CHAPTER 131

Seizures and Epilepsy

Hanalise V. Huff, MD, MPH, and Kenneth R. Huff, MD

Seizures are a common medical problem in children. Diagnosing an episode that does not contain generalized convulsing movements as a seizure is sometimes problematic, however. Seizure is an episodic, stereotypical behavior syndrome of abrupt onset with loss of voluntary control, resulting in loss of responsiveness and rarely provoked by external stimuli. Frequently, the occurrence of this behavior correlates with interictal brain electrical discharges on electroencephalography (EEG), and the behavioral ictus (ie, seizures) should match temporally with a period of electrical hypersynchrony if it occurs during the EEG recording.

A detailed history of the nature of the episodic behavior from an eyewitness or a video recording is paramount in making the diagnosis of a seizure disorder and elucidating the type of seizure problem. The EEG is most often an adjunct to diagnosis. It is abnormal in many individuals who do not have clinical seizures, and it may be normal interictally in many patients with clinical seizures because of its sampling limitations. Special techniques can sometimes help alleviate these limitations.

Epilepsy is a seizure problem that implies recurrence of seizures. Identifying the type of seizure problem is important in devising the management plan. Seizures can simply be classified as primary generalized seizures, that is, involving the whole cerebrum from the outset, or partial seizures. Some partial seizures can secondarily generalize, however, thereby clinically mimicking primary generalized seizures after their onset. Distinguishing these entities illustrates the importance of eyewitness information. Many treatment options are available, but the therapeutic plan must be individualized to the child’s seizure type or clinical syndrome to optimize seizure control and minimize side effects. With appropriate treatment, most children with seizure disorders are not handicapped scholastically or socially and can enjoy normal lives.

Epidemiology

Fifty million people worldwide have epilepsy, with 3 to 4 million of those in the United States (1.2% of the US population). Approximately 0.5% to 1.0% of all children experience at least 1 afebrile seizure. In children younger than 18 years, the new onset epilepsy incidence rate per year is approximately 0.05%. Recurrent seizures can occur as a component of a static encephalopathy after brain malformation or dysgenesis, encephalitis or meningitis, metabolic disorder, hypoxic-ischemic injury, or severe head trauma. Such secondary or symptomatic seizures make up approximately one-third of childhood epilepsies. The remaining two-thirds of epileptic seizures occur presumably as part of a genetic epileptic syndrome. As genetic knowledge increases, eventually the specific cause or association of seizures in most children will be diagnosed.

Clinical Presentation

Children present with a history given by observers of an episode of abrupt onset characterized by a loss of ability to respond to external stimuli (Box 131.1). The child may experience various difficult-to-describe sensory, emotional, or psychic phenomena (ie, aura) before losing consciousness. Observers then see convulsive muscle activity, after which the patient may be sleepy. With some seizures, observers may note only an akinetic or staring spell; however, other seizures present with dramatic, rhythmic spasms of the face, extremities, or torso. Major motor seizures are frequently also associated with systemic autonomic changes, including changes in skin vascular supply causing color change, sweating, saliva production, and loss of sphincter control. Approximately 10% of children have a headache before or after their seizure. With the exception of the common provocative factors of fever, intercurrent illness, and sleep deprivation and the much rarer provocative factors of the reflex epilepsies, most seizure episodes are neither provoked nor attenuated by environmental factors. Between episodes, a child’s general physical and neurologic examination may be entirely normal.

Pathophysiology

A seizure represents a sudden, synchronous depolarizing change in the electrical activity of a network of neurons that becomes widely propagated over the cortex, affecting awareness, responsiveness to external stimuli, and motor control. The propagation may be enhanced by defects in cell ion channels. Focal seizure disorders may result from a focal cortical lesion, such as a glial scar caused by a remote insult (eg, trauma, infarct), or a dysgenesis or primary cortical dysplasia that disrupts the electrical circuitry. The focal abnormality also could contain hamartomatous immature cells and abnormal synaptic properties and allow for periodic, abnormal transmission of impulses.

