Topical Review Article

The

Age-Dependent Epileptic Encephalopathies Jane

F.

Donat, MD

Abstract The most severe epilepsies that affect neonates, infants, and children include Ohtahara, West, and Lennox-Gastaut syndromes. These three syndromes display considerable similarities and transitional features in their clinical symptoms, seizure phenomena, and electroencephalographic abnormalities. This review examines the similarities and differences between these three syndromes and the other severe epilepsies of infancy and childhood, and discusses the hypothesis that the three disorders form a continuum of epileptic encephalopathies that have a predictable age-related evolution. J Child Neurol ( 1992;7:7-21).

and Lennox-Gastaut syndromes are among the most severe epileptic conditions of infancy and childhood. Each of these epilepsies presents at a different age and each exhibits a stereotyped association of seizures and electroencephalographic (EEG) findings that are essentially pathognomonic for each syndrome. These differences distinguish the syndromes from one another as well as from other severe epilepsies. However, these three syndromes also have major characteristics in common: diffuse cerebral dysfunction, intractable seizures, and poor prognosis, with developmental arrest or mental retardation. A detailed comparison of the seizures and EEG findings, including characteristics that have been considered unique to each syndrome, underscores striking similarities and overlap between the syndromes (Table

Ohtahara, West,

1). This review will cover each of the age-related syndromes, with emphasis on their epileptic and electroencephalographic features. It will compare and contrast each syndrome with the others and discuss relationships with other infant and childhood epilepsies. Brief general summaries of clinical course and prognosis will be included, but details of diagReceived Jan 10, 1991. Received revised June 12, cepted for publication July 18, 1991.

1991. Ac-

From the Department of Pediatrics, Children’s Hospital, Ohio State University School of Medicine, Columbus, OH. Presented in part at the annual meeting of the American Epilepsy Society, November 14, 1990. Address correspondence to Dr J.F. Donat, Children’s Hospital, 700 Children’s Drive, Columbus, OH 43205.

nosis and treatment will not be discussed. The latter aspects are addressed in more detail in articles in the reference list.

Concept of the Age-Dependent Epileptic Encephalopathies The idea that these three syndromes represent successive stages in maturation of an epileptic process was proposed by Ohtahara et al.2,3 According to this concept, a nonspecific epileptogenic mechanism interacts with

brain responses that differ

according

to

the level of brain development at the time the epileptic process is active. 2,4 These interactions result in symptoms and signs that are characteristic of or unique to the particular age of the affected patient. As an affected patient ages, the age-related symptoms presented earlier abate, and the patient may then go on to show symptoms and signs that are characteristic of the next age or degree of brain maturation. If the epileptogenic process abates or attenuates, the later stages may not be present or may be modified; if the epileptogenic process first becomes active late, only the later stages will be seen.

Ohtahara

Syndrome

-

Early Infantile Epileptic Encephalopathy Ohtahara syndrome was called &dquo;early infantile epileptic encephalopathy&dquo; by Ohtahara et al, who first described the rare neonatal form of severe epileptic 7

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TABLE 1

Comparison of Ohtahara, West,

encephalopathy.’,6

and Lennox-Gastaut

brief and a developmental delay, Prior to Ohtahaon EEG. burst-suppression pattern ra’s description, similar cases were included in the literature as neonatal West syndrome or were not distinguished from more usual neonatal seizures. Ohtahara’s 14 patients developed seizures within the first 3 months of life, usually within the first 10 days. The seizures were repetitive &dquo;tonic spasms&dquo; (brief tonic seizures), which may be indistinguishable from infantile spasms. Ohtahara recorded the duration of each episode to be less than 10 seconds. The seizures were isolated or occurred in series, with each spasm separated by 9 to 15 seconds, consisting of 10 to 40 seizures in a series. A minority of Ohtahara’s patients also had partial seizures. The 11 patients with Ohtahara syndrome reported by Clarke et ah also had myoclonic seizures. The interictal EEG in Ohtahara syndrome shows an invariant burst-suppression pattern without wake or sleep cycling. The bursts last 1 to 5 seconds and consist of high-amplitude (up to 350 VLV) mixed frequencies with prominent multifocal spikes and sharp waves. The periods of suppression last 3 to 10 seconds. Ohtahara et al said that the tonic seizures were associated with a desynchronization of the EEG, 6,8 which appears to be9 similar to the ictal EEG findings in West Miscellaneous causes, most commonly brain malformations, appear to underlie this condition. Prognosis is poor. Four of the patients reported by Ohtahara et al died in infancy.6 All survivors were severely handicapped. Treatment has been largely unsuccessful.’ Ohtahara reported that the response tonic seizures,

