10, NO. 4 DECEMBER 1990

Epileptic Syndromes and Seizures in Infants

Classifying infants' seizure disorders into epileptic syndromes allows the physician to determine the appropriate diagnostic evaluation, optimize therapy, and predict outcome. Classification also assembles disorders having common etiology and pathophfsiology. However, problems arise in the attempt to apply these schemes clinically, because of overlap and poor delineation of certain types of disorders. A significant number of children, especially infants, c a n n a be classified at all. T h e inability of the infant to communicate and the immature and dynamic state of the central nervous system in the infant are primarily responsible. Both the prominent changes observed in the electroencephalogram (EEG) during normal development and the variety of EEG patterns associated with clinical seizures in infants exemplify this last observation.' Three factors have improved the approach to diagnosis and treatment of seizures in infants. The ~ first is prospective investigation of e t i o l ~ g y .Second is a classification of epilepsies that includes childhood epilepsies (Table Third is the application of video1EEGlpolygraphic recordings to newborns4 and infants"." with seizures.

LOCALIZATION-RELATED EPILEPSIES The clinical features of partial seizures in infancy have only recently been examined by videoEEG monitoring."' The majority of infants studied by video-EEG have had complex partial seizures. The partial seizures observed in infancy frequently have motor manifestations. 'The face and upper extremity are most consistently involved, with clonic and tonic features. Either adversive or contraversive head and eye deviation is noted. T h e in-

fants frequently assume a posture resembling the asymmetric tonic neck response. Automatisms consisting of facial grimacing, sucking, chewing, and eyelid fluttering often accompany the motor activity. They are more complex in the older infant and child.' Autonomic phenomena, which include apnea, tachycardia, flushing or pallor of the skin, and pupillary changes, commonly occur. Most infants have an alteration in level of consciousness. T h e seizures typically last from 1 to 5 minutes, with a tendency for the younger infant to have more prolonged ictal events.' Simple partial seizures are uncommon in infants. Usually, other seizures are also observed. A significant proportion of patients with complex partial seizures have normal routine interictal EEGs, and this may be especially true in infank7 The interictal tracings may reveal spikes, sharp waves, and spike and slow-wave complexes. Focal abnormalities of background, consisting of localized delta activity and focal attenuation of normal background activity, are common. Infants often have multifocal abnormalities on the interictal EEG. T h e ictal EEG activity is similar to that observed in the older child and adult. T h e most common ictal discharge is a burst of localized, highfrequency activity followed by higher amplitude rhythmic sharp waves or spikes in the 2 to 8 Hz range and then by rhythmic slow waves. Most studies of ictal EEG activity in infants have involved surface recordings. Invasive techniques, including depth electrodes and subdural grids, have been used in children under 2 years of age to achieve The temporal and fronmore precise locali~ation.~ tal lobes are the areas from which the seizures most commonly originate. T h e majority of localization-related epilepsies

Departments of Pediatrics and Neurology, Yale University School of' Medicine, New Haven, Connecticut Reprint requests: Dr. Novotny, Department of Pediatrics, Yale University School of Medicine, 333 Cedar St.; PO Box 3333, New Haven, CT 06510 Copyright 0 1990 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, N Y 100 16. All rights reserved.

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Edward J. Novotny, Jr., M.D.

EPILEPTIC SYNDROMES AND SEIZURES I N INFANTS-NOVOTNY Table 1. International Classification of Epilepsies and Epileptic Syndromes* 1. Localization-related (focal, local, partial) epilepsies and syndromes

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1.1 Idiopathic (with age-related onset) 1.2 Symptomatic 1.3 Cryptogenic 2. Generalized epilepsies and syndromes 2.1 Idiopathic (with age-related onset: listed in order of age) Benign neonatal convulsions Benign neonatal familial convulsions Benign myoclonic epilepsy in infancy 2.2 Cryptogenic or symptomatic (in order of age) West syndrome (infantile spasms, Blitz-Nick-Salaam Krampfe) 2.3 Symptomatic 2.3.1 Nonspecific etiology Early myoclonic encephalopathy Early infantile epileptic encephalopathy with burst suppression 2.3.2 Specific syndromes Epileptic seizures may complicate many disease states. Under this heading are included diseases in which seizures are a presenting or dominant feature 3. Epilepsies and syndromes undetermined whether focal or generalized 3.1 With both generalized and focal seizures Neonatal seizures Severe myoclonic epilepsy in infancy 3.2 Without unequivocal generalized or focal features 4. Special syndromes 4.1 Situation-related seizures (Gelegenheitsanfalle) Hemiconvulsion-hemiplegia-epilepsy Isolated seizures or isolated status epilepticus Seizures occurring only when there is an acute metabolic or toxic event caused by factors such as alcohol, drugs, eclampsia, or nonketotic hyperglycemia 'Adapted from the International League Against Epilepsy ILAE revised clas~ification.~

are symptomatic of underlying brain abnormalities. Cerebral infarcts, ulegyria, and porencephalic cysts of prenatal or perinatal origin are observed in many infants. Congenital infections from toxoplasmosis, cytomegalovirus, and Herpes simplex virus may also result in focal structural abnormalities. Acute or chronic encephalitis is also a cause of partial seizures in infancy. Children with encephalofacial angiomatosis (Sturge-Weber syndrome) usually present with partial seizures associated with progressive hemiparesis. Cortical developmental anomalies and neoplasms are also common causes of localization-related epilepsies.1° Detailed neuroimaging studies are critical in the evaluation of these children. Few investigations have delineated either the natural history or response to antiepileptic drug therapy of partial seizures in infants. In one study, 40% of infants with partial seizures developed secondarily generalized seizure^.^ Spontaneous remission rates of partial seizures in childhood have ranged from 10 to 62% in retrospective studies." Well-planned prospective studies are urgently needed.


