EPILEPSY SYNDROMES2

EDWARD C. MADER, JR.

PIOTR W. OLEJNICZAK

Epilepsy syndromes are based on the nonrandom clustering of electroclinical findings in individuals with epilepsy. In contrast to diseases, epilepsy syndromes do not have a single well-defined etiology. In the epilepsy monitoring unit all epilepsy patients should receive a preliminary epilepsy syndrome diagnosis based on age at the onset of epilepsy, seizure types, neurological condition, family history, and other clinical data. Routine electroencephalography (EEG) is extremely helpful in syndrome classification, but video EEG monitoring is often necessary to reach a definitive syndrome diagnosis. Selecting an appropriate epilepsy syndrome will narrow down the choice of etiologies and guide the selection of special tests to confirm or exclude specific epileptic diseases. It will also usually allow the neurologist to predict the course of the disease and to estimate the probability of remission or seizure control with antiepileptic drugs. But even when a specific etiology has already been demonstrated, it is not prudent to omit a syndrome diagnosis. A good match between syndrome and etiology will put the diagnosis on solid ground, whereas a mismatch will prompt a review of the evaluation to explain the discrepancy. Syndrome diagnosis will also prevent the uncritical acceptance of an etiology based on radiological findings when, in fact, those findings and the patient’s seizures are not causally related.

EPILEPSY SYNDROMES: AN OVERVIEW

Table 10-1 is a summary of adult and pediatric epilepsy syndromes that are currently recognized by the International League against Epilepsy (ILAE) and catalogued in the

ILAE website: Http://www. ilae-epilepsy. org/ctf/syn_frame .html (1—37). The list does not include epilepsy syndromes that are not yet recognized by the ILAE (38). It also excludes benign nonfamilial neonatal seizures, febrile seizures, and other disorders classified by the ILAE as “conditions with epileptic seizures that do not require a diagnosis of epilepsy” (39,40). We have retained the official ILAE name of most of the syndromes and adopted some of the names in the recent proposal of the ILAE Task Force on Classification (41). We have also assigned each syndrome a unique abbreviation, which we will use throughout the chapter instead of the full syndrome name. Thus, the reader might need to refer to this table from time to time. In keeping with the recommendations of the ILAE Task Force on Classification, we will treat LKS as a subtype of ECSWS, not as a separate syndrome (41). The other differences between the ILAE list and our list are mainly the result of our more liberal notion of a syndrome. Thus, we listed MTLE, LTLE, FLE, OLE, and PLE as separate syndromes even if these entities were listed by the ILAE as “MTLE with hippocampal sclerosis,” “MTLE defined by specific etiologies,” and “neocortical epilepsies: other types defined by location and etiology.” Although common names are still used for BFNS, ADN-FLE, FTLE, and FFEVF, these syndromes will probably be expanded and renamed in the future to accommodate nonfamilial and sporadic forms in the same way that “benign familial infantile seizures” was renamed to BFNIS. We are aware of the endless controversy of syndrome classification, but some organization is necessary in discussing epilepsy syndromes (42). Therefore, we divided the syndromes into five groups: encephalopathic epilepsies, idiopathic generalized epilepsies, idiopathic focal epilepsies, symptomatic focal epilepsies, and reflex epilepsies.

There are already many publications that describe each epilepsy syndrome in detail, and it is not our intention to discuss them individually. For a detailed discus-

TABLE 10-1. EPILEPSY SYNDROMES. The syndromes are classified into six groups. The official ILAE name is retained for most syndromes, but modified for some. Each epilepsy syndrome is assigned a unique abbreviation (column next to syndrome). These abbreviations are used instead of the full syndrome names throughout this chapter. The reference number corresponds to the main reference for the syndrome (see reference list).

Encephalopathic Epilepsies

Early myoclonic encephalopathy

EME

Ref. 1

Ohtahara syndrome

OS

Ref. 2

West syndrome

WS

Ref. 3

Lennox-Gastaut syndrome

LGS

Ref. 4

Epilepsy with continuous spike-waves during sleepa

ECSWS

Refs. 5, 6

Migrating focal seizures of infancyb-e

MFSI

Ref. 7

Dravet syndromec

DS

Ref. 8

Myoclonic encephalopathy in nonprogressive disordersde

MEND

Ref. 9

Progressive myoclonus epilepsies

PME

Ref. 10

Idiopathic Generalized Epilepsies

Benign myoclonic epilepsy of infancy

BMEI

Ref. 11

Childhood absence epilepsy

CAE

Ref. 12

Juvenile absence epilepsy

JAE

Ref. 13

Juvenile myoclonic epilepsy

JME

Ref. 14

Epilepsy with generalized tonic-clonic seizures onlyf

EGTCS

Ref. 15

Generalized epilepsy with febrile seizures plus

GEFS+

Ref. 16

Epilepsy with myoclonic absences

EMA

Ref. 17

Epilepsy with myoclonic astatic seizuresg

EMAS

Ref. 18

Idiopathic Focal Epilepsies

Benign familial neonatal seizures

BFNS

Ref. 19

Benign familial and nonfamilial infantile seizures

BFNIS

Ref. 20

Benign childhood epilepsy with centrotemporal spikes

BCECTS

Ref. 21

Benign childhood epilepsy with occipital spikes—Panayiotopoulos type

BCEOS-1

Ref. 22

Benign childhood epilepsy with occipital spikes—Gastaut type

BCEOS-2

Ref. 23

Autosomal-dominant nocturnal frontal lobe epilepsy

ADNFLE

Ref. 24

Familial temporal lobe epilepsiesh

FTLE

Ref. 25

Familial focal epilepsy with variable foci

FFEVF

Ref. 26

Symptomatic Focal Epilepsies

Mesial temporal lobe epilepsyi

MTLE

Ref. 27

Lateral temporal lobe epilepsiesi

LTLE

Ref. 28

Frontal lobe epilepsiesi

FLE

Ref. 29

Parietal lobe epilepsiesi

PLE

Ref. 30

Occipital lobe epilepsiesi

OLE

Ref. 31

Hemiconvulsion hemiplegia and epilepsy syndrome

HHE

Ref. 32

Rasmussen syndrome

RS

Ref. 33

Reflex Epilepsies

Idiopathic photosensitive occipital lobe epilepsy

IPOLE

Ref. 34

Visual pattern-sensitive epilepsy

VPSE

Ref. 35

Primary reading epilepsy

PRE

Ref. 36

Epilepsy with startle-induced seizures

ESIS

Ref. 37

A.  ECSWS includes Landau-Kleffner syndrome (LKS) and the non-LKS type of ECSWS.

B.  MFSI is used here instead of "migrating partial seizures of infancy" (MPSI).

C.  DS was originally known as "severe myoclonic epilepsy of infancy" (SMEI).

D.  MEND is used here instead of "myoclonic status in nonprogressive disorders" (MSNE).

E.  MFSI and MEND are considered as "syndromes in development" by the ILAE.

F.  EGTCS includes the syndrome of "grand mal on awakening" (GMA).

G.  EMAS is also known as "myoclonic-astatic epilepsy" (MAE) or "Doose syndrome."

H.  The two types of FTLE, mesial FTLE and lateral FTLE, are most likely separate syndromes.

I.  These syndromes are listed by the ILAE as "MTLE with hippocampal sclerosis," "MTLE defined by specific etiologies," and "neocortical epilepsies: other types defined by location and etiology."