Patients have

severe

syndrome.9

numerous

Syndromes

of the seizures to

(ACTH)

was

2

adrenocorticotropic

hormone

poor.2

Early Myoclonic Encephalopathy

Dalla Bernardina et af1° and Aicardill described &dquo;early myoclonic encephalopathy,&dquo; a disorder with many similarities to Ohtahara syndrome, in 25 patients. Patients usually present within the first 10 days, always within 3 months. The seizure disorder is characterized by fragmentary or erratic myoclonic jerks and massive myoclonus as the predominant seizures, in contrast to the primarily tonic seizures of Ohtahara syndrome. Partial seizures are frequent. &dquo;Tonic spasms&dquo; occurred up to 5 months later in the patients reported by Dalla Bernardina et al.l° The EEG pattern in these patients consists of a burstsuppression pattern similar to that found in Ohtahara syndrome. The massive myoclonic seizures coincide with the bursts&dquo;, 12 (Figure 1). Infants with early myoclonic encephalopathy, like those with Ohtahara syndrome, are severely neurologically impaired, and many died in early infancy. The entity tends to be familial, with deterioration, and many cases may be caused by so-far undefined inborn errors of metabolism. Identified inborn errors include propionic acidemia, nonketotic hyperglycinemia, and D-glyceric acidemia. Heterogeneous causes were found in a more recent reports. 13 Ohtahara felt that the encephalopathy he described was a separate entity from early myoclonic encephalopathy. Whether these are truly two different disorders is uncertain,11 and may await publication of larger series that include video-EEG

8

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essary to exclude infants with acute asphyxia14,15 and include only infants who have persistence of the

disorder. 18

Relationship Between Syndrome

Ohtahara

Syndrome

and West Of the 14

FIGURE 1

Burst-suppression in a 1-month-old (36 weeks gestational age) boy with neonatal epileptic encephalopathy. This pattern is considered to be interictal in Ohtahara syndrome but ictal in early myoclonic encephalopathy, in which generalized body jerks coincide with the bursts (arrow). identification of the seizures. Patients reported by Clarke et al7 and Lombroso14,15 are illustrative of the overlap that appears to exist between these two syndromes. Clarke et al considered their 11 patients to have Ohtahara syndrome, but unlike Ohtahara’s patients, those treated by Clarke et al had erratic myoclonus, and in one case there was an etiology (nonketotic hyperglycinemia) that is characteristic of early myoclonic encephalopathy. Lombroso reported 29 neonates who he considered to have early myoclonic encephalopathy. He described erratic myoclonus with and without bursts on EEG (like early myoclonic encephalopathy) and flexor spasms (like Ohtahara syndrome) that occurred with bursts on EEG (unlike Ohtahara syndrome, in which flexor spasms occur with desynchronization on EEG). Etiologies included malformations, which are more characteristic of Ohtahara syndrome, and inborn er-

which are more characteristic of early myoclonic encephalopathy. It may also be difficult to differentiate Ohtahara syndrome and early myoclonic encephalopathy from transient neonatal disorders that result in neonatal seizures and on EEG, such as In his series of patients with perinatal asphyxia.16,1

rors,

burst-suppression

early myoclonic encephalopathy, Lombroso14,15 included asphyxiated infants whose seizures abated within 2 weeks. To reliably discriminate between the epilepsies and the transient disorders, it may be nec-

cases of Ohtahara syndrome reported by Ohtahara et a1,6 ten showed an evolution from Ohtahara syndrome to West syndrome. Eight of the 10 surviving patients reported by Clarke et af also developed West syndrome after the neonatal period. In their nine early myoclonic encephalopathy patients, Dalla Bernardina et all° differentiated the &dquo;tonic&dquo; spasms that developed between 2 weeks and 5 months from infantile spasms. Aicardi,&dquo; however, considered these later seizures in early myoclonic encephalopathy patients to be tonic forms of infantile spasms and said that hypsarrhythmia developed on the EEG at this time. Patients with early myoclonic described by Otani et al 12 and Lombrosol also later developed infantile spasms and hypsarrhythmia. A change in the EEG pattern to hypsarrhythmia

encephalopathy

occurred between 3 and 10 months in the patients described by Ohtahara et al.19 Ohtahara noted that the burst-suppression pattern disappeared first from the wake EEG, which then showed It is notable that at this point the EEG would be similar to the burst-suppression variant of hypsarrhythmia, which shows the same wake-sleep relationship and is most commonly found in younger West syndrome patients21,22 (Figure 2). Although both Ohtahara syndrome and early myoclonic encephalopathy may be followed by West syndrome later, Lombrosol4 considered Ohtahara syndrome to be an early variant of West syndrome, and early myoclonic encephalopathy to be a distinct epileptic syndrome. When the onset of West syndrome occurs at less than 3 months of age, the disorder tends to be atypical: there are more focal seizures and focal EEG abnormalities, the hypsarrhythmia pattern is less typical or burst-suppression precedes hypsarrhythmia.4,23 There is a higher proportion of symptomatic disorders and worse prognosis.4,24 Early-onset West syndrome may be a transitional form between Ohtahara syndrome and typical West syndrome. The development of West syndrome following a neonatal burst-suppression EEG pattern is not unique to Ohtahara syndrome and early myoclonic encephalopathy. The more common transient neo-

hypsarrhythmia. 20

9

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spasms,32 and have

seizures with infantile described in other conditions.

