The Spectrum of Epilepsies Associated with Generalized Spike-and-Wave Patterns

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Chapter 10 The Spectrum of Epilepsies Associated with Generalized Spike-and-Wave Patterns

Introduction

The generic term epilepsy embraces a particular group of paroxysmal brain disorders, but by itself is of limited clinical value. Intense clinical and genetic research over the last few decades has identified a large number of well-defined epilepsy syndromes with different clinical, EEG, neuropsychological, and neuroimaging profiles, natural history and prognosis, and conditions that ultimately require different management. There is evidence that early treatment can reduce the risk of seizure recurrence,1 and its efficacy depends largely on the appropriate drug choice in relation to the particular clinical syndrome.2 Therefore, identification of the particular form or syndrome is the cornerstone of meaningful, optimal management of the individual patient.2,3

THE INTERNATIONAL CLASSIFICATION OF EPILEPTIC SEIZURES AND SYNDROMES: BASIC CONCEPTS AND DEFINITIONS

Apart from assisting patients’ clinical management and prognostication, recognition of different syndromes enables effective communication between clinicians and clinical and genetic research. The current classification of epileptic seizures4 and epilepsies5 of the International League Against Epilepsy (ILAE) and also the new ILAE proposal6,7 are essentially organized around two dichotomies in terms of their topography between generalized and localized (partial or focal) and in terms of their etiology between idiopathic epilepsies (genetically determined) and symptomatic epilepsies (due to cerebral pathology). The ILAE classification is currently under revision, but is still valid. Presumed symptomatic epilepsies, in which no certain etiology can be demonstrated, are sometimes referred to as “cryptogenic.” Generalized epilepsies manifest with generalized seizures, whose first ictal clinical changes reflect involvement of both hemispheres and in which initial EEG changes are bilateral, as, for example, the typical absences (TA) that are associated with 3-Hz GSW (Figure 10-1). Localization-related epilepsies (also called focal or partial) manifest with focal (or partial) seizures, in which the initial activation of a group of neurons is limited to a part of one hemisphere5; the EEG shows focal abnormalities, but GSW discharges may occur as a result of secondary bilateral synchrony (SBS).8

image

Figure 10–1 Generalized spike-and-wave discharges in patients with idiopathic and symptomatic generalized absence epilepsies.

Reprinted with permission from Panayiotopoulos CP. A Clinical Guide to Epileptic Syndromes and Their Treatment. 2nd ed. London: Springer; 2007.

CONVENTIONS AND LIMITATIONS OF THE ILAE CLASSIFICATION SYSTEM AND SYNDROMIC DIAGNOSIS IN CLINICAL PRACTICE

Identification of the seizure type(s) is the quintessential element of an epileptic syndrome and the first step for its definition.2 However, it is not always straightforward, particularly on historical evidence (accounts of patients and witnesses) only. TA in idiopathic generalized epilepsy (IGE), for example, may share some principal clinical features with limbic complex partial seizures (CPS) (such as unresponsiveness and automatisms), and one must turn to either their onset (presence or absence of aura) or immediately post-termination (presence or absence of confusion) to make an educated clinical hypothesis. Interictal EEG studies will assist diagnosis by showing focal epileptiform activity or GSW, but even so the rate of misdiagnosis is high with the generalized epilepsies being erroneously diagnosed as focal rather than the converse.9,10 Important reasons for such misdiagnosis include usually short-lived “focal” clinical symptoms and signs, such as unilateral jerks and rotatory seizures in juvenile myoclonic epilepsy (JME),1013 versive absences,14 and in addition, well-recognized asymmetrical or focal interictal EEG changes.11,15,16 Such electroclinical focalities within the generalized seizures are interpretable within the model of generalized corticoreticular epilepsy, but stand uncomfortably within the inflexible and simplified generalized versus focal dichotomy of the ILAE seizure and syndrome classification system.17 Focal epilepsies may (also) present with rapidly generalized convulsions and infrequently with interictal GSW discharges as in SBS.

In this chapter, we will discuss primarily the various syndromes of IGE, whose GSW is the defining electrographic trait. From the brief foreword, it follows that GSW discharges do not always indicate IGE or indeed generalized epilepsies, and Table 10-1 includes all the main epilepsies and syndromes that are associated with 3–4 Hz GSW. The interictal EEG alone cannot be used for establishing or excluding the diagnosis of epilepsy (including IGEs) or provide oversimplified clues for reliable syndromic diagnosis; this can only be based on a comprehensive electroclinical synthesis for the individual patient, without which EEG interpretation may be completely meaningless and even misleading.2,17

TABLE 10–1 Epilepsy Syndromes and Conditions Associated with GSW Discharges

  Seizures Types Interictal EEG
IGE TA, MS, GTCS, rarely tonic Normal background 2.5–4 Hz regular GSW, nonlocalizing focal
Absence syndromes TA, late GTCS, rarely MS (in JAE)
CAE, JAE
Phantom TA Brief TA, GTCS; frequent ASE
Myoclonic syndromes   3-6 Hz irregular GPSW with fragmentations
BMEI MS
JME MS, GTCS, TA (35%)
EMA/PMA TA, GTCS, rarely MS and absence status epilepticus
GTCS only GTCS GSW at 2.5–6Hz, regular or irregular ± fragmentations
Mixed/unclassified TA, MS, GTCS, tonicabsences
Generalized Cryptogenic/Symptomatic Epilepsies