'I'he term "idiopathic" refers to disorders in which there is no underlying cause other than a

possible genetic influence. Idiopathic epilepsies customarily signify a good long-term prognosis. Benign neonatal convulsions, benign familial neonatal convulsions, and benign myoclonic epilepsy of infancy are the three idiopathic generalized epilepsies occurring during the first 2 years of life.

Benign Neonatal Convulsions This syndrome, which has been well characterized for over a decade, is synonymous with "fifth day fit~."'*.~"t has been estimated that 2 to 7% of neonates with seizures have this type of epileptic syndrome.12 These infants have normal psychomotor development and a low risk of recurrence of seizures. Therefore the diagnosis can be confirmed only after a several-month period. T h e clinical criteria for benign neonatal convulsions were first defined in l977.I4 'The seizures typically occur between 1 and 7 days of age in infants born after 39 weeks of gestation with no evidence of' perinatal complications (Apgar score of greater than 9 at 5 minutes). T h e seizures begin at a mean age of 104 hours. Focal o r multifocal clonic seizures, but not tonic seizures, occur. 'I'heir duration is 1 to 3 minutes. They increase in frequency; often, status epilepticus develops and lasts for approximately a day. T h e infants become lethargic and hypotonic, often in association with antiepileptic treatment. T h e signs of generalized encepha-



Benign Neonatal Familial Convulsions


This is a rare disorder initially described by Rett in 1964.16Fewer than 100 cases in 14 families have since been reported." These newborns commonly have onset of their seizures during the first 2 to 3 days of life. They are usually born at term and are appropriate for gestational age in regard to weight, height, and head circumference. The most important clinical feature is the family history of similar seizures occurring in siblings or parents. Autosomal dominant inheritance has been proposed.17 An investigation for metabolic causes and structural abnormalities should be included in the evaluation of these infants. T h e seizures have been characterized as both focal and multifocal clonic. Rare tonic seizures have also been described. The duration of clinical seizures is from 1 to 5 minutes. They frequently occur throughout the first week of life, often persisting longer than those in infants with benign neonatal convulsions. The EEG findings have not been well characterized. Various background abnormalities have been noted, including the "theta pointu alternant"

pattern. Normal EEGs have been described, but severe background abnormalities have not been reported. Normal psychomotor development is usual but there is a risk of developing epilepsy in childhood or as adults. The epilepsy that later develops has not been well characterized.

Benign Myoclonic Epilepsy in Infancy Myoclonic epilepsy during childhood has been The majority of infants poorly characteri~ed.'~.'~ with this type of seizure have other, more severe forms of myoclonic epilepsy or mixed seizures. The occurrence of the benign form of myoclonic epilepsy is very rare and must be distinguished from benign nocturnal m y ~ c l o n u s . ~ ~ The clinical description of benign myoclonic ~' is often a epilepsy is based on few s t ~ d i e s .There family history of epilepsy. T h e seizures usually begin between 4 and 24 months of age. T h e children have normal psychomotor development prior to onset of the seizures. The seizures are brief, generalized myoclonic, often described as "head nods" or "spasms." They vary in intensity and often are not initially noticed by parents. They frequently occur in clusters. Each seizure lasts only a few seconds. The infant loses neck tone and the head frequently drops forward. There is extension of the upper extremities and flexion of the lower extremities. T h e eyes deviate upward. Consciousness is usually preserved. More severe seizures may result in falling. Interictal, waking EEGs are usually normal, but during sleep generalized spike or polyspike and wave discharges are seen. The ictal recordings are characterized by bursts of generalized, irregular (2 to 3 Hz) spike or polyspike and wave discharges on a normal background. The EEG features distinguish this group from infants with benign nocturnal myoclonus, who have normal EEGs during their myoclonic episodes. The seizures continue for several years, and generalized tonic-clonic seizures may occur in later childhood. T h e myoclonic seizures frequently respond to treatment with valproic acid and are usually exacerbated by sedative anticonvulsants such as phenobarbital and benzodiazepines. Most children have experienced normal psychomotor development or only minor difficulties with school performance. CRYPTOGENZC OR SYMPTOMATIC

Infantile spasms is the single epileptic disorder in this category; it is the most common epilepsy

