The language disturbance predominates in children with LKS. In the classic pattern, a child who has developed language normally develops an aphasia that is most pronounced in the receptive realm. Concurrently or soon after, an EEG abnormality is noted over one or both temporal lobes, strongly activated by sleep. Behavior and attention may also be adversely affected. Children with LKS may also have seizures, but these are usually sporadic and few in number. In rare instances, LKS may begin before significant language has developed, and the “acquired” nature of the syndrome may not be evident, the presentation mimicking pure language delay or an autistic spectrum disorder (ASD). How often LKS plays a role in the language and behavioral regression seen in children with ASD is a matter of current debate; however, it now appears that LKS plays a role in only a very small minority of the larger population of children with ASD.

TEMPORAL LOBE EPILEPSY (TLE)

TLE is the most common localization-related (focal) epilepsy. The classic seizure associated with the temporal lobe is the CPS. When a cause for TLE can be identified, such as mesial temporal sclerosis, a glioma, hamartoma, or a dysgenetic lesion in the temporal lobe, this kind of epilepsy can be considered a symptomatic epilepsy. In cases in which all testing is normal, temporal lobe epilepsy is classified as cryptogenic epilepsy.

The classic temporal lobe seizure may begin with staring, possibly associated with automatisms such as fumbling movements of a hand or chewing or lip-smacking behaviors. During the seizure prodrome, psychic symptoms such as the subjective feeling of fear or a déjà vu phenomenon may occur. Here, the term prodrome is misleading because such psychic symptoms represent the beginning of the ictal discharge rather than a warning that one is to occur. Temporal lobe seizures may spread to ipsilateral motor cortex resulting in contralateral clonic movements or the seizure may secondarily generalize and evolve to a generalized convulsion.

OTHER PRIMARY GENERALIZED EPILEPSIES

Epilepsy with myoclonic-astatic seizures or Doose syndrome is characterized by myoclonic-astatic seizures that consist of one or more brief myoclonic jerks followed by a loss of posture, often culminating in a fall. There is brief loss of consciousness during the attacks followed by quick recovery. Seizure onset is usually between 1½ and 5 years of age. A large variety of other generalized seizure types occur, including GTC seizures, absence seizures, and tonic seizures.

Benign myoclonic epilepsy of infancy (BMEI) is a syndrome of relatively mild myoclonic seizures typically presenting between the ages of 1 and 5 years. The syndrome usually remits, but it is possible that learning and developmental difficulties occur at a higher frequency in affected individuals compared to the general population. The myoclonic seizures are accompanied by polyspikes, and strobe stimulation may elicit the jerks in a subset of infants.

Reflex-induced myoclonic epilepsy may represent a subset of benign myoclonic epilepsy of infancy in which the myoclonic jerks are elicited by sound or touch. Severe myoclonic epilepsy of infancy is a childhood-onset epilepsy that is refractory to treatment and is associated with an ongoing neurological deterioration caused by the seizures (epileptic encephalopathy). The typical presentation begins with repetitive, prolonged febrile seizures during the first year of life. Epilepsy with continuous spike wave of slow sleep (CSWS) is a relatively rare epileptic encephalopathy associated with neuropsychological impairment and a variety of possible seizure types, both generalized and focal.

Epilepsy with continuous spike wave of slow sleep (CSWS) is a relatively rare epileptic encephalopathy associated with neuropsychological impairment and a variety of possible seizure types, both generalized and focal. Clinical seizures in this syndrome range from rare or no seizures to seizures that occur several times per week.

Epilepsia partialis continua describes refractory, highly focal, sometimes fragmentary motor seizures due to a lesion of the contralateral motor cortex. It is often associated with Rasmussen’s syndrome, a unilateral, apparently inflammatory disorder of unknown etiology occurring in childhood and associated with cognitive deterioration and progressive atrophy of the involved hemisphere.