Seizures in Childhood

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Chapter 586 Seizures in Childhood

A seizure is a transient occurrence of signs and/or symptoms resulting from abnormal excessive or synchronous neuronal activity in the brain. The International Classification of Epileptic Seizures divides epileptic seizures into 2 large categories: In focal (partial) seizures, the first clinical and electroencephalographic (EEG) changes suggest initial activation of a system of neurons limited to part of one cerebral hemisphere; in generalized seizures, the first clinical and EEG changes indicate synchronous involvement of all of both hemispheres (Table 586-1). Approximately 30% of patients who have a first afebrile seizure have later epilepsy; the risk is about 20% if neurologic exam, EEG, and neuroimaging are normal. Febrile seizures are a special category. Acute symptomatic seizures occur secondary to an acute problem affecting brain excitability such as electrolyte imbalance or meningitis. Most children with these types of seizures do well, but sometimes such seizures signify major structural, inflammatory, or metabolic disorders of the brain, such as meningitis, encephalitis, acute stroke, or brain tumor; the prognosis depends on the underlying disorder, including its reversibility or treatability and the likelihood of developing epilepsy from it. Unprovoked seizure is not an acute symptomatic seizure. Remote symptomatic seizure is thought to be secondary to a distant brain injury such as an old stroke.

Table 586-1 TYPES OF EPILEPTIC SEIZURES

SELF-LIMITED SEIZURE TYPES

Focal Seizures

Focal sensory seizures

• With elementary sensory symptoms (e.g., occipital and parietal lobe seizures)

• With experiential sensory symptoms (e.g., temporo-parieto-occipital junction seizures)

Focal motor seizures

• With elementary clonic motor signs

• With asymmetrical tonic motor seizures (e.g., supplementary motor seizures)

• With typical (temporal lobe) automatisms (e.g., mesial temporal lobe seizures)

• With hyperkinetic automatisms

• With focal negative myoclonus

• With inhibitory motor seizures

Gelastic seizures

Hemiclonic seizures

Secondarily generalized seizures

Reflex seizures in focal epilepsy syndromes

Generalized Seizures

Tonic-clonic seizures (includes variations beginning with a clonic or myoclonic phase)

Clonic seizures

• Without tonic features

• With tonic features

Typical absence seizures

Atypical absence seizures

Myoclonic absence seizures

Myoclonic atonic seizures

Negative myoclonus

Atonic seizures

Reflex seizures in generalized epilepsy syndromes

CONTINUOUS SEIZURE TYPES

Generalized Status Epilepticus

Generalized tonic-clonic status epilepticus

Clonic status epilepticus

Absence status epilepticus

Tonic status epilepticus

Myoclonic status epilepticus

Focal Status Epilepticus

Epilepsia partialis continua of Kojevnikov

Aura continua

Limbic status epilepticus (psychomotor status)

Hemiconvulsive status with hemiparesis

PRECIPITATING STIMULI FOR REFLEX SEIZURES

Visual stimuli

• Flickering light—color to be specified when possible

• Patterns

• Other visual stimuli

From International League Against Epilepsy: Epileptic seizure types and precipitating stimuli for reflex seizures (website), May 13, 2009. http://www.ilae-epilepsy.org/Visitors/Centre/ctf/seizure_types.cfm. Accessed October 8, 2010.

Epilepsy is a disorder of the brain characterized by an enduring predisposition to generate seizures and by the neurobiologic, cognitive, psychological, and social consequences of this condition. The clinical diagnosis of epilepsy usually requires the occurrence of at least 1 unprovoked epileptic seizure with either a second such seizure or enough EEG and clinical information to convincingly demonstrate an enduring predisposition to develop recurrences. For epidemiologic purposes epilepsy is considered to be present when ≥2 unprovoked seizures occur in a time frame of >24 hr. Approximately 4-10% of children experience at least 1 seizure in the first 16 yr of life. The cumulative lifetime incidence of epilepsy is 3%, and more than half of the cases start in childhood. The annual prevalence is 0.5-1%. Thus, the occurrence of a single seizure or of febrile seizures does not necessarily imply the diagnosis of epilepsy. Seizure disorder is a general term that is usually used to include any one of several disorders including epilepsy, febrile seizures, and possibly single seizures and seizures secondary to metabolic, infectious, or other etiologies (e.g., hypocalcemia, meningitis).

An epileptic syndrome is a disorder that manifests one or more specific seizure types and has a specific age of onset and a specific prognosis. Several types of epileptic syndromes can be distinguished (Tables 586-2 to 586-4). This classification has to be distinguished from the classification of epileptic seizures that refers to single events rather than to clinical syndromes. In general, seizure type is the primary determinant of the type of medications the patient is likely to respond to, and the epilepsy syndrome determines the type of prognosis one could expect. An epileptic encephalopathy is an epilepsy syndrome in which the severe EEG abnormality is thought to result in cognitive and other impairments in the patient. Idiopathic epilepsy is an epilepsy syndrome that is genetic or presumed genetic and in which there is no underlying disorder affecting development or other neurologic function (e.g., petit mal epilepsy). Symptomatic epilepsy is an epilepsy syndrome caused by an underlying brain disorder (e.g., epilepsy secondary to tuberous sclerosis). A cryptogenic epilepsy (also termed presumed symptomatic epilepsy) is an epilepsy syndrome in which there is a presumed underlying brain disorder causing the epilepsy and affecting neurologic function, but the underlying disorder is not known.