Sion of epilepsy syndromes, we recommend the ILAE Web site: Http://www. ilae-epilepsy. org/Visitors/Centre/ctf/ Syndromes. cfm (1—37), and the following textbooks: Epilepsy: A Comprehensive Textbook, second edition (2007), by Engel, Pedley, Aicardi, Dichter, and Moshe; and The Treatment of

Epilepsy: Principles and Practice, fourth edition (2006), by Wyllie, Gupta, and Lachhwani. The appendix at the end of this chapter gives an outline of the most important features of the epilepsy syndromes. The following features are listed for each syndrome: seizure types; ictal and interictal

EEG features; activating effects of sleep, photic stimulation, hyperventilation, and other factors; course and evolution; and common etiological factors. The appendix is intended to complement the text, so the reader might find it useful to glance through it from time to time.

The next section deals with the clinical diagnosis of epilepsy syndromes based on age at presentation, seizure types, and other clinical features. With these clinical data, the physician can formulate a preliminary syndrome diagnosis. The third section is the most important section of the chapter. Here, we will discuss the electroclinical diagnosis of epilepsy syndromes using data obtained from electrophysiological studies, especially video EEG monitoring. The emphasis is on distinguishing epilepsy syndromes based on their typical ictal and interictal EEG findings. The effects of sleep and other activating factors on these electroclinical features are also described. The fourth section briefly describes the different etiological factors or diseases that are associated with the epilepsy syndromes. Some are clearly the cause or substrate of the epilepsy; in other cases, a causal relationship between the disease and epilepsy is difficult to ascertain. A detailed discussion of individual diseases is beyond the scope of this chapter; the reader should refer to the appendix for a summary of the most commonly encountered diseases in each syndrome. The chapter is concluded with a brief comment about the place of epilepsy syndrome diagnosis in the overall scheme of epilepsy health care.

CLINICAL DIAGNOSIS OF THE EPILEPSY SYNDROME

Epilepsy is a condition of chronic, recurrent seizures. All patients with epilepsy should initially receive a preliminary epilepsy syndrome diagnosis based on age at the onset of epilepsy, seizure types, and other clinical data. Electroencephalography (EEG), especially video EEG monitoring, is necessary for a definitive diagnosis of an epilepsy syndrome (see next section).

Age at Initial Presentation

Table 10-2 classifies the epilepsy syndromes according to the typical age period at presentation. In age-dependent syndromes, the onset of seizures is relatively restricted to the neonatal period, infancy, childhood, or adolescence.

Three epilepsy syndromes begin in the neonatal period (up to the age of 3 months): OS, EME, and BFNS (1,2,19). OS and EME are encephalopathic epilepsies that must be distinguished from each other and from other causes of neonatal seizures (43). BFNS should be distinguished from benign nonfamilial neonatal seizures (fifth-day fits), which is now listed by the ILAE under “conditions with epileptic seizures that do not require a diagnosis of epilepsy” (39,44).

TABLE 10-2. AGE PERIOD AT PRESENTATION OF EPILEPSY SYNDROMES. Age-dependent syndromes are classified according to period of typical onset: neonatal period, infancy, childhood, or adolescence. Syndromes that are less age-dependent are listed last.

Neonatal Period Ohtahara syndrome (OS)

Early myoclonic encephalopathy (EME)

Benign familial neonatal seizures (BFNS)

Infancy

West syndrome (WS)

Migrating partial seizures of infancy (MFSI)

Dravet syndrome (DS)

Myoclonic encephalopathy in nonprogressive disorders (MEND) Benign myoclonic epilepsy of infancy (BMEI)

Benign familial and non-familial infantile seizures (BFNIS)

Childhood

Lennox-Gastaut syndrome (LGS)

Epilepsy with continuous spike-and-wave during sleep (ECSWS) Hemiconvulsion hemiplegia and epilepsy syndrome (HHE) Benign childhood epilepsy with centrotemporal spikes (BCECTS) Benign childhood epilepsy with occipital spikes— Panayiotopoulos type (BCEOS-1)

Benign childhood epilepsy with occipital spikes—Gastaut type (BCEOS-2)

Childhood absence epilepsy (CAE)

Epilepsy with myoclonic absences (EMA)

Epilepsy with myoclonic astatic seizures (EMAS)

Adolescence

Juvenile absence epilepsy (JAE)

Juvenile myoclonic epilepsy (JME)

Epilepsy with generalized tonic-clonic seizures only (EGTCS) Epilepsy with febrile seizures plus (GEFS+)

Less Specific Age Relationship

Autosomal-dominant nocturnal frontal lobe epilepsy (ADNFLE) Familial temporal lobe epilepsies (FTLE)

Familial focal epilepsy with variable foci (FFEVF)

Mesial temporal lobe epilepsy (MTLE)

Neocortical epilepsies (LTLE, FLE, OLE, PLE)

Rasmussen syndrome (RS)

Reflex epilepsies (IPOLE, VPSE, PRE, ESIS)

Progressive myoclonus epilepsies (PME)

Epilepsy with onset in infancy and toddlerhood (excluding the first 3 months) should raise the suspicion of an encephalopathic epilepsy (45). West Syndrome (WS) is the most common encephalopathic epilepsy during infancy; it can develop in infants with obvious brain disorder (some have OS) or in those who are apparently healthy (3). WS must be distinguished from the less common encephalo-pathic epilepsies of infancy including MFSI, DS, MEND, and early-onset LGS (7-9,46). ECSWS, PME, HHE, and RS may also begin in infancy (6,10,32,33). BMEI and BFNIS are the only ILAE-recognized benign idiopathic epilepsy syndromes of infancy (16,20). The remaining infantile epilepsies are symptomatic of malformative, destructive, or degenerative diseases of the brain.

Childhood is notable for the propensity of idiopathic focal and generalized epilepsies (47,48). Of the idiopathic focal epilepsies, BCECTS is the most common, followed by BCEOS-1; BCEOS-2 is relatively uncommon (21—23,47). The familial focal idiopathic epilepsies ADNFLE, FTLE, and FFEVF rarely begin in childhood, and their incidence is far less compared to BCECTS and BCEOS-1. The most prevalent idiopathic generalized epilepsy in children is CAE

(12). Occasionally, JAE, JME, or EGTCS may begin in childhood (13—15,48). EMA and EMAS may have a less favorable course and should be distinguished from LGS (17,18). LGS is the most common childhood encepha-lopathic epilepsy; it may emerge de novo or develop in a child with antecedent WS (4). Other childhood epilepsy syndromes with a significant risk of neurological sequelae include ECSWS, HHE, and RS (5,6,32,33). Some neurodegenerative diseases are initially expressed in childhood as PME (10).

