Epilepsy

John M. Pellock

Seizure is the manifestation of a sudden, uncontrolled surge of neuronal firing. After a first seizure, approximately 50% of the patients will have a second one within 6 months. After two seizures, children have an approximately 80% chance of recurrence (1). Epilepsy, recurrent unprovoked seizures, is the most common neurological disorder in children.

Epilepsy affects 0.5% to 1% of children through age 16 years. Each year, 20,000 to 45,000 children are diagnosed with epilepsy. Of children 5 to 14 years of age, 325,000 are affected with epilepsy (2). Child neurologists spend at least 50% of their clinical time caring for patients with epilepsy because of seizures and their comorbidity. Epilepsy is more common in children with mental retardation and other underlying neurological and psychiatric disorders (3). Epilepsy of early childhood onset is more likely to indicate an underlying brain disorder than is epilepsy of middle childhood onset, which is likely to have an unknown or genetic cause (4,5).

Neurologists and psychiatrists have common ground not only in diagnosis but also in their prescribing of antiepileptic drugs (AEDs). In addition, psychiatrists might be asked to evaluate and treat epilepsy‘s comorbidities—depression, attention deficit hyperactivity disorder (ADHD), and anxiety—before or in conjunction with neurologists (3).

This chapter reviews (a) epilepsy and seizures, including their incidence, classification, etiology, and differential diagnosis; (b) AEDs and their effects on seizures and psychiatric disorders; and (c) psychiatric comorbidities of epilepsy.

Seizure Classification

The International League against Epilepsy has proposed a classification based on the clinical manifestations of the seizure and the electroencephalogram (EEG) (6). It differentiates partial from generalized seizures.

Partial seizures begin locally within a specific brain region, whereas generalized seizures have no clear focal onset. Partial seizures are further divided into those expressed by confusion or mild alteration of consciousness (complex partial) and those without alteration of consciousness (simple partial). Generalized seizures are defined by the presence or absence of the motor activity that accompanies the events, and are typically associated with impairment or a loss of consciousness (Table 5.1).

Seizures previously referred to as “grand mal” are convulsive, and include tonic, clonic, and tonic-clonic seizures, and seizures that have partial onset with secondary generalization.
The term grand mal may include seizures that have partial onset with secondary generalization. Thus, defining a seizure as grand mal or convulsive does not help determine a possible focal onset. However, documenting a partial (focal) onset is crucial in diagnosing localized pathology, such as mesial temporal sclerosis or a tumor. The term petit mal had been applied to “small seizures” that could include myoclonic seizures or staring spells, which could be either generalized absence or complex partial seizures. The clinical behavior associated with a partial seizure depends on the area of the brain that is affected; a behavioral or focal motor event will correlate with the cortical area involved. In adolescents, the most common focus for partial seizures is the temporal lobe. Those seizures often begin with an aura, such as fear or déjà vu. In young children, extratemporal partial seizures are more common.

TABLE 5.1 CLASSIFICATION OF EPILEPSY

Partial (focal, local) seizures
Definition: The first clinical and/or EEG changes indicate initial involvement of part of one hemisphere. Partial seizures are classified on the basis of an impairment of consciousness.
1. Simple, partial seizures (no impairment of consciousness)
2. Complex partial seizures (with impairment of consciousness)
3. Partial seizures with secondary generalization
Generalized seizures
Definition: The first clinical and/or EEG changes indicate initial involvement of both hemispheres. Consciousness is impaired.
1. Absence/atypical absence
2. Myoclonic
3. Clonic
4. Tonic
5. Tonic-clonic
6. Clonic-tonic-clonic
7. Atonic

NONEPILEPTIC EVENTS

On the other hand, what appears to be a seizure is occasionally a nonepileptic event, sometimes termed a “pseudoseizure.” Although these events are paroxysmal and feature altered behavior, they do not produce an alteration on the EEG. Moreover, they often have no identifiable physiological cause and are frequently associated with psychiatric disturbances. In some children and adolescents, sexual or physical abuse has preceded these episodes.