Table 586-2 CLASSIFICATION FOR EPILEPSY SYNDROMES WITH AN INDICATION OF AGE OF ONSET, DURATION OF ACTIVE EPILEPSY, PROGNOSIS, AND THERAPEUTIC OPTIONS

Table 586-3 IDENTIFIED GENES FOR EPILEPSY

Table 586-4 CHILDHOOD EPILEPTIC SYNDROMES WITH GENERALLY GOOD PROGNOSIS

SYNDROME	COMMENT
Benign neonatal familial convulsions	Dominant, may be severe and resistant during a few days Febrile or afebrile seizures (benign) occur later in a minority
Infantile familial convulsions	Dominant, seizures often in clusters (overlap with benign partial complex epilepsy of infancy)
Febrile convulsions plus syndromes (see Table 586-2)	In some families, febrile and afebrile convulsions occur in different members, GEFS+ The old dichotomy between febrile convulsions or epilepsy does not always hold
Benign myoclonic epilepsy of infancy	Often seizures during sleep, one rare variety with reflex myoclonic seizures (touch, noise)
Partial idiopathic epilepsy with rolandic spikes	Seizures with falling asleep or on awakening; focal sharp waves with centrotemporal location on EEG; genetic
Idiopathic occipital partial epilepsy	Early childhood form with seizures during sleep and ictal vomiting; can occur as status epilepticus Later forms with migrainous symptoms; not always benign
Petit mal absence epilepsy	Cases with absences only, some have generalized seizures. 60-80% full remission In most cases, absences disappear on therapy but there are resistant cases (unpredictable)
Juvenile myoclonic epilepsy	Adolescence onset, with early morning myoclonic seizures and generalized seizures during sleep; often history of absences in childhood

EEG, electroencephalogram; GEFS+, generalized epilepsy with febrile seizures plus.

From Deonna T: Management of epilepsy, Arch Dis Child 90:5–9, 2005.

Evaluation of the First Seizure

Initial evaluation of an infant or child during or shortly after a suspected seizure should include an assessment of the adequacy of the airway, ventilation, and cardiac function as well as measurement of temperature, blood pressure, and glucose concentration. For acute evaluation of the 1st seizure, the physician should search for potentially life-threatening causes of seizures such as meningitis, systemic sepsis, unintentional and intentional head trauma, and ingestion of drugs of abuse and other toxins. The history should attempt to define factors that might have promoted the convulsion and to provide a detailed description of the seizure and the child’s postictal state. Most parents vividly recall their child’s initial convulsion and can describe it in detail.

The 1st step in an evaluation is to determine whether the seizure has a focal onset or is generalized. Focal seizures may be characterized by motor or sensory symptoms and include forceful turning of the head and eyes to one side, unilateral clonic movements beginning in the face or extremities, or a sensory disturbance such as paresthesias or pain localized to a specific area. Focal seizures in an adolescent or adult usually indicate a localized lesion, but investigation of focal seizures during childhood may be nondiagnostic. Focal seizures in a neonate may be seen in perinatal stroke. Motor seizures may be focal or generalized and tonic-clonic, tonic, clonic, myoclonic, or atonic. Tonic seizures are characterized by increased tone or rigidity, and atonic seizures are characterized by flaccidity or lack of movement during a convulsion. Clonic seizures consist of rhythmic muscle contraction and relaxation; myoclonus is most accurately described as shocklike contraction of a muscle. The duration of the seizure and state of consciousness (retained or impaired) should be documented. The history should determine whether an aura preceded the convulsion and the behavior of the child immediately preceding the seizure. The most common aura experienced by children consists of epigastric discomfort or pain and a feeling of fear. The posture of the patient, presence and distribution of cyanosis, vocalizations, loss of sphincter control (particularly of the urinary bladder), and postictal state (including sleep, headache, and hemiparesis) should be noted.

In addition to the assessment of cardiorespiratory and metabolic status described, examination of a child with a seizure disorder should be geared toward the search for an organic cause. The child’s head circumference, length, and weight are plotted on a growth chart and compared with previous measurements. A careful general and neurologic examination should be performed. The eyegrounds must be examined for the presence of papilledema, retinal hemorrhages, chorioretinitis, coloboma, or macular changes, as well as retinal phakoma. The finding of unusual facial features or associated physical findings such as hepatosplenomegaly point to an underlying metabolic or storage disease as the cause of the neurologic disorder. Positive results of a search for vitiliginous lesions of tuberous sclerosis using an ultraviolet light source and examination for adenoma sebaceum, shagreen patch, multiple café-au-lait spots, a nevus flammeus, and the presence of retinal phakoma could indicate a neurocutaneous disorder as the cause of the seizure.

Localizing neurologic signs such as a subtle hemiparesis with hyperreflexia, an equivocal Babinski sign, and a downward-drifting extended arm with eyes closed might suggest a contralateral hemispheric structural lesion, such as a slow-growing temporal lobe glioma, as the cause of the seizure disorder. Unilateral growth arrest of the thumbnail, hand, or extremity in a child with a focal seizure disorder suggests a chronic condition such as a porencephalic cyst, arteriovenous malformation, or cortical atrophy in the opposite hemisphere.

586.1 Febrile Seizures

Mohamad A. Mikati

Febrile seizures are seizures that occur between the age of 6 and 60 mo with a temperature of 38°C or higher, that are not the result of central nervous system infection or any metabolic imbalance, and that occur in the absence of a history of prior afebrile seizures. A simple febrile seizure is a primary generalized, usually tonic-clonic, attack associated with fever, lasting for a maximum of 15 min, and not recurrent within a 24-hour period. A complex febrile seizure is more prolonged (>15 min), is focal, and/or recurs within 24 hr. Febrile status epilepticus is a febrile seizure lasting >30 min.