Exactly what initiates the change in dynamic between excitatory and inhibitory influences on the neuron, the synchronous depolarization of the neurons, and the widespread network propagation is not well understood, and a rigorous analysis of abnormal neuronal and cerebral neurophysiology is beyond the scope of this chapter. Several different physiologic mechanisms, including disrupted neuronal circuitry; voltage- and ligand-gated membrane ion channel abnormalities; abnormal excitatory or inhibitory neurotransmitter or receptor production, degradation, or uptake, including a critical protein interaction involving the γ-aminobutyric acid (GABA) type A α-2 subunit of its inhibitory receptor; and perhaps glial support mechanisms, could each be involved depending on the type of epilepsy or epilepsy syndrome. One example is familial childhood absence epilepsy, which results from abnormal thalamocortical circuitry that is in some way developmentally vulnerable. Another example is cryptogenic West syndrome (ie, infantile spasms), an “inter-neuronopathy” that has been associated with several genes, including LIS1, DCX, and ARX (sometimes resulting in agyria), which are important in GABAergic inhibitory interneuron development. A third example is the neuronal voltage-gated sodium channel subunit gene, SCN1A, which is mutated in the mild phenotype of “generalized epilepsy with febrile convulsions plus” and also mutated but in different regions of the gene sequence in the much worse phenotype of Dravet syndrome, which was previously known as severe myoclonic epilepsy of infancy. Neonates are more susceptible because of a paradoxical excitatory effect of GABA receptors in immature neurons, a relative abundance of N-methyl-D-aspartate receptors, and a peak in dendritic spines and synapse numbers. Further understanding of the mechanism involved in familial epilepsy syndromes awaits the definition of relevant genes, their expression and product functions, as well as the effects of changes in exon base pair sequence, regulatory regions of the genome, or epigenetic mechanisms on membrane polarization, synaptic function, and circuitry physiology.

Seizure Types

Seizures can be simply classified by their ictal appearance as either primary generalized seizures, which include grand mal seizures, generalized tonic-clonic convulsions, and petit mal (absence) seizures (so named because of the child’s complete loss of awareness at the outset of the episode), or focal (ie, localization-related) seizures, which include focal motor, psychomotor, and other partial disorders (Box 131.2). Epilepsy syndromes are also a useful means of classifying seizures by their clinical patterns (ie, diagnosis, therapy, and prognosis). Even with a known genetic cause, the same gene can produce more than 1 epileptic syndrome (Box 131.3). The examples presented here are not an exhaustive list of seizure syndromes; rather, they are among the more important types encountered in practice.

Two-thirds of nonfebrile seizures in children result from a focal seizure disorder. Psychomotor seizures are focal seizures that usually are preceded by a sensory aura or sometimes emotional behavioral manifestations and have a wide range of ictal behaviors, including focal clonic jerking, aversive or asymmetric hypertonic posturing, and more complex stereotypic fumbling or fingering behaviors. Seizures may be followed by postictal confusion or drowsiness. In some instances, children have partial sensory awareness but are unable to respond during seizures. In other cases, however, they are completely unconscious. The initial partial motor manifestations may not be seen by the observer before the movements rapidly generalize. Partial seizures are more often associated with focal brain pathologic processes, including traumatic lesions, infarcts, malformations, infections (eg, viral encephalitis, cerebral cysticercosis), and hippocampal sclerosis. The latter is rare in children but has been associated with a distant history of a prolonged febrile seizure. A few of these etiologies may be found with a characteristic appearance on magnetic resonance (MR) imaging; however, in most cases the etiology and its location are not apparent on MR imaging alone and require a combination of techniques to find the source of the resistant seizures.

Benign epilepsy syndromes occur in children with normal developmental history, respond well to therapy, and remit without sequelae. Rolandic seizures, or benign epilepsy with central temporal spikes, is a relatively common partial seizure syndrome that sometimes is familial and has a good prognosis for resolving by adolescence. These episodes commonly occur when children are falling asleep, during sleep, or on awaking. Motor manifestations involve the tongue, mouth, or face but can sometimes generalize to the rest of the body. The clinical syndrome is accompanied by a characteristic focal EEG discharge over the central temporal region of the scalp. Other benign syndromes include benign familial infantile seizures; benign infantile seizures with mild gastroenteritis; childhood occipital epilepsy characterized by visual symptoms and EEG occipital spike-wave discharges; and Panayiotopoulos syndrome, which is characterized by paroxysmal autonomic dysfunctions such as vomiting and other gastrointestinal motility problems, pallor, mydriasis, and cardiorespiratory and thermoregulatory abnormalities (lasting up to 30 minutes), often ending in generalized convulsing and largely occurring in sleep.