It is common for idiopathic generalized epilepsies to begin in adolescence (49). Included in this group are JAE, JME, EGTCS, and GEFS+ (13-16,49). PME that is initially expressed in this age period must be distinguished from JME (10). The familial idiopathic focal epilepsies ADNFLE, FTLE, and FFEVF may present in adolescence (24-26). These syndromes must be distinguished from the symptomatic focal epilepsies, which are not much different from those with onset in adulthood (49). The most common is MTLE with hippocampal sclerosis (27). LTLE, FLE, PLE, OLE and other neocortical epilepsies caused by malformative, vascular, and neoplastic lesions are also common (28-31). Rasmussen Syndrome (RS) is the most devastating focal epilepsy syndrome in this age group (33). Some reflex epilepsies initially become manifest at adolescence (34-36).

Most adult-onset epilepsy syndromes are not age-dependent and may also begin in adolescence or childhood. Epilepsies that are initially expressed in adult life are usually focal and symptomatic. A large number of patients with MTLE and hippocampal sclerosis begin having seizures in adolescence (27). Symptomatic epilepsy caused by extratemporal lesions also becomes increasingly important with increasing age (28-31). A wide array of diseases and lesions have been associated with adult-onset symptomatic epilepsy. Some reflex epilepsies begin in adult life (34-36). Although most idiopathic generalized epilepsies encountered in adults started in adolescence (e. g., JAE, JME, EGTCS) (13-15), it is not uncommon for an idiopathic generalized epilepsy to begin in adult life (e. g., JME, EGTCS) (50).

Seizure Types

The different seizure types are listed in Table 10-3. The scheme used is a modification of the classification scheme recently proposed by the ILAE Classification Core Group (41). A detailed discussion of each seizure type is available on the ILAE Web site (see references 51-71).

TABLE 10-3. SEIZURE TYPES. The list is a modification of the ILAE Classification Core Group proposal. Alternative or original names and other comments are in parenthesis.

Bilateral-onset seizures

Typical absences (typical absence seizures) atypical absences (atypical absence seizures) myoclonic absences (myoclonic absence seizures) tonic-clonic seizures (primary generalized tonic-clonic seizures) clonic seizures tonic seizures

Epileptic spasms (infantile spasms) bilateral epileptic myoclonus (including massive bilateral myoclonus) eyelid myoclonia

Myoclonic-atonic seizures (myoclonic-astatic seizures) atonic seizures

Focal-onset seizures

Focal clonic seizures jacksonian seizures (jacksonian march) focal atonic seizures (inhibitory motor seizures) asymmetric tonic seizures (supplementary motor area (SMA) seizures)

Focal myoclonus (including multifocal myoclonus and erratic myoclonus)

Focal sensory seizures (with elementary or complex symptoms) aphasic seizures rolandic seizures

Hippocampal-amygdaloid seizures hemiclonic seizures hyperkinetic seizures

Dyscognitive seizures (complex partial seizures) autonomic seizures

Focal seizures with secondary generalized tonic-clonic seizures focal seizures with secondary generalized absence seizures

Status epilepticus seizures

Epilepsia partialis continua hemiclonic status supplementary motor area status aura continua

Limbic status (complex partial status epilepticus)

Autonomic status

Absence status (typical or atypical)

Myoclonic-absence status

Myoclonic status

Tonic status

Tonic-clonic status

Subtle status

The seizure types that are expressed in each of the epilepsy syndromes are listed in the appendix. Except for the rare spontaneous or provoked seizure in the clinic, good historytaking is initially the only means to identify a patient’s seizure types. On purely clinical grounds, the physician can broadly characterize the seizures as absence seizures, seizures with brief symmetric bilateral movements, epileptic falls, focal epileptic myoclonus, focal-onset seizures, tonic-clonic seizures, reflex seizures, or status epilepticus. Video EEG monitoring is often necessary to accurately diagnose specific seizure types (see Electroclinical Diagnosis).

Absence seizures are usually experienced by children and adolescents with idiopathic generalized or encepha-lopathic epilepsy, and some of these patients continue having absences as adults (48,49). As a rule, absences do not occur in infancy and are rare before the age of 4 years. Typical absences are expressed by all patients with CAE and JAE, by 10%—30% of patients with JME, and by a few patients with EGTCS and GEFS+ (51). Some authors consider typical absences as the only seizure type in CAE (tonic-clonic seizures may occur but only after childhood) (12). In addition to absences, tonic-clonic seizures, myoclonus, or both are often present in JAE. However, early-onset JAE with absences only can masquerade as CAE. In general, absences are very frequent in CAE (>10 per day) and moderately frequent in JAE (1—5 per day). The EEG may also help differentiate childhood-onset JAE from CAE (see Electroclinical Diagnosis). Atypical absences are common in LGS, ECSWS, and other encephalopathic epilepsies, often in combination with other seizure types (52). Myoclonic absences are absence seizures with axial hypertonia and prominent rhythmic (~3-Hz) jerking of the shoulders and arms (53). This is the principal seizure type of patients with EMA (17).

Seizures with brief symmetric or nearly symmetric bilateral movements include epileptic spasms, tonic seizures, atonic seizures, and bilateral epileptic myoclonus. Epileptic spasms, once called infantile spasms and thought to be specific for WS, have been described in other syndromes (OS, LGS) and in older children and adults (54). Nevertheless, epileptic spasms that begin in infancy and occur in clusters indicate WS. Tonic seizures are the hallmark of LGS, but also occur in OS, WS, EMA, and EMAS (55). Patients with EMA or EMAS do not exhibit tonic seizures early, but those who later do usually experience a less benign course (17,18). Because tonic seizures are brief and occur mainly (sometimes exclusively) in sleep, they are easily overlooked. Video EEG monitoring is necessary to detect or exclude tonic seizures in order to distinguish LGS from ECSWS, MEND, MFSI, DS, and early EMAS. Atonic seizures are expressed as pure ictal atonia or as atonia mixed with other ictal elements in LGS and other epilepsy syndromes (56). Atypical absences with prominent atonia suggest ECSWS (5,6). Bilateral epileptic myoclonus is the main seizure type in JME and BMEI (57). It can also occur as a minor seizure type in JAE and GEFS+. It is often expressed as myoclonic-atonic seizures in EMAS (58) and as myoclonic absences in EMA (17). Bilateral myoclonus is also common in EME, DS, MEND, and PME (1,8—10). Whether bilateral or focal, myoclonus is caused either by activation (positive myoclonus) or by interruption of muscle activity (negative myoclonus) (59,60).