Between 2% and 5% of neurologically healthy infants and children experience at least 1, usually simple, febrile seizure. Simple febrile seizures do not have an increased risk of mortality even though they are concerning to the parents. Complex febrile seizures may have an approximately 2-fold long-term increase in mortality, as compared to the general population over the subsequent 2 yr, probably secondary to coexisting pathology. There are no long-term adverse effects of having ≥1 simple febrile seizures. Specifically, recurrent simple febrile seizures do not damage the brain. Compared with age-matched controls, patients with febrile seizures do not have any increase in incidence of abnormalities of behavior, scholastic performance, neurocognitive function, or attention. Children who develop later epilepsy might experience such difficulties. Febrile seizures recur in approximately 30% of those experiencing a first episode, in 50% after 2 or more episodes, and in 50% of infants <1 yr old at febrile seizure onset. Several factors affect recurrence risk (Table 586-5). Although about 15% of children with epilepsy have had febrile seizures, only 2-7% of children who experience febrile seizures proceed to develop epilepsy later in life. There are several predictors of epilepsy after febrile seizures (Table 586-6).

Table 586-5 RISK FACTORS FOR RECURRENCE OF FEBRILE SEIZURES

MAJOR

Age <1 yr

Duration of fever <24 hr

Fever 38-39°C

MINOR

Family history of febrile seizures

Family history of epilepsy

Complex febrile seizure

Day care

Male gender

Lower serum sodium

Having no risk factors carries a recurrence risk of about 12%; 1 risk factor, 25-50%; 2 risk factors, 50-59%; 3 or more, 73-100%.

Modified from Mikati MA, Rahi A: Febrile seizures: from molecular biology to clinical practice, Neurosciences 10:14–22, 2004.

Table 586-6 RISK FACTORS FOR OCCURRENCE OF SUBSEQUENT EPILEPSY

RISK FACTOR	RISK FOR SUBSEQUENT EPILEPSY
Simple febrile seizure	1%
Neurodevelopmental abnormalities	33%
Focal complex febrile seizure	29%
Family history of epilepsy	18%
Fever <1 hr before febrile seizure	11%
Complex febrile seizure, any type	6%
Recurrent febrile seizures	4%

Modified from Mikati MA, Rahi A: Febrile seizures: from molecular biology to clinical practice, Neurosciences 10:14–22, 2004.

Genetic Factors

The genetic contribution to incidence of febrile seizures is manifested by a positive family history for febrile seizures. In many families the disorder is inherited as an autosomal dominant trait, and multiple single genes causing the disorder have been identified. In most cases the disorder appears polygenic, and the genes predisposing to it remain to be identified. Identified single genes include FEB 1, 2, 3, 4, 5, 6, and 7 genes on chromosomes 8q13-q21, 19p13.3, 2q24, 5q14-q15, 6q22-24, 18p11.2, and 21q22. Only the function of FEB 2 is known: it is a sodium channel gene, SCN1A.

Almost any type of epilepsy can be preceded by febrile seizures, and a few epilepsy syndromes typically start with febrile seizures. These are generalized epilepsy with febrile seizures plus (GEFS+), severe myoclonic epilepsy of infancy (SMEI, also called Dravet syndrome), and, in many patients, temporal lobe epilepsy secondary to mesial temporal sclerosis.

GEFS+ is an autosomal dominant syndrome with a highly variable phenotype. Onset is usually in early childhood and remission is usually in mid-childhood. It is characterized by multiple febrile seizures and several types of afebrile generalized seizures, including generalized tonic-clonic, absence, myoclonic, atonic, or myoclonic astatic seizures with variable degrees of severity.

Dravet syndrome is considered to be the most severe of the phenotypic spectrum of febrile seizures plus. It constitutes a distinctive separate entity that is one of the most severe forms of epilepsy starting in infancy. Its onset is in the 1st yr of life, characterized by febrile and afebrile unilateral clonic seizures recurring every 1 or 2 mo. These early seizures are typically induced by fever, but they differ from the usual febrile convulsions in that they are more prolonged, are more frequent, and come in clusters. Seizures subsequently start to occur with lower fevers and then without fever. During the 2nd yr of life, myoclonus, atypical absences, and partial seizures occur frequently and developmental delay usually follows. This syndrome is usually caused by a new mutation, although rarely it is inherited in an autosomal dominant manner. The mutated gene is located on 2q24-31 and encodes for SCN1A, the same gene mutated in GEFS+ spectrum. However, in Dravet syndrome the mutations lead to loss of function and thus to a more severe phenotype.

The majority of patients who had had prolonged febrile seizures and encephalopathy after vaccination and who had been presumed to have suffered from vaccine encephalopathy (seizures and psychomotor regression occurring after vaccination and presumed to be caused by it) have Dravet syndrome mutations, indicating that their disease is due to the mutation and not secondary to the vaccine. This has raised doubts about the very existence of the entity termed vaccine encephalopathy.

Work-Up

The general approach the patient with febrile seizures is delineated in Figure 586-1. Each child who presents with a febrile seizure requires a detailed history and a thorough general and neurologic examination. These are the cornerstones of the evaluation. Febrile seizures often occur in the context of otitis media, roseola and human herpesvirus 6 (HHV6) infection, shigella, or similar infections, making the evaluation more demanding. Several investigations need to be considered.

Figure 586-1 Management of febrile seizures.

(Modified from Mikati MA, Rahi A: Febrile seizures: from molecular biology to clinical practice, Neurosciences 10:14–22, 2004.)