Kotagal et al (7) reported paroxysmal nonepileptic events in 134 (15.2%) of 883 children and adolescents during a six-year period in the Cleveland Clinic Epilepsy Monitoring Unit (EMU). In that study, of children 5 to 12 years old, 61 had a diagnosis of nonepileptic events, including conversion disorder (psychogenic seizures), inattention, daydreaming spells, stereotypic movements, hypnic jerks, or paroxysmal movements. Of those children, 25% had concomitant epilepsy. Of adolescents, 12 to 18 years old, 48 had nonepileptic events. Of these adolescents, 83% had a conversion disorder and 19% had concomitant epilepsy. Thus, the demonstration of a nonepileptic behavior does not rule out the presence of epilepsy.

Having a family review the video-recorded event is a good way to document that the behavior in question represents the “seizure” reported. In cases of different types of episodes, management is quite difficult.

When both the clinical evaluation and the EEG suggest pseudoseizures, psychiatric consultation is advisable because of the high incidence of underlying psychiatric disorders (8,9). Frequently diagnosed nonepileptiform paroxysmal disorders in children and adolescents are listed in Table 5.2.

Children and adolescents with mental retardation, autism, or other pervasive developmental disorder (PDD) are subject to another diagnostic pitfall. Clinicians may misinterpret
recurrent movements or behaviors (stereotypies) as seizures. In any case, a comprehensive diagnostic assessment from a neurologist may be indicated because children with these disorders may have a high rate of seizures. Similarly, children who are blind or deaf or both also have stereotypies, some of which are self-stimulating. Overall, the prognosis of nonepileptic events is better in children than in adults (10).

TABLE 5.2 SYMPTOMS OF NONEPILEPTIFORM PAROXYSMAL DISORDERS

Unusual movement	Jitteriness	Self-stimulation
	Masturbation	Tics (Tourette’s syndrome)
	Shuddering	Paroxysmal choreoathetosis or dystonia
	Benign sleep myoclonus	Pseudoseizures
	Startle responses	Eye movement
	Paroxysmal torticollis	Head nodding
Episodic features of specific disorders	Tetralogy spells	Hyperthyroidism
	Hydrocephalic spells	Gastroesophageal reflux
	Cardiac arrhythmias	Rumination
	Hypoglycemia	Drug poisoning
	Hypocalcemia	Cerebrovascular events
	Periodic paralysis
Loss of tone or consciousness	Syncope	Narcolepsy/cataplexy
	Drop attacks	Attention deficit
Respiratory derangements	Apnea	Hyperventilation
	Breath holding
Perceptual disturbances	Dizziness	Headache
	Vertigo	Abdominal pain
Behavior disorders	Head banging	Acute psychotic symptoms
	Night terrors		fugue
	Sleepwalking		phobia
	NIghtmares		panic attacks
	Rage		hallucinations
	Confusion		autism
	Fear
From Pellock JM. Other nonepileptic paroxysmal disorders. In: Wylie E, Gupta A, Lachhwani DK, eds. The treatment of epilepsy, principles and practice. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2006:632, with permission.

Etiology and Diagnosis of Childhood Epilepsy

The etiology of childhood epilepsy is often population-specific. For example, neurocysticercosis commonly causes epilepsy in citizens of Central America, where cysticercosis is endemic. The age of onset of epilepsy is also important. For example, children with inborn errors of metabolism, congenital malformations, and perinatal injuries tend to present with epilepsy at a young age. Genetic factors and head trauma are more common causes in the older child and adolescent. Although various type-specific gene abnormalities cause certain varieties of epilepsy, it is still unclear why specific mutations, which are associated with epilepsy, have variable expression, including different ages of onset in members of the same family (11).

The history and clinical characteristics of the events serve as the basis of the preliminary diagnosis. During a medical history, the physician should inquire whether activities such as staring spells or myoclonic jerks, which might represent seizures, also occur. In a similar fashion, the physician should ask about possible localized symptoms of seizures. For example, the parents may have noted momentary jerking of one limb or conjugate eye deviation prior to the onset of a seizure.

▪ FIGURE 5.1A EEG as seen in a child with absence seizures.

▪ FIGURE 5.1B Electroencephalogram (EEG) as seen in a child with complex partial seizures. (Parts A and B from Rothner AD. Epilepsy. In: Kaufman DM, Solomon GE, Pfeffer CR, eds. Child and adolescent neurology for psychiatrists. Baltimore: Williams & Wilkins, 1992:98; with permission.)