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lopathy gradually resolve over the next several days, and eventually the neurologic examination is normal. The interictal EEG often has a pattern, referred to as "theta pointu alternant," characterized by the presence of multifocal sharp waves that are often maximum in the central regions and superimposed on a discontinuous background dominated by theta activity. Interhemispheric asynchrony, poor reaction to external stimuli, and inability to define the sleep-wake state by both EEG and polygraphic criteria are also common. This pattern has been observed in 60% of infants with this syndrome, but it is nonspecific. The presence of persistent focal or marked background abnormalities on the EEG, however, excludes the diagnosis. Ictal EEG recordings show runs of sharp waves or sharpslow-wave complexes that frequently arise from the central regions. T h e ictal activity may generalize. Ictal duration is 1 to 3 minutes. The seizures often arise from multiple areas in both hemispheres; if they persistently originate from one region, the possibility of an underlying structural lesion should be considered.15 The efficacy of antiepileptic therapy has not been extensively evaluated in newborns with this syndrome. Many antiepileptic agents have been administered with variable responses. The seizures also may resolve without drug therapy.


in infancy. In 1841, Dr. W. J. West first described this disorder in his own son.'* In 1952, Gibbs and Gibbs introduced the term "infantile spasms" to describe the seizures and identified the associated EEG pattern as "hypsarrhythmia."23T h e triad of infantile spasms, psychomotor retardation, and hypsarrhythmia is commonly referred to as West's syndrome. The incidence of the disorder is 1 per 4000 to 6000 live births; males are affected more than feT h e age of onset is males by a ratio of 1.5 or 2: between 3 and 12 months, with the peak between 4 and 6 months. T h e seizures usually persist for 3 to 8 months and the infantile spasms usually resolve spontaneously by 3 to 4 years of age. Treatment commonly results in cessation of spasms by 1 to 2 years of age. Rare patients have continued to have infantile spasms beyond age 7 years. T h e characteristics of infantile spasms have been well defined by Kellaway et a1.' T h e typical spasm consists of an abrupt contraction of a muscle group followed by a tonic phase lasting 2 to 10 seconds. Depending on the predominant muscle group involved, infantile spasms have been divided into three main types: flexor, extensor, arid mixed. T h e flexor and mixed types are the most common. The flexor type is often referred to as the "salaam" or "jackknife" spasm, and brief flexion of the head and neck is described as "head nodding." Sudden extension of the neck, arching of the back, and extension of the limbs are observed in the extensor spasm. These spasms may be associated with crying, autonomic changes, changes in facial expression, and oculomotor manifestations. A cry may occur at both the initiation and the termination of a spasm. T h e movements and alterations in tone are commonly bilateral and symmetrical. T h e spasms typically occur in clusters of a dozen seizures. T h e duration of the cluster is several seconds to a minute. A strong association with the sleep-wake cycle is noted, with most clusters occurring during drowsiness, at onset of sleep, or during arousal. Infants may appear lethargic and less responsive after the cluster of spasms, but some infants become more alert. Precipitating factors include febrile illnesses, sleep deprivation, immunizations, and visual and auditory stimuli. 'The distinctive interictal EEG pattern, observed in 66 to 90% of infants, is hypsarrhythmia, a background of predominantly high-voltage, irregular polymorphic delta waves admixed with irregular, multifocal spikes and sharp waves that vary considerably in location and frequency throughout the recording. The pattern may be observed in children who do not have infantile spasms, but these children usually have severe neurologic impairment. T h e spike- and slow-wave activity may

become better organized and synchronous, either in association with treatment or as the child grows older, a pattern referred to as "modified hypsarr h ~ t h m i a . " ?Asymmetrical ~ or unilateral hypsarrhythmia has also been described25(Fig. 1). 'This is often associated with localized structural lesions or developmental abnormalities. Prospective studies have demonstrated that hypsarrhythmia may evolve from EEGs with multifocal epileptiform activity and diffsuselyabnormal backgrounds or from records with focal slow-wave abnormalities." Hypsarrhythmia may resolve within 1 to 2 weeks after treatment. T h e EEG may remain normal but more frequently changes, with either slow spikes and waves or focal or multifocal spikes and sharp waves. T h e ictal pattern most commonly noted is the electrodecremental pattern, which consists of a high-amplitude spike or spike and slow-wave complex followed by an abrupt attenuation of the background. Often, a train of low voltage 12 to 20 Hz activity is seen at the onset. T h e duration of the attenuation is several seconds. A generalized spike or spike and wave complex associated with a myoclonic jerk is the next most common ictal pattern. The causes of infantile spasms can be divided into both symptomatic and cryptogenic categories. T h e majority of children have infantile spasms as a result of underlying pathologic processes in the brain. Twenty-five to 56% of the cases can be classified as idiopathic or cryptogenic. Most of the infants have normal development prior to the onset of the seizures. Because of both the genetic implications of many of the disorders and the rare occurrence of treatable metabolic diseases in the symptomatic category, a thorough diagnostic evaluation is indicated. Particular attention should be given to the ophthalmologic, dermatologic, and neurologic aspects of the physical examination. Neuroimaging studies are essential and magnetic resonance imaging is the procedure of choice. T h e EEG will confirm the presence of the hypsarrhythmic pattern, but this is not an absolute criterion for diagnosis. A metabolic screen for disorders of amino acid and organic acid metabolism may be obtained in cryptogenic cases, but will usually be unrevealing. Three disorders should always be considered in the differential diagnosis of West's syndrome. Tuberous sclerosis, a neurocutaneous syndrome, often presents with infantile spasms. Up to 25% of children with infantile spasms have been identified to have this autosomal dominant disorder whose gene has been recently discovered by linkage studies to be on chromosome 9.27," Many of these children continue to have seizures, are recalcitrant to therapy, and have numerous other complications