Lumbar Puncture

Lumbar puncture is recommended in children <12 mo of age after their first febrile seizure to rule out meningitis. It is especially important to consider if the child has received prior antibiotics that would mask the clinical symptoms of the meningitis. The presence of an identified source of fever, such as otitis media, does not eliminate the possibility of meningitis. Seizures are the major sign of meningitis in 13-15% of children presenting with this disease, and 30-35% of such children have no other meningeal signs. According to the American Academy of Pediatrics (AAP) practice parameter, it is strongly recommended in infants <1 yr of age because other signs of the infection might not be present. A child between 12 and 18 mo of age should also be considered for lumbar puncture because the clinical symptoms of meningitis may be subtle in this age group. For the well-appearing child after a febrile seizure, the yield of lumbar puncture is very low. For children >18 mo of age, a lumbar puncture is indicated in the presence of clinical signs and symptoms of meningitis (e.g., neck stiffness, Kernig sign, Brudzinski sign) or if the history and/or physical examination otherwise suggest intracranial infection.

Electroencephalogram

If the child is presenting with his or her first simple febrile seizure and is otherwise neurologically healthy, an EEG need not normally be performed as part of the evaluation. An EEG would not predict the future recurrence of febrile seizures or epilepsy even if the result is abnormal. Spikes during drowsiness are often seen in children with febrile seizures, particularly those >4 yr old, and these do not predict later epilepsy. EEGs performed within 2 wk of a febrile seizure often have nonspecific slowing, usually posteriorly. Thus, in many cases, if an EEG is indicated, it is delayed until or repeated after >2 wk have passed. EEG should therefore generally be restricted to special cases in which epilepsy is highly suspected, and it should be used to delineate the type of epilepsy rather than to predict its occurrence. If an EEG is done, it should be performed for at least 30 min in wakefulness and in sleep according to international guidelines to avoid misinterpretation and drawing of erroneous conclusions. At times, if the patient does not recover immediately from a seizure, then EEG can help distinguish between ongoing seizure activity and a prolonged postictal period sometimes termed a nonepileptic twilight state (NETS).

Blood Studies

Blood studies (serum electrolytes, calcium, phosphorus, magnesium, and complete blood count [CBC]) are not routinely recommended in the work-up of a child with a first simple febrile seizure. Blood glucose should be determined only in children with prolonged postictal obtundation or those with poor oral intake (prolonged fasting). Serum electrolyte values may be abnormal in children after a febrile seizure, but this should be suggested by precipitating or predisposing conditions elicited in the history and reflected in abnormalities of the physical examination. If clinically indicated (e.g., in a history or physical examination suggesting dehydration) these tests are indicated.

Neuroimaging

According to the AAP practice parameter, a CT or MRI is not recommended in evaluating the child after a first simple febrile seizure.

The work-up of children with complex febrile seizures needs to be individualized. This can include EEG and neuroimaging, particularly if the child is neurologically abnormal. Patients with febrile status epilepticus have been reported to have swelling of their hippocampus acutely and subsequent long-term hippocampal atrophy. These patients may be candidates for neuroimaging, because they may be at risk for later temporal lobe epilepsy.

Treatment

In general, antiepileptic therapy, continuous or intermittent, is not recommended for children with one or more simple febrile seizures. Parents should be counseled about the relative risks of recurrence of febrile seizures and recurrence of epilepsy, educated on how to handle a seizure acutely, and given emotional support. If the seizure lasts for >5 min, then acute treatment with diazepam, lorazepam, or midazolam is needed (see Chapter 586.8 for acute management of seizures and status epilepticus). Rectal diazepam is often prescribed to be given at the time of recurrence of febrile seizure lasting >5 min (see Table 586-12 for dosing). Alternatively, buccal or intranasal midazolam may be used and is often preferred by parents. Intravenous benzodiazepines, phenobarbital, phenytoin, or valproate may be needed in the case of febrile status epilepticus. If the parents are very anxious concerning their child’s seizures, intermittent oral diazepam can be given during febrile illnesses (0.33 mg/kg every 8 hr during fever) to help reduce the risk of seizures in children known to have had febrile seizures with previous illnesses. Intermittent oral nitrazepam, clobazam, and clonazepam (0.1 mg/kg/day) have also been used. Other therapies have included intermittent diazepam prophylaxis (0.5 mg/kg administered as a rectal suppository every 8 hr), phenobarbital (4-5 mg/kg/day in 1 or 2 divided doses), and valproate (20-30 mg/kg/day in 2 or 3 divided doses). In the vast majority of cases it is not justified to use these medications owing to the risk of side effects and lack of demonstrated long-term benefits, even if the recurrence rate of febrile seizures is expected to be decreased by these drugs. Other antiepileptic drugs (AEDs) have not been shown to be effective.

Antipyretics can decrease the discomfort of the child but do not reduce the risk of having a recurrent febrile seizure, probably because the seizure often occurs as the temperature is rising or falling. Chronic antiepileptic therapy may be considered for children with a high risk for later epilepsy. Currently available data indicate that the possibility of future epilepsy does not change with or without antiepileptic therapy. Iron deficiency has been shown to be associated with an increased risk of febrile seizures, and thus screening for that problem and treating it appears appropriate.

Bibliography

American Academy of Pediatrics. Febrile seizures: clinical practice guideline for the long-term management of the child with simple febrile seizures. Pediatrics. 2008:1281-1286.

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Chen SY, Tsai CN, Lai MW, et al. Norovirus infection as a cause of diarrhea-associated benign infantile seizures. Clin Infect Dis. 2009;48:849-855.

Guerrini R. Epilepsy in children. Lancet. 2006;367:499-524.

Hartfield DS, Tan J, Yager JY, et al. The association between iron deficiency and febrile seizures in childhood. Clin Pediatr. 2009;48:420-426.

Kimia A, Ben-Joseph EP, Rudloe T, et al. Yield of lumbar puncture among children who present with their first complex febrile seizure. Pediatrics. 2010;126:62-69.

Kimia A, Capraro AJ, Hummel D, et al. Utility of lumbar puncture for first simple febrile seizure among children 6 to 18 months of age. Pediatrics. 2009;123:6-12.