The EEG during the typical episode provides a reliable documentation of the presence, classification, and origin of a seizure. In the usual clinical situation, a routine EEG is performed between events, that is, in the interictal period (12). The interictal EEG may be completely normal or may demonstrate abnormalities, such as generalized spike-and-waves or focal spikes, suggestive of generalized or focal onset epilepsy (Figs. 5.1A,B). An EEG may show focal slowing of background rhythms over a particular region, suggesting a structural lesion. EEGs should include photic stimulation and hyperventilation to activate potential epileptiform activity. When clinical events continue despite normal interictal EEGs, neurologists order prolonged (24 hours) EEG studies or an EEG at the time of day when spells usually develop, such as early morning or with sleep deprivation.

Notably, a normal EEG does not exclude a diagnosis of epilepsy. Moreover, identification of nonspecific abnormalities during a routine EEG does not confirm the diagnosis of epilepsy. Children’s EEG records have numerous normal variants. For example, young children have prominent, central, sharp vertex activity during drowsiness and sleep that is frequently misinterpreted as being indicative of epilepsy but is normal.

Prolonged video-EEG monitoring in an EMU for 3 to 7 days is now standard for determining whether seizures are present and establishing an electroclinical correlation. In other words, it determines if a child’s behavior coincides with a paroxysm of abnormal EEG activity. This monitoring confines children to a specially designed room, but within it they are free to move about and a parent can stay with them. EEG electrodes are glued to their scalp rather than secured with pins. In addition to the scalp electrodes, technicians may apply ones to measure other physiological functions, such as respiration, cardiac activity, and ocular movement, which would reflect sleep stages. The monitoring consists of continual digital recordings of closed circuit video observations of children’s behavior and the simultaneous EEG. While the child is in the EMU, physicians often withdraw AEDs to allow seizure activity to emerge. Although exceptions appear in the literature, the results of video-EEG monitoring are generally accepted as the gold standard.

Neurologists order brain imaging in children in whom cerebral pathology is suspected. However, certain “benign epilepsy syndromes,” such as childhood absence (see further on), do not require imaging. When imaging is performed, magnetic resonance imaging (MRI) is the modality of choice (12). Advanced imaging techniques, such as functional MRI (fMRI), positron emission tomography (PET), and other specialized imaging techniques, are currently appropriate only for those undergoing evaluation for epilepsy surgery.

Epilepsy in Children and Adolescents

EPILEPSY SYNDROMES

Epilepsy is not a single disease but rather a neurological disorder with variable clinical presentations and etiologies. The epilepsy syndromes are defined by their seizure type, age at onset, history and neurological examination, ictal and interictal EEG, family history, etiology, anatomical localization, and, perhaps most importantly, prognosis and heritability (13). These syndromes are generally divided into those characterized by focal (partial) pathology and those that have generalized seizures from the onset. Etiologies may be symptomatic (proven cause), cryptogenic (presumed but unproven), and idiopathic (frequently genetic in otherwise normal individuals).

The age of onset and whether the child is otherwise neurologically normal help differentiate the epilepsy syndrome and comorbid psychiatric features. Table 5.3 demonstrates
the diagnostic approach to the differentiation of epilepsy syndromes based on the child’s age at the onset of epilepsy and the neurological evaluation (14).