not been

West West

Syndrome syndrome refers to the clinical triad of infantile spasms, developmental delay or mental retardation, and hypsarrhythmia on the EEG. Peak age of onset is between 3 and 7 months, usually before 1 year of age.29 In one study, West syndrome had a preva-

FIGURE 2

Hypsarrhythmia variant resembling burst-suppression in a girl with West syndrome (eyes closed, asleep). 3-month-old

natal with

associated and acute in West synseizures 16-18,25-27 may also result drome. Focal or multifocal epileptiform abnormalities may be found on EEGs performed between the neonatal period and the development of West syn-

encephalopathies, usually asphyxia, burst-suppression patterns on EEG

drome . 27 A comparison of the seizures of Ohtahara syndrome with those of West syndrome is hampered by the small number of patients described with Ohtahara syndrome and the lack of intensive videoEEG evaluation of the sort that has been performed in West The repeated &dquo;tonic&dquo; spasms described in Ohtahara syndrome and their ictal EEG

syndrome.9

appear to be similar to infantile spasms’ and to the less common &dquo;juvenile&dquo; spasms of Lennox-Gastaut syndrome. 28 Partial seizures are a prominent feature of early myoclonic encephalopathy and may occur in Ohtahara syndrome. While West syndrome is traditionally identified by its singular seizure-type infantile spasms, partial seizures have also been identified in Partial seizures may overa number of of the burst-suppression bursts lap or begin with in who have EEG early myoclonic encephapatients lopathylo-12,14 and in other neonates who have burst-suppression EEGs.31 These combinations are reminiscent of simultaneous occurrences of partial

changes

patients . 29,30

lence rate of 0.19 per 1000 children under 10 years of age.33 Next to Ohtahara syndrome, West syndrome has the highest association with mental retardation (80% to 90%) of any epileptic syndrome. Most patients have underlying brain diseases (&dquo;symptomatic&dquo; West syndrome). Idiopathic West syndrome or West syndrome due to unknown (&dquo;cryptogenic&dquo;) causes is associated with a lower incidence (50%) of mental retardation.34-3g Almost any diffuse or multifocal brain disease that is symptomatic at or before the time of life when West syndrome occurs has been associated with West syndrome.24,29,36 Most common are neonatal asphyxia, brain malformations, and tuberous sclerosis. Occasionally, West syndrome may occur in patients who have focal cerebral disease.39 Hypsarrhythmia is the unique EEG pattern seen in these patients. It consists of high-amplitude (> 200 VLV) polymorphic delta activity, little theta activity, and abundant multifocal spikes, sharp waves, and discharges in every brain reHypsarrhythmia rarely occurs without infantile spasms, and most patients who have infantile spasms have hypsarrhythmia on EEG.29,41 Hypsarrhythmia may not be present in the waking state, appearing only in non-rapid eye movement (REM) sleep. Normal features of slow-wave sleep (V waves and sleep spindles) frequently are not recognizable. 42,43 Brief periods of voltage attenuation are particularly common in non-REM sleep. A marked exaggeration of this pattern is found in the &dquo;burstsuppression&dquo; variant of hypsarrhythmia,22 which, as mentioned above, is particularly common in younger patients. Hypsarrhythmia disappears in REM sleep.42 Infantile spasms consist of a sudden muscular contraction that is usually generalized. This may be

gion.4spike-and-wave

very quick (myoclonic) or more prolonged, lasting up to 10 seconds (tonic), or consist of both myoclonic and tonic components. 9,44 Infantile spasms have a remarkable tendency to occur in a series or cluster. The interval between spasms ranges from several seconds to half a minute. Several may occur

10

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or there may be dozens. They are espeactivated cially by awakening. The ictal EEG associated with infantile spasms consists of one of several patterns, more than one of A generalized slow-wave which may occur transient followed by a generalized decrement is the most common. Other patterns are a generalized sharp- and slow-wave transient with or without an aftercoming decrement, a generalized decrement alone, or a generalized slow wave alone. Low-voltage &dquo;fast&dquo; activity may be superimposed on the decrement. Other seizures besides infantile spasms have been recorded in West syndrome patients. These include partial, absence, and myoclonic seizures.24,30,32,45 Absence seizures in West syndrome have more commonly been referred to as &dquo;arrest&dquo; phenomena or &dquo;akinesia.&dquo; An absence seizure may follow an infantile spasm or may occur alone. This type of seizure was recorded in 1 % of infantile spasms in patients of Kellaway et a1.9 The absence seizures are associated with prolonged decrements on EEG. West syndrome patients may occasionally also have myoclonic seizures that appear to be separate from the infantile

in

a

row,

together.9

spasms. ACTH is the most effective treatment for infantile spasms. 34,36,46 Other medications that may be effective include valproic acid, nitrazepam, and clonazepam. At follow-up approximately 25% to 50% of patients stop having seizures.~·46-4s