Nørgaard M, Ehrenstein V, Mahon BE, et al. Febrile seizures and cognitive function in young adult life: a prevalence study in Danish conscripts. J Pediatr. 2009;155:404-409.

Provenzale JM, Barboriak DP, VanLandingham K, et al. Hippocampus MRI signal hyperintensity after febrile status epilepticus is predictive of subsequent mesial temporal sclerosis. AJR Am J Roentgenol. 2008;190:976-983.

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586.2 Unprovoked Seizures

Mohamad A. Mikati

History and Examination

Acute evaluation of a first seizure includes evaluation of vital signs and respiratory and cardiac function and institution of measures to normalize and stabilize them as needed. Signs of head trauma, abuse, drug intoxication, poisoning, meningitis, sepsis, focal abnormalities, increased intracranial pressure, herniation, neurocutaneous stigmata, brain stem dysfunction, and/or focal weakness should all be sought because they could suggest an underlying etiology for the seizure.

The history should also include details of the seizure manifestations, particularly those that occurred at its initial onset. These could give clues to the type and brain localization of the seizure. One should question whether there were other previous signs or symptoms that might signify the occurrence of seizures that the parents overlooked or did not report. In some instances, if the events have been going on for a time and there is a question about their nature (e.g., sleep myoclonus versus seizures), then the family can video record the patient and make the video available to the health care provider. Having the parents imitate the seizure can also be helpful. Seizure patterns (e.g., clustering), precipitating conditions (e.g., sleep or sleep deprivation, television, visual patterns, mental activity, stress), exacerbating conditions (e.g., menstrual cycle, medications), frequency, duration, time of occurrence, and other characteristics need to be carefully documented. Parents often overlook, do not report, or underreport absence, complex partial, or myoclonic seizures. A history of personality change or symptoms of increased intracranial pressure can suggest an intracranial tumor. Similarly, a history of cognitive regression can suggest a degenerative or metabolic disease. Certain medications such as stimulants or antihistamines can precipitate seizures. A history of prenatal or perinatal distress or of developmental delay can suggest etiologic congenital or perinatal brain dysfunction. Details of the spells can suggest nonepileptic paroxysmal disorders that mimic seizures (Chapter 587).

Differential Diagnosis

The various types of seizures, as classified by the International League Against Epilepsy (ILAE), are enumerated in Table 586-1. Some seizures might begin with an aura. Auras are sensory experiences reported by the patient and not observed externally. These can take the form of visual (e.g., flashing lights or seeing colors or complex visual hallucinations), somatosensory (tingling), olfactory, auditory, vestibular, or experiential (e.g., déjà vu, déjà vécu feelings) sensations, depending upon the precise localization of the origin of the seizures.

Motor seizures can be tonic (sustained contraction), clonic (rhythmic contractions), myoclonic (rapid shocklike contractions, usually <50 msec in duration, that may be isolated or may repeat but usually are not rhythmic), atonic, or astatic. Astatic seizures often follow myoclonic seizures and cause a very momentary loss of tone with a sudden fall. Atonic seizures, on the other hand, are usually longer and the loss of tone often develops more slowly. Sometimes it is difficult to distinguish among tonic, myoclonic, atonic, or astatic seizures based on the history alone when the family reports only that the patient “falls”; in such cases, the seizure may be described as a drop attack. A mechanistically similar seizure can involve the tone of only the head and neck; this seizure morphology is referred to as a head drop. Tonic, clonic, myoclonic, and atonic seizures can be focal (including one limb or one side only), focal with secondary generalization, or primary generalized. Spasms (axial spasms) consist of flexion or extension of truncal and extremity musculature that is sustained for 1-2 sec, shorter than what is seen in tonic seizures, which last >2 sec. Focal motor seizures are usually clonic and/or myoclonic. These seizures sometimes persist for days, months, or even longer. This phenomenon is termed epilepsia partialis continua.

Absence seizures are generalized seizures consisting of staring, unresponsiveness, and eye flutter lasting usually for few seconds. Typical absences are associated with 3 Hz spike–and–slow wave discharges and with petit mal epilepsy, which has a good prognosis. Atypical absences are associated with 1-2 Hz spike–and–slow wave discharges, with head atony and myoclonus during the seizures and with Lennox-Gastaut syndrome, which has a poor prognosis. Seizure type together with the other nonseizure clinical manifestations helps determine the type of epilepsy syndrome with which a particular patient is afflicted (Table 586-7; Chapters 586.3 and 586.4).

Table 586-7 SELECTED EPILEPSY SYNDROMES BY AGE OF ONSET

NEONATAL PERIOD

Benign familial neonatal seizures (BFNS)

Early myoclonic encephalopathy (EME)

Ohtahara syndrome

INFANCY

Migrating partial seizures of infancy

West syndrome

Myoclonic epilepsy in infancy (MEI)

Benign infantile seizures

Dravet syndrome

Myoclonic encephalopathy in nonprogressive disorders

CHILDHOOD

Early-onset benign childhood occipital epilepsy (Panayiotopoulos type)

Epilepsy with myoclonic astatic seizures

Benign childhood epilepsy with centrotemporal spikes (BCECTS)

Late-onset childhood occipital epilepsy (Gastaut type)

Epilepsy with myoclonic absences

Lennox-Gastaut syndrome

Epileptic encephalopathy with continuous spike-and-wave during sleep (CSWS), including Landau-Kleffner syndrome

Childhood absence epilepsy (CAE)

ADOLESCENCE

Juvenile absence epilepsy (JAE)

Juvenile myoclonic epilepsy (JME)

Epilepsy with generalized tonic-clonic seizures only

Progressive myoclonus epilepsies (PME)