TABLE 5.3 AGE-RELATED EPILEPSY SYNDROMES^a

Age Group	Normal Examination	Abnormal Examination
Preschool	Myoclonic-astatic (myoclonic-astatic, vibratory tonic/GSW rhythmic theta)	Lennox-Gastaut (tonic seizures, atypical absence, partial/slow, i.e., 2.5-Hz spike wave)
School age	Benign, rolandic, benign occipital (sensory, clonic/stereotyped IEDs)	Landau-Kleffner, CSWS (rare seizures/continuous spike waves in sleep
	Childhood absence (absence/3-Hz spike-wave)	Myoclonic absence (myoclonic absence/3-Hz spike-wave)
		Epilepsia partialis continua syndromes (Kojewnikoff, Rasmussen) (epilepsia partialis continua/polymorphic spikes)
Juvenile	Juvenile myoclonic	Progressive myoclonus (myoclonus, other/slowed background)
	Juvenile absence
	GTCS on awakening (as described/generalized fast polyspike waves, PPR)
^aDiagnostic approach is based on seizure semiology/electroencephalographic (EEG) findings; age-related presentations of some common epilepsy syndromes are listed with seizure semiology and interictal EEG findings.
CSWS, continuous spike-wave during slow-wave sleep; GTCS, generalized tonic-clonic seizures; IED, interictal epileptiform discharges; PPR, photoparoxysmal responses.
From Nordli DR, Jr. Diagnostic difficulty in infants and children. J Child Neurol. 2002;17(suppl 1):S28-35 with permission.

COMPLEX PARTIAL EPILEPSY

Complex partial epilepsy usually originates in the temporal lobe and its connections with the limbic system. Less often, it originates in the frontal or occipital lobe. Classically, the child or adolescent with complex partial epilepsy will first experience a conscious sensation, thought, perception, or emotion—the aura. This first part of the seizure localizes the origin of the seizure itself (ictus). Overwhelming fear is the most common aura; others that begin in the limbic system are a rising feeling in the epigastrium or an unpleasant olfactory hallucination (like burning rubber) emanating from the uncus. Déjà vu, jamais vu, or a repetitive thought may also constitute an aura. The aura is followed by an alteration of consciousness as discharges travel through the limbic system. Automatisms occur in at least 75% of patients (15). Examples of automatisms are lip smacking, uncontrollable laughing (gelastic epilepsy), and running in a circle (cursive epilepsy). If the discharges travel to the reticular formation, patients lose consciousness. A secondary generalized tonic-clonic seizure followed by postictal confusion and drowsiness can occur. Such ictal and postictal behaviors are often misinterpreted as psychiatric disturbances. During the ictal automatism or postictal period, children and adolescents may appear to be aggressive if someone tries to restrain them. Although less common in children than adults, patients may have complex partial status epilepticus, a form of nonconvulsive status epilepticus. Complex partial status epilepticus consists of prolonged seizures with automatisms that can masquerade as a fugue state. An EEG during an event is diagnostic.

In about 40% of adolescents and adults with complex partial epilepsy, the interictal EEG demonstrates temporal spikes in the awake state. If both wake and sleep states are recorded, EEGs are abnormal in about 80%. In children with partial complex epilepsy, the
interictal EEG may show bilateral, usually asymmetrical spike-and-wave discharges from the temporal lobes.

TABLE 5.4 DIFFERENTIAL DIAGNOSIS OF STARING SPELLS

Clinical Data		Absence	Complex Partial	Daydreaming
Frequency/day		Multiple	Rarely >1-2	Multiple, situation dependent
Duration		Frequently below 10 sec; rarely >30 seconds	Average duration over 1 min, rarely <10 sec	Seconds to minutes
Aura		Never	Frequently	No
Eye blinking		Common	Occasionally	No
Automatisms		Common	Frequently	No
Postictal impairment		None	Frequently	No
Seizures activated
	By hyperventilation	Very frequently	Occasionally	No
	Photic stimulation	Frequently	Rarely	No
EEG
	Ictal	Generalized spike and wave	Usually unilateral or bilateral temporal or frontal discharges	Normal
	Interictal	Usually normal	Variable; may be spikes or sharp waves in frontal or temporal lobes	Normal
EEG, electroencephalogram.
From Holmes G. Diagnosis and management of seizures in children. Philadelphia: WB Saunders; 1987:177; with permission.

Children and adolescents with complex partial epilepsy, compared with age-matched populations, carry a high incidence of psychiatric comorbidity, including behavior disturbances, depression, anxiety, and suicidality (15).

Complex partial epilepsy must be differentiated from absence epilepsy (petit mal), which has its onset in childhood (16) (Table 5.4). Complex partial epilepsy can begin at any age; however, about 50% of patients with complex partial epilepsy experienced their first seizure before the age of 25 years (17). In children and adolescents, as well as adults, complex partial epilepsy may originate in the frontal lobes.

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