Relationship Between West and Lennox-Gastaut Syndromes Approximately 30% of West syndrome patients develop Lennox-Gastaut Forty-one of Weinman’s49 140 West syndrome patients developed Lennox-Gastaut syndrome; 11 patients showed no seizure-free interval, but the rest had 5-month to almost 6-year intervals between syndromes. Of 83 cases of West syndrome followed by Ohtahara et al 28 developed Lennox-Gastaut for at least 3 between 1 and 2 years of age; syndrome, usually Lennox-Gastaut syndrome accounted for over 87% of later seizure disorders in Ohtahara’s West syndrome patients. Nine percent to 36% of LennoxGastaut syndrome patients have past histories of Patients who have West synWest drome that develops into Lennox-Gastaut syndrome

syndrome. 24,37,49

years ’38

syndrome. 4,49-52

usually have symptomatic causes and have a particularly poor prognosis.2-36,50 Although it has not been documented by videoEEG, it has been observed that with time, infantile

spasms become more prolonged (more tonic) and tend to occur singly rather than in series.’ Thus, they gradually resemble the tonic seizures of Lennox-Gastaut syndrome. In Ohtahara’s patients, infantile spasms in series disappeared between 6 months and 1 year, and single spasms appeared during this same time period; he suggested that the development of single seizures signified that the patient was going to develop Lennox-Gastaut syndrome. Aicardi4 noted that it may be difficult to differentiate infantile spasms from the tonic seizures of Lennox-Gastaut syndrome. He and Jeavons53 suggested that some cases of so-called West syndrome with onset after 1 year of age may be cases of earlyonset Lennox-Gastaut syndrome. Egli et a154 considered tonic seizures to be a more mature form of infantile spasms. Similarities exist between seizures of West syndrome and Lennox-Gastaut syndrome. In occasional cases, there is an overlap between EEG changes during infantile spasms and the tonic seizures of Lennox-Gastaut syndrome. A small percentage of infantile spasms in West syndrome are not associated with the more common ictal EEG events discussed in the last section, but with bursts of &dquo;fast&dquo; activity alone9 (Figure 3A) that look like brief versions of Lennox-Gastaut syndrome tonic seizures. Also, although tonic seizures in Lennox-Gastaut syndrome are usually associated with bursts of generalized spikes55,56 (Figure 3B), as discussed in the next section, some occur with de synchronization on the EEG that is similar to the decrements of infantile spasms. Infantile spasms50,51 and serial myoclonic or tonic seizures that resemble infantile spasms have been reported in Lennox-Gastaut syndrome.28 The uncommon absence seizures of West syndrome coincide with decrements on EEG that are similar to the EEG findings of some atypical absence seizures in Lennox-Gastaut syndrome and other severe epilepsies.51 The myoclonic seizures in West syndrome patients are reminiscent of the &dquo;myoclonic&dquo; variant of Lennox-Gastaut syndrome (see next section). In Ohtahara’s West syndrome patients, hypsarrhythmia most frequently disappeared between 6 months and 1 year of age. Generalized slow spikeand-wave discharges, the characteristic EEG abnormality in Lennox-Gastaut syndrome, appeared between 1 and 2 years of age. 57 Markand58 and Ohtahara observed that the wake EEG first changed to a slow spike-and-wave pattern, while the sleep EEG continued to show hypsarrhythmia. Patients may be seen in late infancy who have both hypsarrhythmia

11

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FIGURE 4

Hypsarrhythmia variant showing increased bilateral synchrony (similar to generalized slow spike-and-wave pattern) in a 9-month-old (28 weeks gestational age) boy with infantile spasms (West syndrome) (awake, eyes open).

FIGURE 3 A. Ictal EEG pattern-generalized burst of &dquo;fast&dquo; rhythms-of infantile spasm in a 4-month-old girl with West syndrome (one of a series of seizures). Note similarities to ictal EEG pattern of tonic seizures in LennoxGastaut syndrome. B. Tonic seizure in a 4-year-old girl with Lennox-Gastaut syndrome. Ictal EEG changegeneralized burst of rapid spikes- show similarities to ictal EEG pattern of infantile spasms.