Epileptic falls can be precipitated by seizures with sudden bilateral movements or atonia (54—58). An ambulant child with WS may fall as a result of epileptic spasms (3). Most falls and injuries in children with LGS are caused by tonic seizures, but atonic seizures and atypical absences account for some of them (4). In EMAS, myoclonic-atonic seizures are responsible for most falls; some are caused by pure atonic or myoclonic seizures (18). Attacks of massive bilateral myoclonus can precipitate falls in BMEI, DS, PME, and rarely in JME (57). Some falling episodes in ECSWS result from atypical absences with atonia or from negative myoclonus (22,23). In ESIS, startle-induced seizures can lead to falls (37). Focal atonic seizures, focal negative myoclonus, or asymmetric tonic seizures can rarely cause falls in FLE (29). Tonic-clonic seizures are perhaps the most important cause of epileptic falls and injury overall. Video EEG monitoring with additional placement of electromyographic surface electrodes will often explain why the patient falls.

Focal epileptic myoclonus can be confined to a small group of muscles or affect multiple noncontiguous muscles in different parts of the body (multifocal myoclonus) (59). Myoclonic jerks can also appear in one body part, disappear, and appear again in another part (erratic myoclonus). Multifocal myoclonus is prominent in EME, DS, MEND and PME (1,8—10). It helps distinguish these syndromes from OS, WS, and LGS. Children with DS manifest myoclonus late or not at all; hence “severe myoclonic epilepsy of infancy” is not a good name for this syndrome (8). It remains uncertain whether LGS with prominent myoclonus is an LGS variant, a separate syndrome, or a phenotypic overlap of syndromes. Nonetheless, before diagnosing LGS in a child with prominent myoclonus, epilepsy syndromes that mimic LGS (e. g., EMAS) must be excluded first.

Focal-onset seizures are usually symptomatic but may be idiopathic, particularly when there are no bilateral-onset seizures. Mesial temporal seizures with typical aura, cognitive dysfunction, and automatisms are highly (but not absolutely) specific for MTLE (61). Lateral temporal seizures are not always heralded by a vestibular, auditory, or visual aura (62). Intratemporal ictal spread is common, making the clinical distinction between MTLE and LTLE difficult. The two FTLE phenotypes, mesial-FTLE and lateral-FTLE, are clinically equivalent to MTLE and LTLE (25). Frontal lobe seizures in patients with FLE are manifested as focal clonic, asymmetric tonic, or complex motor phenomena, without or with mild cognitive dysfunction; they are brief and often occur in clusters during sleep (54). In ADNFLE, ictal semiology (paroxysmal arousal, nocturnal paroxysmal dystonia, or episodic nocturnal wandering) often leads to an incorrect diagnosis of parasomnia (24). Rolandic seizures (oral paresthesia, hypersalivation, dysarthria, drooling) indicative of BCECTS are sometimes seen in BCEOS-1 (21,22). Parietal lobe seizures in PLE may or may not begin with a somatosensory aura (64). Occipital lobe seizures are often experienced as visual phenomena in OLE or BCEOS-2; headache is common and the diagnosis is often migraine (64,23). Autonomic seizures with nausea

And emesis predominate in BCEOS-1 (21). Focal-onset seizures are also prominent in BFNS, BFNIS, FFEVF, HHE, RS, and IPOLE (19,20,26,32—34). Patients with LGS, ECSWS, MFSI, DS, and PME may exhibit focal seizures (other than focal myoclonus) (4—8,10).

Tonic-clonic seizures can be expressed by patients with focal or generalized epilepsy, except neonates and young infants (65). Focal-onset seizures (whether clinically evident or not) can evolve into secondarily generalized tonic-clonic seizures; this is more likely in FLE, OLE, and PLE (29—31). Most of the so-called “primarily generalized” tonic-clonic seizures in JME and other idiopathic generalized epilepsies are preceded by repetitive and rhythmic myoclonus (clonic jerking) (65).

Status epilepticus and short-duration seizures are fundamentally related (Table 10-3). The most common status overall is tonic-clonic status. The status in idiopathic generalized epilepsy is often an absence status with myoclonic elements and a terminal tonic-clonic seizure (66). In LGS, atypical absence seizure status contains tonic elements, begins and ends gradually (no tonic-clonic seizure), lasts longer, and tends to occur more frequently. Adults with a remote history of absences or with no prior epilepsy can manifest de novo absence status during an acute brain insult. FLE or MTLE can be complicated by limbic status (67). Rarely, aura continua is encountered in MTLE or other focal epilepsies (68). Patients with DS, MEND, EMAS, or PME may exhibit myoclonic status; this is rare in JME (69). About half of patients with RS manifest epilepsia partialis continua (70). Protracted autonomic seizures (>30 minutes) are common in BCEOS-1; otherwise, autonomic status is rare (22).

Reflex seizures are evoked by specific stimuli and expressed as tonic-clonic, myoclonic, absence, tonic, or focal seizures (71). Photosensitive seizures may occur in BMEI, JME, EMAS, DS, and PME but, unlike reflex epilepsies, spontaneous seizures predominate in these syndromes (11,14,18,8,10). IPOLE, VPSE, and PRE are idiopathic reflex epilepsies; reflex seizures are evoked by flicker in IPOLE, by visual pattern in VPSE, and by reading in PRE (34—36). Startle-induced seizures are the sine qua non of ESIS; the majority of patients with ESIS also have spontaneous seizures (37).

Other Clinical Data

Clinical course is the product of epilepsy evolution, disease progression, and brain maturation. These processes are intricately intertwined and difficult to separate. From a practical standpoint, the course of epilepsy is described in terms of the cognitive and behavioral abnormalities that develop with time, the evolution of seizure characteristics with age, and the probability of future seizure remission or pharmacological resistance (72—74). These features are summarized for each epilepsy syndrome in the appendix (see “course” entries).

Neurological deficits are more common in some epilepsy syndromes than in others. Long-lasting deficits are caused directly by the underlying disease or develop because of frequent epileptic activity. It is difficult, and often impossible, to determine how much of the deficits are caused by the disease and how much are the result of epileptic activity (75). The actively developing brain is vulnerable to the adverse effects of status epilepticus, seizures, or interictal epileptic activity (76,77). Any of these forms of epileptic activity can exacerbate pre-existing neurological deficits or result in de novo mental retardation or focal deficits.