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Figure 1. A: EEG of a 4-month-old infant who had both tonic and mixed infantile spasms since the age of 3 months. The spasms occasionally had asymmetric features with increased tone on the right side of the body. The infant is awake during this portion of the recording and high-amplitude delta and multifocal sharp waves are present over the left hemisphere. The background over the right hemisphere is mildly slow for age. 8 : Later during the recording the infant falls asleep and the EEG shows evidence of epileptic activity over the right hemisphere. The background over the left hemisphere is more discontinuous. This EEG pattern is referred to as hemihypsarrhythmia.

of this disease. Second, infants with lissencephalypachygyria have characteristic dysmorphic facial features, generalized hypotonia, infantile spasms, and distinct neuroradiologic findings. The infants are described as having a "ferret-like" facies. Agyria or abnormal gyri are noted on neuroimaging (Fig 2). The disorder is usually sporadic but several familial cases have been des~ribed.~' An abnormality of chromosome 17 has been described in one variety. These children often have unusual rhythmic activity on their EEGs characterized by prolonged runs of theta and alpha frequency activity, often maximum in the frontocentral regions. Third, the infant who has hemihypsarrhythmia may have hemimegalencephaly due to a developmental malformation; the opposite hemisphere may be structurally and functionally normal. The skin lesion referred to as a linear sebaceous nevus is associated with a few of these cases. These children are especially important to identify, since surgical therapy may ultimately provide them with an improved long-term prognosis.30

Adrenocorticotrophic hormone (ACTH) continues to be the drug of choice in cryptogenic cases of infantile spasms. ACTH and corticosteroids have produced significant side effects in 37% of 162 children3' and a relapse rate of 30% is common. No difference in response to either prednisone or ACTH was observed in one inve~tigation.~' The benzodiazepine nitrazepam may be effective in some cases of infantile spasms. Valproic acid has also been effective in a small group of infants," but the increased risk of fatal hepatopathy in this age group is a concern. Treatment often controls the seizures, but the children commonly have psychomotor retardation and develop other types of epilepsy and psychiatric disorders.34Seventy to 85% of children have some degree of mental retardation. Almost 30% of children were later diagnosed as having psychiatric disorders, which included both autism and attention deficit disorder. Up to 60% of infants with West's syndrome develop some type of epilepsy following the resolution of the infantile spasms. A

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Figure 2. Magnetic resonance imaging of a 3-year-old girl who was hypotonic since birth and for whom there was a concern of blindness at a few months of age. She developed infantile spasms at 3 months of age and has continued to have poorly controlled seizures and severe psychomotor retardation. The coronal T,-weighted image demonstrates the typical features of lissencephaly, with thick cortical gray matter and a smooth surface.

mortality rate of 20% has been found in several ser i e ~ . 'The ~ prognosis is ultimately dependent on the underlying cause. SYMPTOMATIC

T h e generalized epileptic syndromes found in this category are divided into two, defined by electroclinical criteria. Each has several etiologies. Specific metabolic and neurodegenerative diseases also are associated with certain categories of generalized epilepsies.

Early Myoclonic Encephalopathy Early myoclonic encephalopathy (EME) is characterized by the occurrence during the first few weeks of life of prominent, multifocal myoclonic seizures associated with other both focal and generalized seizures and a suppression-burst pattern on the EEG.?" T h e clinical features include: (1) onset of an encephalopathy in the neonatal period characterized by poor feeding, depression of mental status, and hypotonia; (2) development of erratic, multifocal myoclonus in association with generalized

myoclonic seizures, partial clonic and tonic seizures, and generalized tonic seizures; (3) progression of the encephalopathy often leading to early death. T h e infants are noted to have fluctuations in muscle tone not associated with seizures and have periods of hypotonia alternating with episodes of hypertonia and posturing. The clinical seizures typically consist of irregular, multifocal myoclonus; simple partial seizures; generalized myoclonic seizures; and, occasionally, infantile spasms of the tonic type. T h e seizures, which often occur in series, persist during sleep. T h e infantile spasms appear late in the course of the disorder, at 3 to 4 months of age. The EEG manifestations, which often assist at ~ . ~distinctive ' arriving at a correct d i a g n ~ s i s , ~are (Fig 3). No normal background activity is observed. T h e partial seizures have the usual EEG characteristics of neonatal fits. T h e ictal activity of the myoclonic seizures may consist of generalized spike, polyspike, or spike and slow-wave discharges that are synchronous with the clinical myoclonic activity. The EEG commonly evolves to a hypsarrhythmic pattern by 3 to 5 months of age. The infants always show signs of a generalized encephalopathy with depression of mental status, abnormalities of muscle tone, and corticospinal tract findings. Acquired microcephaly has been documented in a few cases. Neuroimaging studies may be normal initially, but occasionally demonstrate progressive atrophy on serial examinations. A family history of the disorder is often elicited. This suggests that metabolic and genetic causes of this syndrome are common. T h e two most common metabolic diseases identified as causes of EME are nonketotic hyperglycinemia and D-glyceric acidemia. One infant with the organic acidopathy propionic acidemia has been described as having this syndrome. Several infants have been identified as having the familial, spongiform degeneration of gray matter referred to as poliodystrophy, or Alpers' disease. T h e seizures are poorly responsive to antiepileptic drug therapy. Treatment with either ACTH or pyridoxine has been unsuccessful. T h e prognosis of infants with EME is extremely poor. Persistent severe neurologic impairment or death is a common outcome.