and slow

spike-and-wave discharges

on

EEG.59 Blume 60 and Brown and Livingston

the

same

37 felt that

hypsarrhythmia gradually became more synchronized, until a slow spike-and-wave pattern emerged. The hypsarrhythmia variant with increased syn-

chrony22 may be an intermediate form (Figure 4). Although hypsarrhythmia wave are

considered

and slow

to be two

spike-anddistinctly different

EEG patterns, in some cases they may be difficult to tell apart6l (Figure 5). Gastaut et a121,56 and Blume62

described variability in the slow spike-and-wave pattern in the same recording from a more synchronous slow spike-and-wave pattern to a hypsarrhythmialike multifocal asynchronous pattern. Brown and Livingston 37 noted that in slow spike-and-wave patterns, the configuration and distribution of successive bursts were not the same, suggesting that there was generalization from multiple spikes. They suggested that as brain maturation proceeded from a pattern of hypsarrhythmia, the multifocal spike-andwave discharges became more organized and more

synchronous. Multiple independent spike foci may be found in West syndrome patients instead of hypsarrhythmia. They may occur as a transitional pattern between West syndrome and Lennox-Gastaut syndrome, possibly as a developmental stage .63, 64 They may also coexist with generalized slow spike-and-wave discharges in Lennox-Gastaut syndrome patients, and follow the disorder.65 Noriega-Sanchez and Markand66 found that, of 108 patients who had multifocal spike-and-wave discharges on EEG, 16% and 11% had previous EEG findings of hypsarrhythmia and slow spike-and-wave discharges, respectively. Markand58 remarked

12

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on

the close association of the

and Aicardi50 found mental retardation in a much higher percentage (72%) of their patients who had underlying neurologic disorders, when compared with idiopathic cases (22% of whom had mental retardation). Underlying etiologies are generally similar to those of West syndrome, except for a lower incidence of brain malformations in Lennox-Gastaut syndrome and a higher percentage of idiopathic causes.48,SO Like West syndrome, Lennox-Gastaut syndrome most frequently is associated with diffuse or multifocal cerebral disease, but instances of focal pathology have been documented.68 The classic feature of Lennox-Gastaut syndrome is the generalized slow spike-and-wave discharges that are typically found on the waking EEG69 (Figure 5). The slow spike-and-wave discharges repeat in trains lasting at least 2 seconds at frequencies of less than 3 Hz. SO,S8,67 According to Aicardi,4 the spikes are slow (150 ms), often blunted, and followed by irregular 1- to 2-Hz slow waves. They are less regular in amplitude and frequency than three-per-second

outcomes. 67 Chevrie

FIGURE 5 Generalized slow spike-and-wave discharges in a 4-yearold boy with Lennox-Gastaut syndrome (awake, eyes open). Note resemblance to hypsarrhythmia in bipolar derivations (channels 1 through 8).

patterns of hypsarrhythmia, independent multifocal

spike discharges, and slow spike-and-wave discharges : he observed all three patterns in the same patient. Multifocal spike-and-wave discharges may be found in rare older patients who have infantile spasms that have persisted since infancy (Figure 6).

spike-and-wave discharges. They are usually not activated by hyperventilation or photic stimulation but are highly activated by drowsiness and non-REM sleep. The background EEG usually shows diffuse slowing. Multifocal, and sometimes focal, epileptiform discharges are common. During sleep, V waves and sleep spindles may still be discernible despite the marked activation of slow spike-and-wave discharges. Slow spike-and-wave discharges increase in abundance during non-REM sleep, often changing in morphology, becoming even slower in frequency, or developing an increase in multiple spike components; the discharges become less common during REM sleep.43 Whether the prolonged trains of slow spike-andwave discharges found in Lennox-Gastaut syndrome patients are ictal or interictal discharges is a subject of debate. In many instances, no definite be detected, but in some patients, of absence symptoms during the trains of slow spike-and-wave discharges is obvious. The clinical changes may include cessation of activity, staring, drooling, and myoclonic jerking of face or limbs. Reaction-time testing can document the seizures in some patients .70 Because detecting subtle

symptoms

Lennox-Gastaut

the

Syndrome

The clinical triad consists of intractable seizures, mental retardation, and generalized slow spike-andwave discharges on the EEG. SO,S8,67 Peak incidence is between 1 and 7 years of age, most commonly around 2 years of age.5° Lennox-Gastaut syndrome accounts for at least 3% of childhood epilepsieS4 and is approximately as common as West syndrome.33,52 Developmental or mental retardation is found in 80% of patients48 and in a higher percentage of to up those patients with age of onset under 2 years. Patients with earlier onset of seizures also have poorer

can

occurrence

symptoms

in

moderately

or

severely mentally

re-

tarded patients may be impossible, it may be difficult to determine whether slow spike-and-wave discharges should be defined as an ictal or interictal EEG pattern. One half of Lennox-Gastaut syndrome patients

13

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’