An absence seizure may sometimes be difficult to distinguish from a partial seizure (Table 131.1). The absence spell is a brief (2–15 seconds) loss of consciousness without loss of tone. Staring into space and minor movements, such as lip smacking or semi-purposeful- appearing movements of the hands are often the only observed behaviors. There is no postictal period. Because absence seizures occur multiple times per day and children are often unaware of them, parents or guardians may dismiss the subtle behavior change as selective attention or daydreaming; however, these seizures may adversely affect learning and carry a risk of injury. Hyperventilation, a useful diagnostic test that can be performed in the office, may provoke absence seizures. The EEG is generally confirmatory and may also distinguish classic petit mal seizures with 3-per-second spike-wave discharges from variant syndromes. The classic petit mal is more often familial with dominant inheritance, age-specific occurrence between 4 and 16 years as childhood or juvenile absence, and sensitivity to ethosuximide treatment, whereas the atypical variant has a poorer prognosis for early resolution and is more resistant to anticonvulsant therapy. Juvenile myoclonic epilepsy begins during adolescence, but even if symptoms abate, treatment is often necessary into adulthood and is characterized by upper extremity myoclonus (ie, dropping or flinging behaviors) and convulsive seizures in the morning.

Neonatal seizures may be tonic, focal clonic, or multifocal clonic. The seizure problem is less often primary, and a vigorous search for an etiology of the seizure is more often successful than with older children. Problems commonly resulting in neonatal seizures include hemorrhage (eg, germinal matrix hemorrhage in the preterm neonate, subarachnoid or subdural hemorrhage from birth trauma in older neonates); hypoxic-ischemic damage from asphyxia; infections producing postnatal sepsis or meningitis or prenatal encephalitis; drug withdrawal in the newborn exposed to illicit drugs in utero; metabolic problems, including hypoglycemia, hypocalcemia, or hypomagnesemia in the neonate of a diabetic mother; amino or organic acidopathies occurring a few days after feedings have begun; congenital brain malformations; and genetic syndromes, including benign neonatal familial epilepsy, benign familial infantile epilepsy, and pyridoxine-dependent epilepsy.

Several more malignant seizure syndromes exist that have onset at typical ages, perhaps related to more widespread maturational events in brain circuitry or ion channels. Although the appearance of the seizures within each of these syndromes is stereotypical and ultimately interictal cognition is commonly affected, resulting in their designation as an “epileptic encephalopathy,” in fact a wide variety of etiologic diagnoses may produce these syndromes.

West syndrome is an age-related seizure syndrome that involves typical but sometimes subtle movements of flexion contraction of the trunk with the head bowed or sudden raising of the arms, sometimes accompanied by a cry. These behaviors, infantile spasms, occur stereotypically several times in succession in a series. This syndrome, which includes a characteristic EEG and a period of developmental arrest, occurs in infants and children between 3 and 24 months of age. Another, perhaps related, but rarer syndrome of frequent tonic spasms, Ohtahara syndrome, occurs during the neonatal period and is associated with tonic seizures, an abnormal neurologic examination, and often structural brain abnormalities. It is characterized by a different burst-suppression EEG pattern but carries a similar dismal prognosis for impaired intellectual development. Dravet syndrome arises out of typical febrile seizures that then occur without fever and subsequently manifest as staring spells and myoclonic seizures accompanied by delayed cognition. As many as 50% of these children may experience sudden unexplained death in epilepsy (SUDEP) by age 10 years. Landau-Kleffner syndrome involves loss of language abilities at age 3 to 5 years in the context of epileptic seizures and a very abnormal EEG pattern in sleep. It is related to continuous spike and waves during slow wave sleep, which is associated with a more general cognitive decline. A fifth syndrome in older children that is also associated with a different but characteristic EEG pattern, Lennox-Gastaut syndrome, has the same poor prognosis for seizure control and cognitive development but produces several different behavioral seizure types, including tonic, absence, and drop attacks. Different types of brain lesion in these age groups (including focal lesions) can result in the same generalized seizure syndromes. Examples include tuberous sclerosis; neonatal ischemia, hemorrhage, or meningitis; and major central nervous system malformations. Other epileptic encephalopathies include early myoclonic encephalopathy, malignant migrating partial seizures of infancy, Rasmussen encephalitis, and Doose syndrome.