AGE-RELATED (AGE OF ONSET LESS SPECIFIC)

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE)

Familial temporal lobe epilepsies

Autosomal dominant partial epilepsy with auditory features

Generalized epilepsies with febrile seizures plus (GEFS+)

Familial focal epilepsy with variable foci

Reflex epilepsies

Idiopathic photosensitive occipital lobe epilepsy

Visual sensitive epilepsies

Primary reading epilepsy

Startle epilepsy

SEIZURE DISORDERS THAT ARE NOT TRADITIONALLY GIVEN THE DIAGNOSIS OF EPILEPSY

Benign neonatal seizures (BNS)

Febrile seizures (FS)

EPILEPTIC ENCEPHALOPATHIES

Early myoclonic encephalopathy (EME)

Ohtahara syndrome

Migrating partial seizures of infancy

West syndrome

Dravet syndrome

Myoclonic encephalopathy in nonprogressive disorders

Epilepsy with myoclonic astatic seizures

Lennox-Gastaut syndrome

Epileptic encephalopathy with continuous spike-and-wave during sleep (CSWS)

including Landau-Kleffner syndrome

OTHER SECONDARY GENERALIZED EPILEPSIES

Generalized epilepsy secondary to neurodegenerative disease

Progressive myoclonus epilepsies

Lists from International League Against Epilepsy: Table 1: genetic and developmental epilepsy syndromes by age of onset (website). http://www.ilae.org/Visitors/Centre/ctf/CTFtable1.cfm. Accessed October 26, 2010; and International League Against Epilepsy: Table 2. epileptic encephalopathies and other forms of secondary generalized epilepsies (website). http://www.ilae.org/Visitors/Centre/ctf/CTFtable2.cfm. Accessed October 26, 2010.

Family history of epilepsy can suggest a specific one of the known familial epilepsy syndromes. More often, different members of a family with a positive history of epilepsy have different types of seizures and of epilepsy. Head circumference can indicate the presence of microcephaly or of macrocephaly. Eye exam could show papilledema, retinal hemorrhages, chororetinitis, colobomata (associated with brain malformations), a cherry red spot, optic atrophy, macular changes (associated with genetic neurodegenerative and storage diseases) or phakomas (associated with tuberous sclerosis). Skin exam could show a trigeminal V-1 distribution capillary hemangioma (associated with Sturge-Weber syndrome), hypopigmented lesions (sometimes associated with tuberous sclerosis and detected more reliably by viewing the skin under UV light), or other neurocutaneous manifestations such as Shagreen patches and adenoma sebaceum (associated with tuberous sclerosis), or whorl-like hypopigmented areas (hypomelanosis of Ito, associated with hemimegalencephaly). Subtle asymmetries on the exam such as drift of one of the extended arms, posturing of an arm on stress gait, slowness in rapid alternating movements, small hand or thumb and thumb nail on one side, or difficulty in hopping on one leg relative to the other can signify a subtle hemiparesis associated with a lesion on the contralateral side of the brain.

Guidelines on the evaluation and treatment of a first unprovoked nonfebrile seizure include a careful history and physical examination and brain imaging by head CT or MRI. Emergency head CT in the child presenting with a first unprovoked nonfebrile seizure is often useful for acute management of the patient. Laboratory studies are recommended in specific clinical situations: Spinal tap is considered in patients with suspected meningitis or encephalitis, in children without brain swelling or papilledema, and in children in whom a history of intracranial bleeding is suspected without evidence of such on head CT. In the second of these, examination of the CSF for xanthochromia is essential. CSF tests can also confirm with the appropriate clinical setup the diagnosis of glucose transporter deficiency, cerebral folate deficiency, pyridoxine dependency, pyridoxal dependency, mitochondrial disorders, nonketotic hyperglycemia, and neurotransmitter deficiencies. Electrocardiography (ECG) to rule out long QT or other cardiac dysrhythmias and other tests directed at disorders that could mimic seizures may be needed (Chapter 587).

Patients with recurrent seizures with 2 seizures spaced apart by >24 hr warrant further work-up directed at the underlying etiology. Often, particularly in infants, a full metabolic work-up including amino acids, organic acids, biotinidase, and CSF studies is needed. In infants who do not respond immediately to antiepileptic therapy, vitamin B₆ (100 mg intravenously) is given as a therapeutic trial to rule out pyridoxine-responsive seizures, with precautions to guard against possible apnea. The trial is best done with continuous EEG monitoring, including a preadministration baseline recording period. Prior to the B₆ trial, a pipecolic acid level can be drawn, because it is often elevated in this rare syndrome. Pyridoxal phosphate given orally up to 50 mg/kg and folinic acid (up to 3 mg/kg) over several weeks can change pyridoxal dependency and cerebral folate deficiency.

Approach to the Patient and Additional Testing

The approach to the patient with epilepsy is based on the diagnostic scheme proposed by the ILAE Task Force on Classification and Terminology, presented in Table 586-8. This emphasizes the total approach to the patient, including identification, if possible, of the underlying etiology of the epilepsy and the impairments that result from it. The impairments are very often just as important as, if not more important than, the seizures themselves. There are now many epilepsy syndromes that have been associated with specific gene mutations (see Table 586-2). Different mutations of the same gene can result in different epilepsy syndromes, and mutations of different genes can cause the same epilepsy syndrome phenotype. The clinical use of gene testing in the diagnosis and management of childhood epilepsy has been limited to patients manifesting specific underlying malformational, metabolic, or degenerative disorders, patients with severe named epilepsy syndromes (such as West and Dravet syndromes and progressive myoclonic epilepsies), and, rarely, patients with familial syndromes (see Table 586-2).