Mental retardation or developmental delay in a patient with epilepsy should not automatically be attributed to an encephalopathic epilepsy (78). For example, a child with static encephalopathy can have MTLE and focal seizures. Focal seizures are not uncommon in encephalopathic epilepsies, but bilateral-onset seizures usually predominate. In the early stages of ECSWS, DS, and MFSI, cognitive function is often intact and focal seizures may be the only seizure type (5—8). Cognitive impairment has been incorporated in the classic diagnostic criteria of encephalopathic epilepsies. Epileptic spasms, hypsarrhythmia, and developmental delay constitute the classic triad of WS (3). LGS is diagnosed in children with tonic seizures, EEG slow spike-waves, and mental retardation (4). The non-LKS type of ECSWS is often associated with cognitive and behavioral changes (6). Cognitive impairment is the rule in MFSI, DS, and MEND (7,8). Occasionally, patients with intact neurological function will manifest electroclinical features consistent with an encephalopathic epilepsy. In such cases, the emergence of a full-fledged encephalopathic epilepsy must be anticipated, and a tentative syndrome diagnosis should guide treatment and the search for an etiology. EMA and EMAS differ from other idiopathic epilepsies in having a relatively high incidence of neurological sequelae (17,18). All patients with epilepsy and mental retardation should be investigated with routine EEG. In many patients, video EEG monitoring is necessary to detect or exclude an encephalopathic epilepsy and to identify the specific epilepsy syndrome. It is also important to distinguish mental retardation from the cognitive effects of antiepileptic drugs and from subclinical status epilepticus or frequent subclinical seizures.

Focal neurological deficits should not be confused with the transient focal manifestations of seizures or the postictal state. Focal neurological deficits are common in the enceph-alopathic epilepsies and some symptomatic focal epilepsies, but unlikely in the more benign idiopathic generalized and focal epilepsies. Rarely, patients with BCECTS develop cognitive or behavioral abnormalities as the syndrome evolves into a state similar to ECSWS (21,5). The clinical diagnosis of LTLE, FLE, OLE, or PLE is more secure when the focal deficits are consistent with the seizure types (28—31). The hemiplegia in HHE is initially a postictal phenomenon, but becomes a fixed deficit in a matter of days or weeks (32). In RS, focal deficits are initially absent but invariably

BRIEF COMMENT ON THE BENIGN-SEVERE CLASSIFICATION OF EPILEPSY SYNDROMES

The benign-severe dichotomy is useful but cannot be consistently applied (79,80). In EMAS and EMA, the probability of a favorable or poor outcome is virtually 50—50 (17,18). Some cases of WS, LGS, and ECSWS are known to resolve with minimal or no sequelae (80). In most encephalopathic epilepsies, prognosis also depends on etiology and treatment. Some children with BCECTS and BCEOS-1 have subtle cognitive and behavioral abnormalities, and there are some reports of BCECTS evolving to ECSWS (81). BFNS cases complicated by psychomotor retardation, intractable epilepsy, or both have been recognized recently (82). Prognosis is generally favorable in BMEI, but the incidence of mental retardation in this syndrome is significantly higher than in the general


Population (83). Learning disorder is common in CAE despite seizure and spike-wave remission (80). Seizure control is hard to achieve in some patients with JAE, JME, and BCEOS-2 (13,14,23). Intractable MTLE is common but is neither “benign” nor “severe” (27). These examples demonstrate the shortcomings of describing an epilepsy syndrome as benign or severe, and emphasize the importance of an individualized prognosis in the different epilepsy syndromes.


Develop in the course of epilepsy (33). In encephalopathic epilepsy, focal deficits are not always caused by structural lesions. Aphasia and sleep-activated bitemporal spike-waves are required to diagnose the LKS form of ECSWS (5). Symptomatic focal epilepsies with aphasia are distinguished from LKS by means of polysomnography or long-term monitoring.

The evolution of seizure types and neurological deficits reflects the time-dependent maturational, pathological, and adaptive changes in brain structure and function. Age-dependent syndromes evolve in more or less predictable ways, and knowing common paths of evolution can guide diagnosis and prognosis (73). A well-known sequence is OS WS LGS. Infants

With OS or EME develop psychomotor retardation, and about 50% die in infancy or childhood (1,2). EME survivors may go into a persistent vegetative state, continue manifesting myoclonus, or develop severe multifocal epilepsy (1). OS survivors develop WS or focal epilepsy (2). In WS, epileptic spasms usually disappear before the age of 3 years; other seizure types emerge (>50% of cases) and in some (~25% of cases) the seizures are typical of LGS (3). Rarely, epileptic spasms persist into adulthood. Most adults with a history of WS exhibit learning disabilities or mental retardation (72). In LGS, any seizure type can persist, but tonic seizures increase in prominence as cognition declines (73). Seizure remission and normal cognition is uncommon. In PME, myoclonic and tonic-clonic seizures persist until death supervenes in early adulthood (10). Spontaneous remission is the rule in some idiopathic epilepsies (BMEI, CAE, BCECTS, BCEOS); in others (JME, JAE, ADNFLE, FTLE, FFEVF), remission is effectively sustained with antiepileptic drugs (74). Of the idiopathic generalized epilepsy syndromes, EMA and EMAS are exceptional in that the probability of unfavorable outcome is relatively high (~50% of cases) (17,18).

Family history is useful in epilepsy diagnosis, but it can be easily misused by somebody who is not familiar with epilepsy genetics. A negative family history (no relatives with epilepsy) is not unexpected in patients with symptomatic epilepsy (usually caused by an acquired disease). However, most patients with idiopathic epilepsy also have a negative family history (84). Most of the nonfamilial or sporadic forms of idiopathic epilepsy have been attributed to de novo gene mutation (85). Recently, the syndrome of benign familial infantile seizures (BFIS) was expanded and renamed to BFNIS to accommodate sporadic forms. BFNS, ADFLE, FTLE, and other syndromes should probably also be expanded and renamed to include both familial and sporadic forms (86,87). It is evident that most cases of DS are caused by de novo mutation (88). A minority of all patients with idiopathic epilepsy have a positive family history. The majority of these familial cases exhibit complex inheritance (89). The mechanism of complex inheritance in epilepsy is poorly understood. Multiple susceptibility genes presumably interact, or their individual subthreshold effects sum up to produce the epilepsy phenotype. Although infrequent, simple Mendelian inheritance is always possible in patients with idiopathic epilepsy. The currently known epilepsy genes were mostly identified from families with many affected individuals and an autosomal dominant segregation pattern (90). Most genetic diseases with a PME phenotype follow an autosomal recessive pattern. The etiological bases of PME and other genetic epilepsies are discussed later (see “Etiological Diagnosis”).