FIGURE 6 Ictal EEG changes in a 5-year-old girl-generalized sharp- and slow-wave complexes followed by attenuation-are identical to ictal EEG findings in young infants with infantile spasms. This patient, whose interictal EEG showed multifocal spike-and-wave discharges, had Aicardi syndrome and had &dquo;infantile&dquo; spasms persisting since early in-

fancy. more than one seizure type, and patients usuhave several seizure ally including tonic, atonic, myoclonic, and atypical absence. Percentages of the different types of seizures in Lennox-Gastaut

have

types,5°

Myoclonic seizures are usually massive (bilateral symmetrical) body jerks but may be limited to eye blinking or head nodding. They occur as isolated seizures or may be briefly repeated. Brief inhibition of muscle tone may follow.4 A generalized spike-and-wave pattern coincides on EEG. It has been proposed that there is a &dquo;myoclonic variant&dquo; of Lennox-Gastaut syndrome, with greater frequency of myoclonic seizures and better outcome (21% mental retardation, compared with 68% mental retardation for all Lennox-Gastaut syndrome patients). 50,73,74 and

syndrome have been determined primarily by historical data, since comprehensive video-EEG studies such as have been performed in West syndrome9 have so far not been carried out in Lennox-Gastaut syndrome. However, the existing historical data indicate that atypical absence seizures are the most frequent seizures, followed by tonic, then atonic, and then myoclonic seizures .51,71 Generalized tonicclonic and complex partial seizures also occur in a minority of patients. Tonic seizures are the most common seizures when sleep is studied,4 because these are especially activated by non-REM sleep. Duration varies from several seconds to a minute, usually about 10 seconds,51 and is associated with a &dquo;fast recruiting rhythm&dquo; of about 10 Hz (Figure 5B). Roger et a1~2 considered this type of seizure to be necessary for a diagnosis of Lennox-Gastaut syndrome. However, tonic seizures do not appear to be obligate for the diagnosis, since they were absent in 10% to 26% of patients in reports cited by these authors. Tonic seizures also occur in other disorders (see next sec-

benzodiazepines,

tions).

been used in

These patients tend to have a later age at onset and absence of underlying brain disease. Atonic seizures

of

are

falling, according

to

the most

common

Aicardi.4 However,

cause

true

atonic seizures zures

separate from myoclonic-atonic seibe rare.69 The ictal EEG usually conmay

sists of a and-wave

fast-recruiting discharge, but slow spikedischarges or combination of both may be

seen.

Therapy of Lennox-Gastaut syndrome is compliby the multiple seizure types and the lack of

cated exact

documentation of seizure types in many in-

stances. 75 Seizures tend to be intractable to medical management, which typically includes valproic acid, or

some

14

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the

ketogenic

diet. ACTH has

patients. 4,76 Corpus callosotomy

has been effective in

tacks. ,77

Other

patients with epileptic &dquo;drop at,

Epilepsies

With Similarities

to Lennox-Gastaut

Syndrome

Multifocal spike-and-wave pattern as an intermediate EEG pattern between West syndrome and Lennox-Gastaut syndrome was discussed in an earlier section. Multifocal spike-and-wave discharges can also occur as a stable EEG pattern and in these patients is often associated with underlying brain disease, mental retardation, and a severe seizure disorder, although the course tends to be less severe than Lennox-Gastaut syndrome. 66,78 Tonic seizures associated with electrodecremental episodes have been reported in these patients. 79 Several authors4,80,81 described &dquo;pseudo-LennoxGastaut syndrome&dquo; in some cases of partial epilepsy, especially of frontal lobe origin. The disorder is similar to Lennox-Gastaut syndrome but is sometimes transient, and these cases may have been induced by intercurrent illness or medication toxicity. Tonic seizures have also been reported in some cases of partial

epilepsy.82 Electrical status

epilepticus in sleep (also called spike-waves during slow sleep&dquo;), 43,83,84 epileptic aphasia (Landau-Kleffner) syndrome, 85-87 atypical benign partial epilepsy of childhood,4,88 and occipital lobe epilepsy89 resemble Lennox-Gastaut syndrome in that patients with these disorders develop generalized slow spike-and-wave discharges during slow-wave sleep. More restricted (regional or focal) epileptiform activity occurs during the wake portion of the EEG in these patients (Figure 7). Patients with electrical status epilepticus in sleep tend &dquo;continuous

to show

active seizure disorder and somewhat mental deterioration during a period of progressive months or several years, with the process then appearing to burn out, running a more static or resolving course thereafter. Unlike Lennox-Gastaut syndrome, patients with these epilepsies do not have tonic seizures in sleep. Lennox-Gastaut syndrome is customarily defined by the presence of slow spikeand-wave discharges in the waking EEGso,s6,67,81; this feature usually easily differentiates it from the abovementioned syndromes, in which slow spike-andan

in

discharges present only sleep. However, precise differentiation is made difficult by the fact that some reports of Lennox-Gastaut syndrome include patients who do not have slow spike-and-wave discharges in the waking state .58,90 Other authors’1,91 do not require the presence of slow spike-and-wave dis-

wave

FIGURE 7 A. Occipital spike-and-wave discharges during the waking state in an 8-year-old boy. B. Diffusion of spike-and-wave discharges resembling a generalized slow spike-and-wave pattern occurred during sleep in the same patient.

are

charges on the EEG as essential for inclusion as Lennox-Gastaut syndrome; this makes it difficult to separate Lennox-Gastaut syndrome from these other severe epileptic syndromes. Relationship Between Lennox-Gastaut Syndrome and the Severe Myoclonic Epilepsies In most instances, Lennox-Gastaut syndrome can be readily differentiated from the other severe epilepsies of late infancy and childhood by the presence in the other disorders of primarily faster (> 2.5 Hz) atypical spike-and-wave discharges and myoclonic seizures as the predominant type of seizure (Figure .