Early Infantile Epileptic Encephalopathy with Burst Suppression Early infantile epileptic encephalopathy (EIEE) was first described by Ohtahara et al. in 1976.38This electroclinical syndrome is character-

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Figure 3. A: EEG of a Pday-old male infant born at 37 weeks' gestation who is comatose and having episodes of posturing, myoclonus, and hiccoughs. A suppression-burstpattern is present, which did not change throughout the 40minute recording or with stimulation. B: Later in the record an electrographic seizure arises from the right central region and spreads along the midline. No clinical signs were noted during this event. This is the characteristic EEG pattern occurring in infants with early myoclonic encephalopathy.

ized by the onset of seizures in the first 20 days of life associated with a suppression-burst pattern on EEG. The clinical characteristics of the seizures differentiate it from early myoclonic encephalopathy and the early onset sets it apart from infantile spasms. Whether this is a distinct clinical syndrome remains controversial. Of the reported cases, the majority have onset of seizures during the first week of life."8.39T h e infants have all been born at term. The seizures are brief tonic spasms accompanied by excessive salivation, irregular respirations, and other autonomic changes. The predominant seizure type is the tonic spasm, which may be generalized or localized to one extremity or side of the body. Other seizure types except rnyoclonus are observed in these newborns. Seizures occur more frequently on arousal. Shortly after onset of the seizures, the infants develop profound hypotonia, lethargy, and poor feeding. The interictal EEGs all demonstrate a suppression burst pattern. This pattern is easily distinguished from the normal trace alternans pattern of

quiet sleep of the term neonate by the marked suppression of EEG activity for a few seconds followed by bursts of irregular delta admixed with excessive sharp transients and by its poor reactivity to external stimuli. Ictal recordings have not been well characterized. The infants show evidence of a severe encephalopathy. The seizures are recalcitrant to antiepileptic therapy, including ACTH, corticosteroids, or the ketogenic diet. Neuroradiologic studies often reveal generalized cerebral atrophy or hemiatrophy. Metabolic studies have been normal. One infant was discovered to have nonketotic hyperglycinemia and other infants had evidence of severe developmental malformations of the brain. The infants with this age-dependent encephalopathy have a poor long-term outcome. There is significant overlap between this syndrome and early myoclonic encephalopathy, the major difference being the absence of myoclonic seizures in EIEE. Further investigations of infants with these syndromes are required to determine whether they represent distinct disorders.

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Certain metabolic and degenerative diseases may have generalized epilepsies as a major clinical characteristic. Nonketotic hyperglycinemia and Dglyceric acidemia present with a severe myoclonic epilepsy in early infancy. Prior to the advent of neonatal screening programs and early dietary treatment, u p to one third of infants with phenylketonuria developed hypsarrhythmia. Today, this is an extremely rare cause of infantile spasms except for certain variants referred to as "malignant hyperphenylalaninemia~.~ T h e early infantile variant of neuronal ceroidlipofuscinosis is a neurodegenerative disease in which infants between 6 and 18 months of age present with multifocal and generalized myoclonus.41 They have a progressive generalized encephalopathy. A characteristic sequence of changes of the EEG pattern is noted with gradual attenuation of the background activity referred to as the "vanishing EEG."41'rhis disorder is readily diagnosed by obtaining either skin o r lymphocytes for both light and electron microscopic examination. T h e hexosaminidase deficiencies, Tay-Sachs and Sandhoff diseases, present with stimulus-induced myoclonus, which is present during the first few weeks of life. Eventually, these infants develop partial seizures and spontaneous multifocal myoclonus. T h e megalencephaly, ophthalmologic findings, and family history may all provide evidence for these diagnoses. Many other metabolic diseases, including pyridoxine dependency, multiple carboxylase deficiency, subacute necrotizing encephalomyopathy (Leigh's syndrome), and the urea cycle disorders, often present in infancy with seizures and other distinctive clinical features. However, in these infants the epileptic manifestations have no characteristic features that suggest a specific disease.