ELECTROCLINICAL DIAGNOSIS OF THE EPILEPSY SYNDROME

EEG is required to diagnose the epilepsy syndrome, which, by definition, is an electroclinical syndrome. Routine EEG is indicated in patients with possible or definite epilepsy; repeating the study once or twice may increase the diagnostic yield of routine EEG in some of these patients (91). Long-term EEG monitoring is also indicated if the goal is to reach a definitive epilepsy syndrome diagnosis (92). Noninvasive video EEG monitoring is usually preferred over ambulatory EEG (93). Other physiological events (e. g.,

Muscle potentials, limb movements, eye movements) can also be monitored during the course of long-term monitoring (94). Other neurophysiological tests (e. g. evoked potentials, polysomnography) can provide information that is not readily obtained with video EEG monitoring. Neuroimaging can reveal a lesion and corroborate a particular syndrome, but it can also lead one away from the correct syndrome diagnosis. The appendix lists the salient electroclinical features of each epilepsy syndrome (see “interictal EEG” and “ictal EEG” entries).


BRIEF COMMENT ON THE USE OF THE TERM "GENERALIZED" TO DESCRIBE EPILEPTIC PHENOMENA

There is a large body of experimental evidence (including recently published quantitative EEG, functional imaging, and animal studies) telling us to stop describing seizures and interictal activity as “generalized” (95—101). These studies have correlated “generalized” ictal or interictal activity with activation of specific cortical regions (often bifrontal), discrete cortical areas, or specific thalamocortical networks (a large portion of the cortex and thalamus is spared), but not with diffuse, homogeneous, or widespread cortical activation (which is implied by the term “generalized”) (95—101). The fact that 3-Hz spike-waves may be expressed as fragments or focal discharges also suggests that the extent of cortical activation can fluctuate and be more circumscribed. The word “bisynchronous” may be more appropriate in that it does not imply the extent of activation, only that both hemispheres are activated simultaneously. However, computerized EEG analysis of some so-called “bisynchronous” ictal or interictal discharges have shown that activation does not really occur in synchrony (primary bilateral synchrony). Instead, part of one hemisphere is activated first, followed by activation of the contralateral area (secondary bilateral synchrony) (102). Meticulous measurements have revealed timing differences of up to 20 milliseconds in the epileptiform discharges of each hemisphere, with discharges in one hemisphere leading the discharges in other. Despite these difficulties, it is still appropriate to describe bilateral activity as “bisynchronous” if the discharges appear simultaneous on visual inspection of the EEG; otherwise, the word “bilateral” can be used. However, the use of the term “generalized” is hard to justify.


BRIEF COMMENT ON THE VALUE OF THE INTERICTAL EEG IN EPILEPSY SYNDROME DIAGNOSIS

Long-term monitoring is performed primarily to record seizures and their EEG correlates. In general, the ictal EEG is more useful than the interictal EEG for diagnosing seizure


Types and syndromes. However, the interictal epileptiform discharge is quite distinctive in some epilepsy syndromes (e. g., BCECTS, CAE, MTLE), and failure to demonstrate it with proper technique can cast doubt on the diagnosis (91,103). Among the epilepsy syndromes, ECSWS is unique in requiring an interictal epileptiform pattern (CSWS) for diagnosis (5,6). The interictal background activity of some syndromes (e. g., EME, OS, WS, LGS) is highly suggestive of the syndrome (1—4). Even if the diagnostic value of the interictal EEG varies among syndromes, combined interictal EEG and seizure analysis is likely to be more informative than seizure analysis alone. The search for interictal epileptiform discharges and background changes must be guided by the preliminary syndrome diagnosis.

A large number of interictal changes are state-dependent, and some occur only with certain types of activation. The search must focus on high-yield epochs, but different sleep-wake stages should also be sampled.


Absences and Spike-Waves

The type of absence seizure expressed depends on the epilepsy syndrome (104). Patients with idiopathic generalized epilepsy (except SMEI and EMAS) manifest typical absence seizures (41), and those with LGS, ECSWS, or EMAS manifest atypical absence seizures (42). The early stage of LGS or the active phase of ECSWS can be confused with a benign epilepsy syndrome if atypical absence is the only seizure type and neurological function is still intact.

Typical absences are the hallmark of CAE and JAE (12,13). Patients with JME, EGTCS, or GEFS+ also have absence seizures, but not as the main seizure type (14—16). Two subtypes of typical absence have been delineated based on whether the “blank stare” is the only change (simple absence) or is accompanied by a motor component such as myoclonus, change in tone, or automatism (complex absence) (92). Some authors consider typical absence as the only seizure type in CAE; tonic-clonic seizures can occur later but never in childhood (105). This view is not shared by other authors (106). Typical absences are also prominent in JAE, often in combination with tonic-clonic and myoclonic seizures. JME patients may manifest typical absences, but these are overshadowed by myoclonic or tonic-clonic seizures (106). “CAE evolving to JME” has more in common with JME than with CAE (including prognosis) (104). It is not easy to distinguish CAE from childhood-onset JAE with typical absences and no other seizure type. As a rule, typical absences occur more frequently in CAE than in JAE (106). The impairment of consciousness is profound in CAE, moderate in JAE, and minimal in JME (12—14). The EEG can also help differentiate JAE from CAE.

Typical or 3-Hz spike-and-wave and interruption of consciousness indicate typical absence seizure (Figure 10-1) (51). Shorter duration 3-Hz spike-waves are also common

FIGURE 10-1. 3-Hz spike-waves during typical absence seizure. The patient failed to respond to auditory stimuli (clicks) during this brief discharge. Note the bifrontal (F3, F4) voltage peak of the spikes and slow waves. Source: Adapted from Noachtar S, Wyllie E (232):192.

FIGURE 10-3. Atypical spike-waves in the interictal EEG. These discharges are common in juvenile myoclonic epilepsy and usually appear as repetitive 4-6 Hz polyspike-waves without any associated myoclonus. Source: Adapted from Fisch BJ (107):289.


(Figure 10-2). Typical 3-Hz spike-and-wave patterns appear as bisynchronous rhythmic 2.5- to 4—Hz spike-wave complexes that begin and end abruptly (12,51). The probability of detecting cognitive dysfunction or motor arrest is proportional to the duration of the discharge and the sensitivity of the detection method; simple observation is unlikely to detect any clinical change if the discharge is brief (<3 seconds). Most 3-Hz spike-wave activity lasts about 10 seconds (>30 seconds is unusual). The discharge is initially 3.5—4 Hz, but slows down to 2.5—3 Hz (12). Each spike-wave complex contains one or two (or rarely three) spikes and a slow wave. The discharge is typically symmetric with a frontal voltage maximum. Postictal changes do not occur, and the background resumes as soon as the seizure stops. The ictal 3-Hz spike-waves of JAE are in many respects similar to those of CAE, except for a slightly higher discharge rate (3.5-4.5 Hz),

FIGURE 10-2. 3-Hz spike-waves in the interictal EEG. A test word presented during this brief discharge was recalled later by the patient. The apparent broad distribution of this discharge is in part an effect of the referential montage (compare with Figure 10-1 above). Source: Adapted from Fisch BJ (107):288.