Table 586-8 PROPOSED DIAGNOSTIC SCHEME FOR PEOPLE WITH EPILEPTIC SEIZURES AND WITH EPILEPSY

Epileptic seizures and epilepsy syndromes are to be described and categorized according to a system that uses standardized terminology and that is sufficiently flexible to take into account the following practical and dynamic aspects of epilepsy diagnosis:

1 Some patients cannot be given a recognized syndromic diagnosis.

2 Seizure types and syndromes change as new information is obtained.

3 Complete and detailed descriptions of ictal phenomenology are not always necessary.

4 Multiple classification schemes can, and should, be designed for specific purposes (e.g., communication and teaching; therapeutic trials; epidemiologic investigations; selection of surgical candidates; basic research; genetic characterizations).

This diagnostic scheme is divided into five parts, or axes, organized to facilitate a logical clinical approach to the development of hypotheses necessary to determine the diagnostic studies and therapeutic strategies to be undertaken in individual patients:

Axis 1: Ictal phenomenology, from the Glossary of Descriptive Ictal Terminology, can be used to describe ictal events with any degree of detail needed.

Axis 2: Seizure type, from the List of Epileptic Seizures. Localization within the brain and precipitating stimuli for reflex seizures should be specified when appropriate.

Axis 3: Syndrome, from the List of Epilepsy Syndromes, with the understanding that a syndromic diagnosis may not always be possible.

Axis 4: Etiology, from a Classification of Diseases Frequently Associated with Epileptic Seizures or Epilepsy Syndromes when possible, genetic defects, or specific pathologic substrates for symptomatic focal epilepsies.

Axis 5: Impairment, this is an optional, but often useful, additional diagnostic parameter that can be derived from an impairment classification adapted from the WHO ICIDH-2.

From International League Against Epilepsy: Table 2: proposed diagnostic scheme for people with epileptic seizures and with epilepsy (website). http://www.ilae-epilepsy.org/Visitors/Centre/ctf/table2.cfm. Accessed October 26, 2010.

Additional testing in infants and children with recurrent seizures, depending on the clinical findings, can include measurement of serum lactate, pyruvate, acyl carnitine profile, creatine, very long chain fatty acids, and guanidino-acetic acid. Blood and serum are tested for white blood cell lysosomal enzymes, serum coenzyme Q levels, and serum copper and ceruloplasmin levels (for Menkes syndrome). Serum isoelectric focusing is performed for carbohydrate deficient transferrin.

CSF glucose testing looks for glucose transporter deficiency, and CSF can be examined for cells and proteins (for parainfectious and postinfectious syndromes, and for Aicardi Goutieres syndrome which also shows cerebral calcifications). Other laboratory studies include immunoglobulin G (IgG) index, NMDA (N-methyl-D-aspartate) receptor antibodies, and measles titers.

Urine is tested for urinary sulfite indicating molybdenum cofactor deficiency and for oligosaccharides and mucopolysaccharides.

MR spectroscopy is performed for lactate and creatine peaks.

Gene testing looks for specific disorders that can manifest with seizures, including SCN1A mutations in Dravet syndrome; ARX gene for infantile spasms in boys; MECP2, CDKL5, and protocadeherin 19 for Rett syndrome and similar presentations; syntaxin binding protein for Ohtahara syndrome; and polymerase G for infantile spasms and other seizures in infants. Gene testing can also be performed for other dysmorphic or metabolic syndromes.

Other tests include neurotransmitter metabolites for neurotransmitter disorders including pyridoxal-responsive seizures, cerebral folate deficiency, adenylsuccinate lyase deficiency, and specific neurotransmitter disorders. Muscle biopsy can be performed for mitochondrial enzymes, and skin biopsy for inclusion bodies seen in neuronal ceroid lipofuschinosis and Lafora body disease is sometimes needed.

Most patients do not require a work-up anywhere near this extensive. The pace and extent of the work-up must depend critically upon the clinical nonepileptic features that accompany the seizures, the family and antecedent personal history of the patient, the medication responsiveness of the seizures, the likelihood of identifying a treatable or palliable condition, and the wishes of the family to assign a specific diagnosis to the child’s illness.

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586.3 Partial Seizures and Related Epilepsy Syndromes

Mohamad A. Mikati

Partial seizures account for approximately 40% of seizures in children and can be divided into simple partial seizures, in which consciousness is not impaired and complex partial seizures, in which consciousness is affected. Simple and complex partial seizures can each occur in isolation, one can temporally lead to the other (usually simple to complex), or each can progress into secondary generalized seizures (tonic, clonic, atonic, or most often tonic-clonic).

Simple Partial Seizures

These can take the form of sensory seizures (auras) or brief motor seizures, the specific nature of which gives clues as to the location of the seizure focus, as described earlier. Brief motor seizures are the most common and include (focal tonic, clonic or atonic seizures. Often there is a motor (Jacksonian) march from face to arm to leg, adversive head and eye movements to the contralateral side, or postictal (Todd’s) paralysis that can last minutes or hours, and sometimes longer. Unlike tics, motor seizures are not under partial voluntary control; seizures are more often stereotyped and less likely than tics to manifest different types in a given patient.