Seizures have long been known to be an important sign of neurologic disease in the newborn. T h e incidence of these phenomena has ranged from 0.5% to 20%, depending on the clinical dia g n ~ s i s Over . ~ ~ the last decade, intensive bedside video/EEG/polygraphic monitoring in neonates with suspected seizures has established two important points4 First, a significant number of clinical phenomena thought to represent seizures have no ac-

companying EEG changes on surface recordings. Second, many seizures diagnosed by EEG criteria have no associated clinical features. These new findings have resulted in recent changes in the clas~ification,~~ diagnosis,44 and therapy45 of seizures in the newborn. These studies have also illustrated particular clinical methods that can be used to distinguish seizures from other abnormal

behavior^.^ The behavioral phenomena that most consistently correlate with EEG seizure discharges are partial motor and myoclonic seizures. Clonic seizures involving one limb, one side of the body, or axial structures such as the tongue and face reliably have accompanying synchronous EEG discharges. These clonic movements are rhythmic and occur at a slow rate of 1 to 4 times per second. A feature more commonly observed in neonates is multifocal or migratory clonic activity. T h e EEG discharges typically consist of runs of rhythmic sharp-slowwave complexes that spread ipsilaterally over the hemisphere from which they originate (Fig 4). Focal tonic seizures, in which the infant shows sustained deviation of the eyes, with or without head deviation, and asymmetric posturing of the limbs or trunk are also frequently associated with electrographic seizures, consisting of rhythmic, high-frequency sharp waves and spikes arising from the occipital or frontotemporal regions. Generalized myoclonic seizures also have associated electrocortical discharges. T h e myoclonus occurs sporadically or in a few slow series of jerks. T h e EEG typically shows high amplitude spike-wave, sharpwave, and slow-wave transients synchronized with the motor activity. Behavioral phenomena that have a variable association with EEG seizure discharges are the subtle neonatal seizures described as generalized tonic and irregular myoclonic. Subtle seizures may be further divided by their clinical features into those involving the mouth and tongue, the eyes, and more complex movements such as pedaling, swimming, and stepping. Premature neonates often have simple subtle seizures with eye, mouth, and tongue mo~ements.~"'The electrographic seizures in premature infants are very distinctive: they have a characteristic progression, spreading throughout multiple cortical regions with minimal accompanying clinical signs (Fig 5). In the term infant, who has more complex motor automatisms, there is often no associated EEG discharge. Myoclonic activity, which is irregular, multifocal, and often stimulus-induced, is typically not associated with any changes in electrocortical activity. These infants usually have markedly abnormal EEGs for gestational age with suppressed and poorly differen-

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Specific Syndromes



Figure 4. Electrographic seizure in a 9-day-old infant, of 27 weeks' estimated gestational age, with severe perinatal asphyxia. A: Onset of the seizure arising from the left temporal region is indicated by the large vertical arrow. An interictal spike is also shown by the horizontal arrow. These spikes were recurring erratically every 3 to 7 seconds immediately prior to the ictus. B: No clinical signs were noted during this portion of the seizure (32 to 42 seconds into the ictus), while repetitive 2 to 3 Hz sharp slow waves occurred in the left frontotemporal region. C: In this period (76 to 86 seconds) rhythmic 1 Hz clonic activity of the right side of the face was noted. D: Toward the end of the ictus (1 14 to 124 seconds) the sharp-slow-wave complexes recur every 4 seconds. They eventually stop entirely at 150 seconds.


tiated background. Episodes described as generalized tonic seizures are rarely the result of an epileptic discharge.47 These episodes most probably represent decerebrate and decorticate posturing from acute intracranial pathologic processes. Clinical attributes can differentiate clonic seizures from tremors and clonus. Clonic seizures have slower, more rhythmic motor activity that cannot be restrained. Tremor, clonus, and other nonepileptic motor automatisms are typically induced by various tactile, noxious, and auditory stimuli. Nonepileptic phenomena also demonstrate properties of spatial and temporal summation by increasing in intensity with increased intensity or frequency of the stimulus. 'These latter behaviors are abnormal and usually indicate the existence of an encephalopathy, but they do not represent behaviors that warrant treatment with antiepileptic therapy. Other useful clinical characteristics are the typical change in heart rate, respiratory pattern, pupil size, and blood pressure with true epileptic events.

Perinatal asphyxia, central nervous system infections, intracranial hemorrhages, and cerebral infarcts are the most common disorders responsible for neonatal seizures. Developmental anomalies, acute metabolic disorders, and rare inborn errors of metabolism are less common causes. Certain types of seizures are observed in infants with specific disorders. Persistent partial motor seizures are typically observed in infants with strokes.I5 Clonic seizures are commonly seen in infants with hypocalcemia. Subtle and tonic seizures are more commonly observed in infants with hypoxic-ischemic encephalopathy. Studies have shown that prognosis is closely linked to etiology. T h e presence of structural lesions on neuroimaging studies also has a significant correlation with long-term outcome. The EEG has been a valuable tool in determining prognosis in the premature and full-term neonate with seiz u r e ~ . ' .If~ specific criteria are used to grade the severity of the background abnormality in the EEG, the degree of abnormality predicts long-term

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TIME (Sec)



Figure 5. Subclinical electrographic seizure in a 2-day-old, 29-week estimated gestational age neonate with severe perinatal asphyxia and bilateral intraventricular hemorrhages. The seizure begins with low-amplitude rhythmic alpha activity in the left temporal region (arrow). This builds up in amplitude and spreads to the left central region 25 seconds into the ictal event. Fifty seconds into the seizure, irregular, sharp-slow waves appear over the entire left hemisphere, are of higher amplitude anteriorly, and spread to the right frontal region. Rhythmic alpha activity arises from the right central region 80 seconds into the seizure, when the infant opens the left eye. The sharp-slow-wave activity is maximum over the left temporal region with spread over the entire cortex 125 seconds into the seizure. The seizure lasted 215 seconds.