The presence of discontinuities, a larger number of spikes, and longer duration (despite less impairment in consciousness)

(13). The fragmentation of 3-Hz spike-waves in sleep or with treatment can mislead the inexperienced electroencephalog-rapher (see “Activation of Seizures. . .” below).

Atypical generalized spike-and-wave patterns appear either as an irregular complex of multiple spike-and-wave activity or as bifrontal, rhythmic, 4- to 6-Hz spike-and-wave in the interictal EEG of patients with JME, JAE, PME, and other syndromes (Figure 10-3) (107). Sleep modifies the 4- to 6-Hz pattern in the same way as it affects 3-Hz spike-waves, resulting in increasingly irregular admixtures of spikes and slow waves. Atypical spike-waves repeating at a rate of 6 Hz should not be confused with the normal EEG variant known as 6-Hz phantom spike-waves (107).

Myoclonic absences are absence seizures with prominent rhythmic typical 3-Hz spike-and-wave (range is 2.5-4.5 Hz) accompanied by bilateral myoclonic jerks of the shoulders, arms, and legs (rarely face) (53). This seizure phenotype is expressed in EMA, often in conjunction with pure absences (17). Eyelid myoclonia with absences are the hallmark of Jeavon’s syndrome, a form of photosensitive idiopathic epilepsy (104,108). Perioral myoclonia with absences has also been described as a seizure phenotype in idiopathic epilepsy (38). Because all three seizure types have the same EEG correlate (3-Hz spike-wave), only the motor events distinguish these mixed seizures from typical absence and from each other.

Atypical absence seizures are usually associated with the generalized slow spike-and-wave pattern, and are not as specific as nocturnal tonic seizures for identifying LGS, but they are much easier to recognize (52). Atypical absences usually have a gradual onset and termination (typical absences start and end abruptly), longer duration (typical absences usually last 10 seconds), milder impairment of consciousness (patients tend to continue their activity),

FIGURE 10-4. Slow spike-waves during atypical absence. The interictal version is shown in Figure 10-5 below. Other than the slightly more regular appearance of the ictal discharge, the ictal and interictal versions are not easy to distinguish. Source: Adapted from Pedley TA, Mendiratta A, Walczak TS (122):550.

More prominent postictal confusion (postictal recovery of consciousness in typical absences is rapid), and associated motor manifestations (eyelid or perioral myoclonia, loss of postural tone, neck-stiffening, head-nodding, etc) (52). The active phase of ECSWS is frequently associated with atypical absences (in some this is the only seizure type) and cognitive dysfunction, thus mimicking LGS (5,6). Tonic seizures are common in LGS but essentially absent in ECSWS (4—6). Focal motor seizures often occur in ECSWS but are rare in LGS (4). Regardless, EEG is often the only means to distinguish these syndromes (see CSWS pattern). Atypical absences are also common in EMAS (18). Tonic absences have been detected by video EEG recording in some patients with encephalopathic epilepsies (109).

The generalized slow spike-and-wavepattern is usually present in the EEG during atypical absence seizures (Figure 10-4) (52), but is more commonly seen as an apparently interictal pattern (Figure 10-5). Whether ictal or interictal, the slow spike-and-wave pattern consists of 1- to 2.5-Hz bisynchronous sharp - and slow-wave complexes. It also differs from 3-Hz spike-waves in having a more irregular morphology, a variable discharge rate, and a less uniform appearance. A bifrontal or bitemporal voltage maximum is present in almost all cases; voltage asymmetry with shifting laterality is also common. Slow spike-waves often coexist with multifocal spikes in the EEG of patients with LGS (4). Sleep modifies the appearance of slow spike-waves and multifocal spikes; in LGS, the slow spike-waves may become more continuous and mimic the CSWS pattern of ECSWS or create a discontinuous pattern sometimes resembling burst-suppression (4).

Continuous spike-waves in slow-wave sleep (CSWS) is the sine qua non of ECSWS, a unique “epilepsy syndrome” that can be diagnosed in the absence of clinical seizures (110). Also known as electrical status epilepticus in sleep (ESES), CSWS is a clinically interictal EEG pattern consisting of bilateral slow (2- to 2.5-Hz) spike-waves that are activated in slow-wave sleep and are present in 85%—100% of stage 3 and 4 sleep epochs (Figure 10-6) (110). Polysomnography, all-night EEG, or video EEG monitoring is necessary to detect CSWS. Similar slow spike-waves (which are not CSWS per se) appear sporadically or in short bursts in the waking EEG of patients with ECSWS. In the non-Landau-Kleffner syndrome form of ECSWS, the spike-waves are maximal over the frontal head regions and associated with cognitive and behavioral disturbances (6). In ECSWS due to Landau-Kleffner syndrome (LKS), the spike-waves arise from the posterior temporal area and are associated with aphasia (Figure 10-25) (5). LKS is likely when the EEG of a child with acquired aphasia shows bitemporal spikes and/or CSWS; the resolution of aphasia with antiepileptic therapy is confirmatory (110). Most (but not all) patients with LKS manifest clinical seizures before or after the onset of aphasia (5). Patients with LKS or non-LKS ECSWS often exhibit focal seizures (temporal lobe seizures in LKS, frontal lobe seizures in non-LKS) and atypical absences (5,6). Both types of ECSWS also have a nonactive and active phase

FIGURE 10-5. Slow spike-waves in the interictal EEG. Despite the long duration of the discharge, there is no clinical evidence of an alteration of consciousness. Source: Adapted from Pedley TA, Mendiratta A, Walczak TS (122):549.


FIGURE 10-6. Conti nuous spike-waves in slow-wave sleep (CSWS). To qualify as CSWS, bilateral slow (2-2.5 Hz) spike-waves must be present in 85-100% of stage 3 and 4 NREM sleep epochs. Source: Adapted from Pedley TA, Mendiratta A, Walczak TS (122):558.


(5—6,110). In the nonactive phase, focal seizures occur infrequently; the wake EEG shows focal slow waves, spikes, or spike-waves (temporoparietal in LKS, frontal in non-LKS), and infrequent bursts of bilateral slow spike-waves (absent in many LKS and some non-LKS); and the sleep EEG shows more slow spike-waves (although present in <85% of slow-wave sleep epochs) and attenuated or absent sleep spindles in the non-LKS type. In the active phase, focal seizures are more frequent, and atypical absences and atonic seizures occur (with or without ictal EEG correlates); the wake EEG changes of the nonactive phase are enhanced; and the sleep EEG shows definite CSWS (slow spike-waves in >85% of slow-wave sleep epochs) (5—6,110).