15

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develop late in the course of Lennox-Gastaut syndrome. This occurred in 70% of the 20 patients

the spike-and-wave slower rates may occur-92 discharge usually fast, In the latter cases, there may be confusion with the

may

Lennox-Gastaut syndrome. Although frequent myoclonic seizures are the most prominent feature in these patients, absence, atonic, and tonic seizures may occur.4 Aicardi and Gomes93 emphasized that complete differentiation of the Lennox-Gastaut syndrome from the severe myoclonic epilepsies cannot be made in every case. There are patients who at the onset resemble one of the absence or myoclonic epilepsies, but who with time show evolution of sei-

average of 12 years after onset. In these older Lennox-Gastaut syndrome patients slow spike-andwave discharges may still be seen but may occur as brief bursts, isolated transients, or mixed with atypical spike-and-wave discharges (Figure 9). These changes appear to reflect the natural evolution of the Lennox-Gastaut syndrome EEG over time.

and EEG features toward Lennox-Gastaut

The Severe Myoclonic Epilepsies The severe myoclonic epilepsies are a heterogeneous group of disorders95-97 that affect the same age groups as West and Lennox-Gastaut syndromes. However, these patients have a lower association with mental retardation (36%). Difficulties in the perinatal period and positive family histories of seizures are the most common associated factors. Among infants and young children with predominantly myoclonic seizures, Alcardl4’92,96 distinguished a group who had preceding febrile seizures and severe generalized tonic-clonic, partial, and absence seizures. These patients with &dquo;cryptogenic myoclonic epilepsy&dquo; are similar to those reported by Dalla Bernardina et al98 and Dravet et af3,99 as &dquo;severe myoclonic epilepsy of infancy.&dquo; These patients do not have the nocturnal tonic seizures that are characteristic of the Lennox-Gastaut syndrome. Patients tend to show deterioration in mental abilities and slowing in the background EEG coinciding with

8). Although the frequency of is

zure

types

syndrome56,94 (see

next

section).

who have the Lennox-Gastaut syndrome, presence of spike-and-wave discharges at higher frequencies is associated with a better prognosis. Blume et al67 obtained a median 12-year follow-up on 57 patients who had slow spike-and-wave discharges on EEG; seven of 15 patients who had normal intellect had some spike-and-wave discharges on EEG at frequencies greater than 2.5 Hz; no patients with normal intellect had spike-andwave discharges at frequencies of less than 1.5 Hz. Generalized atypical spike-and-wave discharges In

patients

FIGURE 8 Generalized atypical spike-and-wave istic of the myoclonic epilepsies.

Hughes63 followed for 15 to 40 years and was noted an

FIGURE 9 Combination of

discharges character-

wave

tonic,

generalized atypical and slow spike-anddischarges in a 15-year-old boy with intractable myoclonic, and absence seizures.

16

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the stage of severe seizures, similar to the regression that is common in West and Lennox-Gastaut syndromes. Subsequently, however, the course becomes more static, although mental retardation is a

frequent outcome. Patients with &dquo;myoclonic-astatic epilepsy&dquo; have seizures that start during the first 5 years of life. 98, 100,101 Boys are more frequently affected, and there appears to be a genetic predisposition. The usual seizure is a generalized myoclonic jerk followed by loss of muscle tone. Dooselol felt that the background EEG in these patients showed characteristic diffuse or parasagittal 4- to 7-Hz rhythmic activity. These patients may have nocturnal tonic seizures similar to those of the Lennox-Gastaut syndrome. The course appears to be variable, including patients with good and poor prognoses. The presence of tonic seizures appears to indicate a poor outcome.

&dquo;Myoclonic-absence epilepsy&dquo;lo2-l04 becomes symptomatic in early childhood, with seizures consisting of repetitive myoclonic jerks, associated absence phenomena, and with generalized three-persecond spike-and-wave discharges (indistinguishable from that of typical petit mal epilepsy) or atypical spike-and-wave discharges. The myoclonus is usually severe, and a succession of myoclonic jerks may give a tonic appearance. In some patients, this disorder evolves into the Lennox-Gastaut syndrome.