outcome better than the clinical e~amination.'.'~often receive treatment based on clinical criteria Diagnosis of the type of seizure clinically and alone. V01pe~~ recommends that treatment with anelectrographically also permits prognostication. In- tiepileptic agents be withheld in infants with genfants with tonic or subtle seizures often have dif- eralized tonic and subtle seizures, especially subtle fuse, severe encephalopathies and a poorer out- seizures in the full-term infant. come. A unique ictal EEG pattern characterized by We still do not know what criteria should be bursts of rhythmic 8 to 12 Hz activity is often seen used to determine the initiation or adequacy of in newborns with severe encephalopathies (Fig 5 ) . therapy. Several studies have shown that the maThese infants often have a poor prognosis. Further jority of electrical seizures in the newborn are of investigations combining both EEG and neuroim- short duration and have no accompanying clinical aging may refine the ability to determine prog- signs. They persist even after treatment.4.4"50Should nosis. clinical or electrical criteria be used to judge therT h e most important aspect of treatment is apeutic efficacy? Both clinical and electrical seiearly and accurate diagnosis. Recent intensive zures in the human neonate typically last less than monitoring studies have identified certain types of 3 minutes. Further information is needed to deterseizures that have a high association with epileptic mine whether brief, subclinical electrical seizures discharges. Particular clinical features can there- are deleterious to the immature nervous system. fore be used to determine whether an event is an Until this has been obtained, therapy should be epileptic seizure or not. Patients with clonic, partial guided by the response of clinical seizures that are tonic, and generalized myoclonic seizures can determined to be epileptic.

The duration of therapy should be guided by the risk of recurrence of seizures and the possible toxicity induced by treatment. Infants with cerebral malformations and significant structural lesions are at high risk of having later seizures, whereas infants with hypoxic-ischemic encephalopathy or metabolic causes have a much lower recurrence risk. Thus, if the neurologic examination and interictal EEG are normal, the probability that the infant will have later seizures is very small. The recent concern about the risks of drug toxicity to the developing nervous system has also dictated that the duration of therapy be kept to a minimum.51 Antiepileptic therapy is discontinued in most infants prior to discharge from neonatal intensive care and rarely is treatment continued for greater than 4 to 8 weeks following di~charge.~" Phenobarbital has been the drug of choice in treatment of neonatal seizures. This drug is given as a single loading dose of 15 to 20 mglkg and increased in 5 to 10 mglkg increments until serum concentrations of 40 mglliter are achieved.45Phenytoin is often a second-line drug. It is given at a dosage of 30 to 35 mglkg at a rate no greater than 1 mglkglmin. Both drugs have long half-lives (up to 100 hours) and similar maintenance dosages of 2 to 5 mglkglday. Valproic acid, primidone, and the benzodiazepines diazepam and lorazepam have all been used in newborns. In general, it is recommended that agents that are most effective in controlling the seizures be used and the duration of therapy be minimized. Further consideration should be given to short-acting agents such as benzodiazepines. Until further information regarding the long- and short-term toxicity of these agents is obtained, phenobarbital should remain the drug of choice and be used for a short duration.


may not be associated with fever. Between 18 and 2 1 months of age, the children develop generalized myoclonic seizures, which frequently occur in clusters several times a day. Often the myoclonic seizures increase in intensity immediately prior to a generalized clonic or tonic-clonic fit. T h e myoclonus may cause the child to fall or may appear only when the child is performing a motor task. Partial seizures with complex partial characteristics often develop, with autonomic changes, complex automatisms, and altered consciousness. Partial seizures with secondary generalization occur. During the first year of life, the interictal EEG is characteristically normal. A generalized spikewave or polyspike-wave pattern is then noted during the second year. This pattern may eventually show predominant involvement of one hemisphere. A photoparoxysmal response occurs in 70%. The ictal EEG recordings of the partial clonic and complex partial seizures are typical of partial seizures in older children with runs of localized sharp waves and spikes at 6 to 12 Hz. T h e ictal activity may spread. The generalized myoclonic ictal activity consists of bursts of spikes or polyspike and slow-wave discharges. The children often have signs of cerebellar and corticospinal tract dysfunction on examination. Intellectual impairment is common and variable. The seizures are resistant to drug therapy and typically continue until adolescence. Whether this disorder is a primary generalized epilepsy that is the result of a specific genetic defect or defects with superimposed focal pathology or a secondary generalized epilepsy is an unanswered question. This syndrome does appear to be a specific myoclonic epilepsy that is associated with a poor prognosis.



