Seizures in Children

James J. Riviello Jr

Douglas R. Nordli Jr

INTRODUCTION

A seizure is a paroxysmal neurologic event resulting from excessive central nervous system (CNS) excitation, the hypersynchronous neuronal discharge. Management begins with evaluating the event, formulating a differential diagnosis, selecting appropriate diagnostic studies, and determining treatment, including the need for anticonvulsant medications. Seizures may be precipitated by an acute CNS insult, such as infection, stroke, intracranial hemorrhage, or traumatic brain injury; may result from a primary systemic disorder with secondary effects on the CNS, such as hypoglycemia; or occur with epilepsy, a condition in which recurrent, unprovoked seizures occur. However, many paroxysmal disorders in children are also referred to as seizures but are more properly called nonepileptic paroxysmal events (NEPE). It is important to consider the differential diagnosis of a seizure because NEPE are not treated with anticonvulsant medications. Seizures and epilepsy are similar in adults and children but certain seizure types and epilepsy syndromes are either peculiar to or more common in children.

The evaluation must determine if the seizure results from an acute CNS insult or if it is the initial presentation of epilepsy. A specific treatment may be needed if the seizure occurs during an intercurrent illness. Benign febrile seizures are frequently encountered in children (see the following text), but a seizure with fever (fever lowers seizure threshold) may occur at any age. In discussing seizures and epilepsy, several terms require definition: seizure, epilepsy, epilepsy syndrome, focal onset, generalized onset, status epilepticus, and refractory status epilepticus (Table 143.1).

EPIDEMIOLOGY

The incidence of unprovoked seizures varies from 42.3 to 61.0 per 100,000 population per year and the incidence of acute symptomatic seizures varies from 20 to 39.0 per 100,000 population per year. In the developed world, the annual incidence of epilepsy is about 46 per 100,000 population per year.

For specific childhood epilepsy syndromes, childhood absence epilepsy is the most common syndrome, occurring in 12% overall in several series, followed by benign rolandic epilepsy, 11.5%, and childhood epilepsy with occipital discharges, 9% (now Panayiotopoulos syndrome). In this series, myoclonic atonic epilepsy occurred in 6%; infantile spasms, 4.1%; and the epileptic encephalopathies, electrical status epilepticus of sleep, 1.1%; and Landau-Kleffner syndrome or epileptic aphasia, 0.5%.

CLASSIFICATION

The classification of the seizure and the actual epilepsy syndrome guides management. The first step is to consider the differential diagnosis because not all events referred to as seizures are epileptic events, such as the NEPE (Table 143.2). The seizure refers to the actual clinical manifestations and the epilepsy syndrome is the constellation of signs and symptoms that cluster around the seizure type. Three major classification systems are used: (1) the location of the seizure onset in the brain, either focal or generalized; (2) the seizure duration; and (3) seizure etiology.

TABLE 143.1 Terms from International League Against Epilepsy Task Force on Classification and Terminology

Seizure: sudden clinical event with outward change in neurologic function; etiology from the Greek, “to take hold”
Ictus: a neurologic event, including stroke, epileptic seizure, or an anoxic event
Convulsion: excessive, abnormal muscle contractions, usually bilateral, which may be sustained or interrupted
Epileptic seizure: refers to the clinical manifestations of an epileptic pathophysiology (transient hypersynchronous neuronal discharge), usually self-limited, neuronal activity. Adding the descriptor epileptic to seizure clearly signifies an epileptic etiology separating an epileptic from a nonepileptic seizure.
Epilepsy refers to (1) an epileptic disorder: a chronic neurologic condition characterized by recurrent epileptic seizures, and (2) epilepsies: conditions involving chronic recurrent epileptic seizures.
Epileptic syndromes: a complex of signs and symptoms that define a unique epilepsy condition
Focal: indicates a seizure in which the initial clinical manifestations suggest activation of only one part of a cerebral hemisphere
Febrile seizures: refers to a seizure that occurs in association of a febrile illness
	Simple febrile seizures are isolated, brief generalized convulsions.
	Complex febrile seizures are those that are focal or followed by a postictal deficit (Todd paresis), last >10-15 min, or occur more than once within 24 h.
Generalized: indicates a seizure whose initial clinical manifestations are consistent with more than minimal involvement of both cerebral hemispheres
Status epilepticus: The operational definition of status epilepticus, used for treatment, is a seizure or recurrent seizure without return of consciousness lasting >5 min.
Refractory status epilepticus is now defined as failure to respond to the first two antiepileptic drugs used.