Differential Diagnosis

Seizures are distinguished from nonepileptic paroxysmal disorders based on patient history. The circumstances of place and time as well as details about the symptoms and nature of the behavior are important pieces of data. Syncope may be misdiagnosed as a seizure. Unlike seizure, however, the syncopal episode is frequently situational. It occurs when children are in hot or stuffy environments; when they have been standing in 1 place for a long time, such as during a ceremony or physical education class; or when they see or experience a painful event, such as an injection or phlebotomy. Boys may experience micturition syncope standing in the bathroom shortly after arising in early morning. Syncope often is preceded by symptoms of light-headedness, nausea, tinnitus, and eventually a gradual darkening of vision, sometimes without total loss of auditory perception. Observers may note pale skin color and cool damp skin.

Breath-holding spells are characterized by apnea and loss of responsiveness accompanied by cyanosis or pallid skin color. Breath-holding spells are also situational. Infants or children are often upset or crying just before such spells. They may be frightened by a seemingly minor injury or angry after a toy is taken away or they are disciplined. Children may then throw themselves backward and stiffen while closing their glottis in expiration, and they may even have a few clonic jerks after losing consciousness (see Chapter 52).

Selective attention is frequently mistaken for absence seizure. Selective attention often occurs when children are involved in relatively passive activities (eg, watching television, playing a video game, daydreaming) and do not respond to verbal stimuli, such as hearing their own name called. Generally, the attention lapses do not occur during talking or eating; seizures will occur, however, even during these activities.

Epileptic seizures must also be differentiated from pseudoseizures (ie, psychogenic nonepileptic seizures), which occur most often in patients who have true seizures. Such episodes may include ictal eye closure and pelvic thrusting but also may resemble true seizures accurately, the psychodynamics of secondary gain or other motivation for the behavior may not be readily apparent, and the “need” for attention may be legitimate. The finding that the standard EEG is normal does not exclude a true seizure and thus is not helpful. Pseudoseizures should be suspected in children who may have witnessed seizures in relatives or close friends, who have seizures that consistently recur in the same situations, whose seizure frequency is not decreased with therapeutic levels of anticonvulsants, and whose seizures appear suggestible. Often, diagnosis can be supported in complicated cases by simultaneous video EEG monitoring, which shows a lack of correlation of electrical abnormalities with the behavior in question. Immediate postictal serum prolactin level also may be normal, and psychological assessment may detect underlying emotional problems related to prior trauma (eg, sexual abuse, other major psychological trauma). The prognosis of pseudoseizures in children generally is better than in adults and relates to the more acute psychosocial genesis of the problem in most children.

Infants and older children have several behaviors that mimic seizures. Infantile gastroesophageal reflux (ie, Sandifer syndrome) may have the appearance of brief epileptic tonic spasms but has a consistent temporal relationship to feeding. Benign paroxysmal vertigo occurs in the infant or toddler and presages migraine later in childhood. Infantile shuddering consists of brief, rapid side-to-side shaking of the head and trunk. Older children can experience a paroxysmal dystonia, which is provoked externally and produces a change in truncal tone and posture and a brief cessation of movement. Tics are sudden, brief stereotypical movements preceded by an urge and are partially suppressible. Stereotypies are recurrent movements that are often self-stimulatory and frequently occur with severe autism. None of these entities produces a loss of responsiveness of the child.

Sleep myoclonus is a normal nonepileptic variant that is common in infants; however, in older children accurate diagnosis of paroxysmal events in sleep may be a challenge because the motor behaviors of non-rapid eye movement sleep or other parasomnias may mimic nocturnal frontal lobe epileptic seizures. Video EEG polysomnography is also helpful in distinguishing between frontal lobe epileptic seizures and nocturnal parasomnias, which are not associated with ictal discharges.

Evaluation

History

The history should determine the exact events surrounding the seizure episode. A detailed history of the nature of the behavior from an eyewitness is extremely important (Boxes 131.4 and 131.5). The observer can be asked to video record a subsequent event. The physician must determine whether the child experienced any loss of the child’s normal level of responsiveness. Typically, this change in mental status is abrupt, although a warning behavior or aura that lasts for a few seconds may precede complete loss of responsiveness. The warning behavior or aura for a seizure may be a cry, an expression of fear or anxiety, or nonspecific irritability. The child who is articulate may be able to describe a discrete sensory phenomenon or relate a less distinct or even indescribable sensation.

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