Seizures with Brief Symmetric Bilateral Movements

Seizures that manifest as sudden brief symmetric or nearly symmetric bilateral body movements include epileptic spasms, tonic seizures, atonic seizures, and bilateral epileptic myoclonus (54—57). Epileptic spasms are usually more sustained (0.5—3 seconds) than myoclonus (<0.2 seconds), but not as sustained as tonic or atonic seizures (>5 seconds) (111,112). Video EEG with surface electromyography is often necessary to accurately diagnose these seizures and identify the epilepsy syndrome (94,112).

Epileptic spasm (formerly “infantile spasm”) is a specific seizure type seen in infants with WS (54,113). It is now clear that epileptic spasms can occur in other age groups or syndromes (e. g., OS, LGS) (114—116). The spasm is a sudden, brief, bilateral axial muscular contraction. The type of muscles (flexors, extensors, mixed) and their location (neck, chest, shoulders, proximal limbs, or combinations thereof) determine the clinical appearance of the spasm (54,113). Classical forms of epileptic spasm include jackknife seizures (contraction of abdominal flexors bending the trunk at the waist), salaam seizures (jackknife seizures plus abduction or adduction of the arms), head-nodding, and shoulder-shrugging (54). Spasms can also manifest as subtle behavioral arrest, ocular deviations, or changes in respiration or heart rate. The frequency of spasms varies from a few times a day to several hundreds a day, and spasms usually occur in clusters (usually 10—20 spasms) (54). The jerks are usually symmetric; asymmetric spasms suggest cortical brain injury and structural lesions (113).

A high-voltage slow wave followed by electro decrement is the most common EEG correlate of epileptic spasms (Figure 10-7) (54). The slow wave correlates with the spasm, and the electrodecrement may be a postictal phenomenon. Recording a diamond-shaped burst of electromyogram (EMG) activity (0.5—3.0 seconds in duration) during the spasm increases confidence in the diagnosis (112). This can be achieved in most patients by recording deltoid EMG with surface electrodes during EEG acquisition (EEG-EMG polygraphy). Another ictal EEG

FIGURE 10-7. High-voltage slow wave during an epileptic spasm. The slow wave correlates with the spasm (arrow). In this particular case, the slow wave is followed by electrodecrement. Source: Adapted from Fisch BJ (107):315.

Correlate of epileptic spasm is low-voltage fast activity. The tendency of epileptic spasms to occur in clusters can also help distinguish them from other causes of brief bilateral symmetric jerks (54). In some patients, focal spikes are present before, during, or after a cluster of spasms; in others, focal seizures lead the cluster of spasms (117,118). Therefore, in a subset of patients, focal interictal or ictal activity is involved in driving the spasms or in initiating the cluster of spasms (113,117,118).

Hypsarrhythmia is a distinctive, high-voltage, interictal EEG pattern that is seen in infants with WS (Figure 10-8)

(3). Although classic for WS, it is not present in the EEG of some infants with epileptic spasm (119). In hypsarrhyth-mia, the EEG background activity is completely replaced by a disorganized pattern of irregular high-voltage spike, theta, and delta activity (54). The discharges are usually bilateral and can be symmetric or asymmetric; pronounced asymmetry suggests a gross cortical malformation (e. g., hemimegalencephaly). Modified hypsarrhythmia pertains to the variants of hypsarrhythmia, including hypsarrhythmia

FIGURE 10-8. Hypsarrhythmia in the interictal EEG. The normal background features are lost and are replaced by a disorganized pattern of irregular high-voltage spike, theta, and delta activity. Source: Adapted from Fisch BJ (107):313.

With increased interhemispheric synchrony (which may be a result of maturation of transcallosal pathways), asymmetric hypsarrhythmia (persistent voltage asymmetry), rapid hyp-sarrhythmia variant (which may be a harbinger of paroxysmal fast activity), and hypsarrhythmia with intermittent attenuation (recurrent episodes of generalized, regional, or focal attenuation lasting 2—10 seconds) (54). The last variant, which is analogous to the burst-suppression of OS (see below), is often associated with cerebral malformations (e. g., schizencephaly, Aicardi syndrome, hemimegalen-cephaly) (113). Sleep modifies the appearance of hypsarrhythmia (see “Activation. . .”) (113).

A burst-suppression pattern and seizures in the first 3 months of life suggest EME or OS (Figure 10-9) (1,2). As a rule, this EEG pattern is encountered during sleep in EME and during all states in OS. Tonic seizures predominate in OS, and myoclonus is the main seizure type in EME. However, these two syndromes share many common features and the boundary between them is not always clear (120).

Tonic seizures are the most characteristic seizures in LGS (55,121). Patients with WS and OS can also manifest tonic seizures (55,120). The appearance of tonic seizures in the course of EMA or EMAS has been considered a poor prognostic sign (17,18). The lack of tonic seizures in ECSWS, MFSI, DS, and MEND helps distinguish these syndromes from LGS (5—9,4). Tonic seizures consist of sustained (5- to 20-second) bilateral (often symmetric) contractions of axial and proximal limb muscles resulting in face, jaw, or neck rigidity, shoulder elevation, or back stiffening (55,121). Hip flexor spasm may precipitate a fall and laryngeal spasm may produce a high-pitched cry. Tachycardia, mydriasis, flushing, and other autonomic changes also occur. Brief (0.5- to 0.8-second) tonic seizures, called axial spasms, are difficult to distinguish from epileptic spasms (55). Tonic seizures that are subtle (e. g., eye deviation) or that occur only in sleep are easily overlooked. Video EEG monitoring is often necessary to diagnose tonic seizures (55,92).

FIGURE 10-10. Paroxysmal fast activity during a tonic seizure. This is a burst of 10-25 Hz activity (15 Hz in this case). Note the initial rapid buildup with the discharge reaching a peak within the first second. Source: Adapted from Tatum WO, Farrell K (124):322.

Paroxysmal fast activity (PFA) is the most common ictal correlate of tonic seizures (Figure 10-10). This is a burst of bisynchronous, 10- to 25-Hz, low - to medium-amplitude activity with a bifrontal or central and parasagittal voltage maximum (121,122). The PFA amplitude reaches a peak within 1 second of onset and fluctuates thereafter. Slow spike-waves may lead or trail the PFA. Diffuse attenuation with or without PFA may also occur during tonic seizures (121—123). Tonic seizures are usually associated with an electromyographic interference pattern in the EEG recording, as are voluntary muscle contractions (123). Postictally, bilateral slowing may be present for a few seconds. Interictal PFA is more common than ictal PFA; nearly all patients with LGS have interictal PFA in sleep (Figure 10-11). Studies have shown that tonic muscle activity is common but subtle (e. g., brief eye movements, paraspinal EMG bursts) during so-called “interictal” PFA (123).

FIGURE 10-9. Burst-suppression pattern in a neonate with early myoclonic encephalopathy. The bursts are associated with myoclonic jerks which are evident in the electromyogram channel (see channel labeled “limbs"). Source: Adapted from Clancy RR, Mizrahi EM (233):505.


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