The International League Against Epilepsy (ILAE) developed the International Classification of Epileptic Seizures (ICES), last revised in 2010. The ICES classifies the seizure type, referred to as the semiology, the signs, and the epilepsy syndrome. Seizures are divided into the location of the cortical onset: either focal or
generalized. A focal seizure is defined as one whose initial clinical manifestations indicate activation of only a focal area, or one part of the cortex, or in other words, the initial activation of a focal group of neurons. A generalized seizure is one with “more than minimal involvement of both cerebral hemispheres” or in other words, the initial activation of neurons throughout both hemispheres. A generalized seizure may not simultaneously involve every neuron. This is an important dichotomy because the clinical manifestations of the seizure depend on where the seizure starts and where it spreads and the antiepileptic drugs (AEDs) used to prevent seizure recurrence typically have efficacy for either focal or generalized seizures. The definitions of focal or generalized were revised to emphasize the concept of epileptic networks.

TABLE 143.2 Differential Diagnosis of Seizures

Syncope, convulsive syncope, pallid infantile syncope, breathholding attacks

Cardiac arrhythmias (prolonged QT syndrome)

Narcolepsy, cataplexy, hypersomnia

Hyperekplexia (startle disease)

Rage attacks, episodic dyscontrol, panic attacks

Migraines, especially benign paroxysmal vertigo, acute confusional state, basilar artery migraine

Movement disorders, paroxysmal dystonia, paroxysmal choreoathetosis, tics (especially ocular tics)

Munchausen syndrome, Munchausen by proxy

Night terrors, somnambulism, parasomnias

Sandifer syndrome, gastroesophageal reflux, esophageal spasm

Ocular movements (nystagmus, spasms, spasmus nutans, ocular tics)

Infantile self-gratification

Nonepileptic seizures (pseudoseizures)

Transient ischemic events

Seizure duration is important because aggressive treatment is needed for longer seizures. Status epilepticus, defined as a prolonged seizure lasting greater than 30 minutes or serial seizures without return of consciousness for 30 minutes, is a medical emergency that requires immediate termination. Five minutes of a continuous seizure or serial seizures without return of consciousness is the operational definition of status epilepticus for the purpose of treatment. Most seizures usually have a short duration, lasting less than several minutes, but status epilepticus is more likely to occur in the critically ill. The staging of status epilepticus has been used to guide treatment (Table 143.3), although the recent guideline from the Neurocritical Care Society defines refractory status epilepticus as failure to respond to the first two AEDs given rather than a stage of status epilepticus.

The third system classifies seizures and epilepsy by etiology, dividing them into symptomatic, cryptogenic, and idiopathic (Table 143.4). A symptomatic seizure is one for which the exact cause is identified. A cryptogenic seizure is one in which an underlying specific etiology is presumed because the neurologic state is abnormal (abnormal development or examination) but is not yet identified. The idiopathic seizure is one in which the etiology is not known, meaning that it arises spontaneously or from an obscure unknown cause. Many of the seizures identified as idiopathic are now identified as being associated with an abnormal gene or a channelopathy. A patient presenting with a new-onset seizure or status epilepticus from a specific cause would have an acute symptomatic seizure (review paper). If a past known CNS insult has caused the seizure, this is called a remote symptomatic seizure. However, a patient with epilepsy may have a seizure precipitated by an acute illness, referred to as a remote symptomatic seizure with an acute precipitant or an acute on chronic seizure.

TABLE 143.3 Stages of Status Epilepticus

Incipient stage (0-5 min)
Early stage (5-30 min)
	Special circumstances of the early stage: situations that need immediate seizure control
Transition stage (from early to late; time is variable, depends on underlying condition; e.g., a patient with a brain tumor and increased intracranial pressure may have no remaining compensatory mechanisms)
Late stage (established) (30-60 min)
Refractory stage (>60 min)
Postictal stage

The 2010 classification revision replaces the categories symptomatic; cryptogenic; and idiopathic with genetic, structural/metabolic, and unknown. The distinction between complex partial and simple partial seizures is also eliminated. However, it is important to be familiar with both systems because the terms symptomatic, cryptogenic, and idiopathic are still in common clinical use.

SPECIFIC PEDIATRIC SEIZURES AND EPILEPSY SYNDROMES

Space limitations preclude an all-inclusive review of pediatric seizures and pediatric epilepsy syndromes. We shall therefore summarize the seizure types and epilepsy syndromes that are peculiar
to the younger child. These include febrile seizures, both benign and complex, the most common seizure type and syndrome in childhood, and the severe childhood epilepsy syndromes including infantile spasms and the epileptic encephalopathies. These benign and severe syndromes are distinct from the seizures and epilepsy syndromes that occur in the adult.

TABLE 143.4 Classification of Seizure Etiology

Symptomatic seizure: The exact cause of the seizure has been identified.

Cryptogenic seizure: A specific etiology is presumed because the neurologic state is abnormal (abnormal development or examination) but has not yet identified.