quency of

wave

forms from

next: the discontinuous

one syndrome to the burst-suppression pattern Ohtahara syndrome; after

seen in the neonatal the neonatal period, an increase in continuity is seen in the burst-suppression variant of hypsarrhythmia in the early infantile West syndrome; then in middle infancy, the continuous typical hypsarrhythmia pattern of West syndrome is seen. A decrease in slow-wave abnormality, when compared with hypsarrhythmia, is present in the multifocal spikeand-wave pattern that is transitional between West syndrome and Lennox-Gastaut syndrome. Then, increased synchrony of the multifocal spike-and-wave discharge is found in the generalized slow spikeand-wave pattern of Lennox-Gastaut syndrome. The relationship of seizures and EEG abnormalities to the sleep-wake cycle differs in each syndrome in ways that suggest increasing differentiation. In Ohtahara syndrome, there is no sleep cycle, and the burst-suppression pattern is invariant. In West syndrome, the EEG abnormality is often worse during non-REM sleep, when it may become discontinuous, and the seizures tend to cluster upon awakening. In Lennox-Gastaut syndrome, the EEG abnormality is usually most marked in non-REM sleep, and the seizures segregate to different parts of the sleep-wake cycle: tonic seizures are typical of non-REM sleep, while myoclonic and clustering seizures appear on awakening, and absence seizures increase during

is

drowsiness. 105

Summary of the Common Features of the Age-Dependent Epileptic Encephalopathies The three severe, age-dependent epileptic encephalopathies appear to form a continuum of clinical and EEG abnormalities that show certain overlapping features. The syndromes share a high association with serious underlying brain disease, medical intractability of seizures, and poor outcome. Prognosis is worse with decreasing age. The serial or clustering nature of the typical seizure type is best developed in the two earlier (Ohtahara and West) syndromes but still

can

be detected in

some

seizures in the later

(Lennox-Gastaut) syndrome. The quality of the typical seizure is jerklike (myoclonic) or of intermediate

(spasm) in the two earlier syndromes and prolonged (tonic) in the later syndrome. Absence seizures begin to develop in the intermediate (West) syndrome and are prominent in the later syn-

duration more

drome. There are a number of transitional features in the EEG abnormalities that suggest an evolution toward increasing continuity, synchrony, and fre-

There are also transitional features and overlap between the age-dependent epileptic encephalopathies and other severe epileptic conditions, including those with tonic seizures, those with multifocal spike-and-wave discharges on EEG, and the myoclonic epilepsies. These latter conditions may be more distant members of a larger continuum or spectrum of epileptic conditions that exhibit decreas-

ing severity. Concept of the Age-Dependent Epileptic Encephalopathies The major argument against the concept of the agedependent epileptic encephalopathies is that not all patients with the earlier syndromes (Ohtahara and West syndromes) evolve into the later syndromes (West and Lennox-Gastaut syndromes). However, it Limitations of the

for any illness to have a uniform appearance identical course when it occurs in different The variables of underlying or associated patients. diseases, genetic and social factors, intercurrent illnesses, and medications may each influence the epi-

is

rare

or run an

17

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process. These may act as specific on/off &dquo;switches&dquo; to initiate or terminate the epileptic process at a given age or phase of disease, preventing the full clinical expression of all of the stages of the epileptic encephalopathy in many patients. There are also differences between the disorders that may not be explained by the concept of agedependent encephalopathy. The most obvious of these is the prominence of absence seizures in the Lennox-Gastaut syndrome, which has little analogy in Ohtahara or West syndromes. This difference may be excused by the known inability of the young infant’s brain to sustain synchronized generalized spike-and-wave discharges that are the substrate for the absence seizures. Another difference is the tendency for some etiologies to be associated with only one of the syndromes, such as the affinity of tuberous sclerosis for West syndrome. Some similarities between syndromes may be more apparent than real and could be coincidental; for example, the bursts of &dquo;fast&dquo; rhythms seen on EEG during both infantile spasms in West syndrome and tonic seizures in Lennox-Gastaut syndrome often appear very different, with the former being low in amplitude and wavelike and the latter being high in amplitude and

leptic

spikelike. Perhaps the major limiting factor in confirming or denying a hypothesis of an evolutionary interrelationship among these disorders is the incomplete existing information concerning the nosolthese disorders. West syndrome is the only of ogy well-described entity. The small numbers of cases of Ohtahara syndrome that have been reported have not been evaluated by video-EEG examinations; such studies would help to outline the seizures in the syndrome more accurately and to differentiate it from early myoclonic encephalopathy. Comparison with the Lennox-Gastaut syndrome is difficult for two reasons: one is a similar lack of accurate videoEEG definition of the seizure types; the other is variability in criteria used by different authors for diagnosis of the Lennox-Gastaut syndrome. An additional problem when comparing the seizures in these disorders is the lack of a working definition of epileptic &dquo;spasms&dquo; and how spasms may be differentiated from myoclonic and tonic seizures. Further progress in understanding the interrelationships between the epileptic encephalopathies will depend on future clinical studies designed to more accurately define each syndrome, delineate the characteristics of the seizures that occur in each syndrome, and follow the evolution of the seizures over state of

time.

Acknowledgments The author would like to thank Dr Warren Lo for referring patients for EEG evaluations and Gretchen Herr, R EEG T, for technical assistance.

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