This epileptic - - syndrome has been recently described. It accounts' for 30% of infants with h y o clonic epilepsy and 7% of infants with epilepsy.52 The syndrome is characterized by the occurrence of a clonic, usually generalized seizure during the first year of life that is often associated with a fever. Generalized myoclonic seizures then appear during the second year and many children develop partial seizures at this time. They typically have some degree of psychomotor retardation and their seizures are poorly responsive to antiepileptic therapy. A family history of epilepsy is found in a fourth of these children. The age of onset is between 2 and 10 months of age with the average at 5 to 6 months. Six to 8 weeks following the first seizure other clonic seizures develop, which may or


Gastaut described this syndrome in 1960. A child of 5 to 24 months of age, often febrile, presents with unilateral status epilepticus lasting several hours.53 Following the episode, the child is hemiplegic. The motor deficit usually persists. Three fourths of these children develop localization-related epilepsy within 12 to 36 months of the initial episode of hemiconvulsive status epilepticus. The majority develop complex partial seizures, and a third develop either simple partial or secondarily generalized seizures. The EEG during the acute hemiconvulsion is

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Isolated Seizures or Isolated Status Epilepticus T h e incidence of isolated seizures or status epilepticus is greatest during the first 2 years of life, and infants who will later have epilepsy often present with status epilepticu~.~." Most studies on the morbidity and mortality of status epilepticus in children were performed prior to the advent of current intensive care methods and reported mortality rates of 6 to 11%. These series also reported a high incidence of neurologic sequelae. Recent studies have demonstrated that the mortality and morbidity are now lower and that the outcome is highly dependent on the etiology of the seizure~.~-~~ The majority of infants have generalized seizures, but both simple partial and complex partial status epilepticus have been observed in infants. During the first year of life, acute disorders such as meningitis, encephalitis, and head trauma account for most cases. In the second year, febrile convulsions are most common. 'The cause of the status epilepticus is the most important determinant of outcome. Infants with acutely evolving conditions causing symptomatic seizures had the poorest long-term outcome. Twenty to 40% of infants with status epilepticus had no known etiology or had a high fever at the onset of the seizure. This group of children had a low incidence of neurologic sequelae, less than 2% in one study.' Less than one third of the children with idiopathic status epilepticus had a recurrence of seizures when followed prospectively. Status epilepticus continues to be a medical emergency. Whether prolonged seizures alone result in neurologic sequelae and epilepsy is unknown. Further prospective studies on infants and children with status epilepticus and isolated seizures are needed.

Seizures Occurring Only When There Is an Acute Metabolic or Toxic Event Acute metabolic and toxic disorders are a more common cause of seizures in infants than in adults because of their small size, increased exposure to toxic substances both in utero and postnatally, and the higher incidence of onset of inherited metabolic diseases during infancy. T h e most common metabolic causes are disorders of sodium and glucose balance, with or without associated dehydration. Hypoglycemia is most common in the neonate, with an incidence between 8 and 21%.5%urrent neonatal care standards result in early recognition and treatment of this disorder. T h e infant that is small for gestational age is at greatest risk; over 50% of these infants with symptonlatic hypoglycemia have seizures. If hypoglycemia is diagnosed and treated within 36 hours, few infants experience seizures." These newborns also have a lower incidence of neurologic sequelae. Beyond the neonatal period, hypoglycemia is relatively rare but several metabolic diseases and endocrinopathies may result in hypoglycemia in this age group. The metabolic diseases include glycogen storage diseases and galactosemia. Hypothyroidism, congenital adrenal hypoplasia, and growth hormone deficiency are the most common endocrine disorders. Early diagnosis and treatment of hypoglycemia is critical in order to minimize neurologic sequelae. Both hyponatremia and hypernatremia are common in infancy. Dehydration and water intoxication5%re common causes. T h e history and physical examination provide important information regarding the etiology of the sodium imbalance. Correction of the underlying metabolic disorder is the most critical aspect of the treatment of seizures in these infants. Maternal drug abuse accounts for a small percentage of seizures in the neonatal period. Maternal cocaine abuse has received recent attention as a cause of seizures in the newborn, but many of these infants also have cerebral i n f a r c t i ~ n s . ~ W n l y 1 to 2% of newborns with heroin withdrawal and 8% with methadone withdrawal experience seizures. Infants with barbiturate withdrawal have a higher incidence of seizures, but this is a rare withdrawal syndrome in infancy. Young children have a higher risk of accidental ingestion of many drugs and agents that may result in seizures. Both prescription and over-the-counter drugs have been reported to cause an encephalopathy with seizures. Aspirin, acetaminophen, ibuprofen, and theophylline are widely used drugs that are associated 377 with seizures.

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characterized by the appearance of rhythmic 1 to 2 Hz, sharp slow-wave complexes that arise from the posterior head region, spread ipsilaterally throughout the hemisphere, and eventually become generalized. Following the acute event, persistent focal slowing progressing to a localized attenuation of background develops. Many children have evidence of cortical hemiatrophy on neuroradiologic studies. T h e etiology of hemiconvulsion-hemiplegia-epilepsy (HHE) syndrome is unknown. Meningitis, head trauma, or a focal encephalitis may be identified. The incidence of HHE has decreased over the last two decades. Many children who develop this syndrome have a strong family history of febrile convulsions, making a genetic predisposition likely.

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Epileptic syndromes and seizures in infants.

SEMINARS IN NEUROLOGY-VOLUME 10, NO. 4 DECEMBER 1990 Epileptic Syndromes and Seizures in Infants Classifying infants' seizure disorders into epilep...
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