Complex Partial Seizures

Complex partial seizures usually last 1-2 min and are often preceded by an aura, such as a rising abdominal feeling, déjà vu or déjà vécu, a sense of fear, complex visual hallucinations, micropsia or macropsia (temporal lobe), generalized difficult-to-characterize sensations (frontal lobe), focal sensations (parietal lobe), or simple visual experiences (occipital lobe). Children <7 yr old are less likely than older children to report auras, but parents might observe unusual preictal behaviors that suggest the experiencing of auras. Subsequent manifestations consist of decreased responsiveness, staring, looking around seemingly purposelessly, and automatisms. Automatisms are automatic semipurposeful movements of the mouth (oral, alimentary such as chewing) or of the extremities (manual, such as manipulating the sheets; leg automatisms such as shuffling, walking). Often there is salivation, dilation of the pupils, and flushing or color change. The patient might appear to react to some of the stimulation around him or her but does not later recall the epileptic event. At times, walking and/or marked limb flailing and agitation occur, particularly in patients with frontal lobe seizures. Frontal lobe seizures often occur at night and can be very numerous and brief, but other complex partial seizures from other areas in the brain can also occur at night. There is often contralateral dystonic posturing of the arm and, in some cases, unilateral or bilateral tonic arm stiffening. Some seizures have these manifestations with minimal or no automatisms. Others consist of altered consciousness with contralateral motor, usually clonic, manifestations. After the seizure, the patient can have postictal automatisms, sleepiness, and/or other transient focal deficits such as weakness or aphasia.

Secondary Generalized Seizures

Secondary generalized seizures can start with generalized clinical phenomena (due to rapid spread of the discharge from the initial focus), or as simple or complex partial seizures with subsequent clinical generalization. There is often adversive eye and head deviation to the contralateral side followed by generalized tonic, clonic, or tonic-clonic activity. Tongue biting, urinary and stool incontinence, vomiting with risk of aspiration, and cyanosis are common. Fractures of the vertebrae or humerus are rare complications. Most such seizures last 1-2 min. Tonic focal or secondary generalized seizures often manifest adversive head deviation to the contralateral side, or fencing, hemi- or full figure-of-four arm, or Statue of Liberty postures. These postures often suggest frontal origin, particularly when consciousness is preserved during them, indicating that the seizure originated from the medial frontal supplementary motor area.

EEG in patients with partial seizures usually shows focal spikes or sharp waves in the lobe where the seizure originates. A sleep-deprived EEG with recording during sleep increases the diagnostic yield and is advisable in all patients whenever possible (Fig. 586-2). Despite that, about 15% of children with epilepsy initially have normal EEGs because the discharges are relatively infrequent or the focus is deep. If repeating the test does not detect paroxysmal findings, then 24-hour video EEG monitoring may be helpful and can allow visualization of the clinical events and the corresponding EEG tracing.

Figure 586-2 A, An EEG of partial seizures: (i) spike discharges from the left temporal lobe (arrow) in a patient with complex partial seizures; (ii) left parietal central spikes (arrow) characteristic of benign partial epilepsy with centrotemporal spikes. B, Representative EEGs of generalized seizures: (i) 3/sec spike-and-wave discharge of absence seizures with normal background activity; (ii) complex myoclonic epilepsy (Lennox-Gastaut syndrome) with interictal slow spike waves; (iii) juvenile myoclonic epilepsy showing 4-6/sec spike and waves enhanced by photic stimulation; (iv) hypsarrhythmia with an irregular high-voltage spike and wave activity.

Brain imaging is critical in patients with focal seizures. In general, MRI is preferable to CT and can show pathologies such as changes due to previous strokes or hypoxic injury, malformations, medial temporal sclerosis, arteriovenous malformations, or tumors (Fig. 586-3).

Figure 586-3 Coronal fluid-attenuated inversion-recovery (FLAIR) MRI scan of a 13 yr old with intractable seizures and mesial temporal sclerosis (MTS). The arrow points at the hippocampus with the high-intensity signal characteristic of MTS.

(From Lee JYK, Adelson PD: Neurosurgical management of pediatric epilepsy, Pediatr Clin North Am 51:441–456, 2004.)

Benign Epilepsy Syndromes with Partial Seizures

The most common such syndrome is benign childhood epilepsy with centrotemporal spikes (BECTS) which typically starts during childhood and is outgrown in adolescence. The child typically wakes up at night owing to a simple partial seizure causing buccal and throat tingling and tonic or clonic contractions of one side of the face, with drooling and inability to speak but with preserved consciousness and comprehension. Complex partial and secondary generalized seizures can also occur. EEG shows typical broad-based centrotemporal spikes that are markedly increased in frequency during drowsiness and sleep. MRI is normal. Patients respond very well to AEDs such as carbamazepine. In some patients who only have rare and mild seizures treatment might not be needed.

Benign epilepsy with occipital spikes can occur in early childhood (Panayiotopoulos type) and manifests with complex partial seizures with ictal vomiting or they appear in later childhood (Gastaut type) with complex partial seizures, visual auras, and migraine headaches. Both are typically outgrown in a few years.

In infants, several less-common benign infantile familial convulsion syndromes have been reported. For some of these, the corresponding gene mutation and its function are known (see Tables 586-2 and 586-4), but for others, the genetic underpinnings are yet to be determined. Specific syndromes include benign infantile familial convulsions with parieto-occipital foci linked to chromosomal loci 19q and 2q, benign familial infantile convulsions with associated choreoathetosis linked to chromosomal locus 16p12-q12, and benign infantile familial convulsions with hemiplegic migraine linked to chromosome 1. A number of benign infantile nonfamilial syndromes have been reported, including complex partial seizures with temporal foci, secondary generalized tonic-clonic seizures with variable foci, tonic seizures with midline foci, and partial seizures in association with mild gastroenteritis. All of these have a good prognosis and respond to treatment promptly, often necessitating only short-term (e.g., 6 mo), if any, therapy. Nocturnal autosomal dominant frontal lobe epilepsy has been linked to acetylcholine-receptor gene mutations and manifests with nocturnal seizures with dystonic posturing that respond promptly to carbamazepine. Several other less-frequent familial benign epilepsy syndromes with different localizations have also been described, some of which occur exclusively or predominantly in adults (see Table 586-2).