Idiopathic seizure: There is no identifiable cause other than a possible hereditary predisposition.

Genetic cause: The concept of genetic epilepsy is that as best understood, the epilepsy is the result of a known genetic defect.

Structural/metabolic cause: There is a distinct structural or metabolic condition or disease that has been demonstrated to be associated with a substantially increased risk of developing epilepsy: stroke, trauma, infection.

Unknown cause: The nature of the underlying cause is not known.

FEBRILE SEIZURES

The ILAE defines a febrile seizure as “a seizure in association with a febrile illness in the absence of a CNS infection or acute electrolyte imbalance in children older than 1 month of age without prior afebrile seizures.” Febrile seizures are the most common cause of convulsions in children: Between 2% and 4% of all children in the United States and Europe and 9% to 10% of children in Japan have at least one febrile seizure before age 5 years. Hauser (1994) estimated that in 1990, there were 100,000 cases of newly diagnosed febrile seizures in the United States. Genetic predisposition is an important factor. Overall, siblings and offspring of affected probands have a two- to threefold increased risk of seizures with fever. Based on studies of large families with simple febrile seizures, various genetic loci have been mapped. The literature on the genetics of febrile seizures is substantial and it continues to grow. Linkage analysis has implicated many different chromosomes including 1q, 2q, 2p, 5q, 6q, 8q, 12q, 19p, and 19q. An important linkage has been with genes residing on 2q, which is the location of sodium channel genes, including SCN1A. Recently, another gene, SEZ-6, located on chromosome 17q, has been implicated. Some families have a susceptibility to febrile seizures that persists to an unusually late age, and some of these family members later develop epilepsy. These traits are inherited in an autosomal dominant fashion, and the condition has been termed genetic epilepsy febrile seizures plus (GEFS+). Mutations in the voltage-gated sodium channel genes SCN1A, SCN1B, and SCN2A are involved as well as the GABRG2 gene.

About two-thirds of febrile seizures occur in the first 24 hours of illness. Indeed, in some children, the seizure is the first indication of illness. Febrile seizures are subdivided into simple and complex types. Simple febrile seizures are most common, representing 80% to 90% of all febrile seizures. Simple febrile seizures are isolated, brief generalized convulsions. Parents commonly report diffuse stiffening followed by rhythmic jerking of all limbs lasting less than 1 to 2 minutes. Complex febrile seizures are those that are focal or followed by a postictal deficit (Todd paresis), last more than 10 to 15 minutes, or occur more than once within 24 hours. Factors predisposing to febrile status epilepticus include a younger age (mean age 15 months vs. 19 months for benign febrile seizures), a lower temperature (102.3°F vs. 103.6°F), female gender, first-degree family history of febrile seizures, and structural temporal lobe abnormalities.

About one-third of children with febrile seizures have more than one attack. Independent risk factors for recurrence are first febrile seizure before the age of 18 months, a family history of febrile seizures, a low peak temperature, and a short duration of fever before the seizure. Febrile seizures represent acute symptomatic seizures, also referred to as reactive seizures, and even when recurrent, do not warrant the designation of epilepsy. However, they do have an epileptic pathophysiology.

Children who have an isolated febrile seizure have a risk of developing epilepsy that is similar to that of the general population. This risk increases if simple febrile seizures recur (2% to 3%), if the febrile seizures are complex, there is a family history of afebrile seizures, or neurologic abnormalities were detected before the first febrile convulsion (10% to 13%). When all three features of complex febrile seizures are present (prolonged, focal, repeated), the risk of subsequent epilepsy may be as high as 49%. Mortality is not increased in children with febrile seizures who are neurologically normal.

Simple febrile seizures have not been associated with, nor do they lead to, mental retardation, low IQ, poor school achievement, or behavioral problems. Most studies have also failed to demonstrate any cognitive or behavioral consequences of complex febrile seizures, although some differences have been reported. In children with prolonged febrile convulsions, nonverbal intelligence measures may be slightly lower compared with children with simple febrile seizures and normal controls. Children with complex febrile seizures are also more likely to require special schooling than those with simple febrile seizures.

Whether prolonged febrile seizures cause mesial temporal sclerosis and refractory partial seizures is controversial. Large prospective studies have failed to find an association, but experience in adult epilepsy surgical centers suggests otherwise because many adults with mesial temporal sclerosis have had a prolonged febrile convulsion as a child. Furthermore, magnetic resonance imaging (MRI) in some children with prolonged febrile seizures has shown acute changes in the mesial temporal region that progress over time to mesial temporal sclerosis. There is accumulating evidence that febrile status epilepticus may have long-term consequences. This issue is currently being studied in the United States in a prospective multicenter research effort. The first phase consists of identifying the patients and biomarkers and the next phase will identify who ultimately develops mesial temporal sclerosis.

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