Focal Symptomatic/Cryptogenic Epilepsies Various syndromes of lobar (mainly frontal and temporal lobe) epilepsies Simple or complex partial with semiology reflecting the lobe of origin or propagation Focal slowing/spikes; may show secondary bilateral synchrony Focal Idiopathic Epilepsies Benign rolandic epilepsy Rolandic seizures, rare brief TA Normal background, multifocal, rolandic or occipital spikes, GSW in both rolandic and Panayiotopoulos Syndrome Panayiotopoulos syndrome Autonomic seizures ± eye deviation and motor symptoms. Rolandic and autonomic seizures may coexist in mixed phenotypes; rare TA Epileptic encephalopathy with CSWS Generalized and partial seizures mainly during sleep and typical or atypical absences during awake Continuous SW activity during nnn-RFM sleep (electrical status epilepticus) De Novo Absence-like Status Unremarkable background without interictal spikes; CSW during status   None

IGE

Notwithstanding the aforementioned diagnostic limitations and pitfalls, GSW discharges are the characteristic EEG building blocks of all seizures in IGE that include typical absences (TA), myoclonic seizures (MS), and GTCS. EEG background activity is normal. IGE comprise a group of genetically determined epilepsies, unrelated to any structural brain pathology, and associated with normal neurological and neuropsychological status. Suitable AED include valproic acid VPA (arguably the first choice), clonazepam (CLZ), ethosuximide (ESX), lamotrigine (LTG), levetiracetam (LEV), topiramate (TPM), and zonisamide (ZNS) (with specific indications against main seizure types),1820 whereas carbamazepine (CBZ), oxcarbazepine (OCBZ), vigabatrin (VGB), tiagabine (TGB), gabapentin (GBP), pregabalin (PGB), and phenytoin (PHT) are generally contraindicated, as they can cause seizure worsening.2,2023

EPILEPSY WITH MYOCLONIC-ASTATIC SEIZURES (MAE)2,27,28

MAE is a genetically determined (some patients fall into the spectrum of generalized epilepsy with febrile seizures plus [GEFS+] nonlesional generalized epilepsy that affects previously normal children between 2 and 5 years of age, but has variable course ranging from good responsiveness to treatment, with normal cognitive functions and even remission, to nonprogressive epileptic encephalopathy with seizure intractability and cognitive impairment. Therefore it clinically overlaps with both IGE (see also the 2001 ILAE proposal, where it features within the IGE6) and cryptogenic/symptomatic generalized epilepsies (see relevant following section). Prevalence is around 1to 2% of all childhood epilepsies, onset ranges between 7 months and 6 years, peaking between 2 and 4 years, and two-thirds of patients are boys. Myoclonic-astatic seizures are the defining seizure symptom and consist of a myoclonic jerk immediately followed by loss of muscle tone. Either component can cause falls, head nodding, or bending of the knees. More than half of patients have brief absences, often with myoclonic jerks, facial myoclonias, and atonia. In two-thirds of patients, febrile and nonfebrile GTCS precede myoclonic astatic seizures by several months. Episodes of absence status may occur, usually introduced by inappropriate treatment such as CBZ; they are frequent in the cryptogenic form. Myoclonic-atonic seizures are associated with discharges of irregular GSW or polyspike waves at >2.5 Hz, with the atonic part of the seizure corresponding to the slow wave of the GSW complex and being associated with diffuse electromyography (EMG) paucity. VPA at high doses is the first drug of choice, combined if needed with LEV, ESX, CLZ, or sulthiame. MAE shares many clinical features with cryptogenic Lennox-Gastaut syndrome, particularly its myoclonic form.29

CHILDHOOD ABSENCE EPILEPSY (CAE)2,3032

This is the prototype syndrome of idiopathic absence epilepsy in childhood with prevalence of about 10% of childhood epilepsies and incidence about 7/100,000 of children with nonfebrile seizures. In contrast to BMEI and MAE, CAE predominately affects girls (two-thirds) between 4 and 9 to 10 years, with a peak at 5 to 6 years. There is probable linkage with chromosomes 1p, 8q24, 5q31.1, and 19p13.2.

TA are associated with severe impairment of consciousness (unresponsiveness and interruption of ongoing activities) and are usually multiple per day, hence the term pyknolepsy. They have abrupt onset and termination and last from 4 to 20 sec (mainly around 10 sec). Automatisms occur in two-thirds of the seizures but are not stereotyped. Mild myoclonic elements of eyes, eyebrows, and eyelids may feature at the onset of an absence. More severe and sustained myoclonic jerks of facial ro limb muscles indicate other IGEs. TA are nearly always provoked by hyperventilation, even in the clinic. Other types of seizures are incompatible with CAE except for febrile seizures and solitary or infrequent GTCS (usually in adolescence after absences have remitted).

The interictal EEG may show characteristic rhythmic posterior delta activity and brief, usually regular GSW. Monotherapy with VPA ESX, or LTG is successful in most cases, and remission occurs before the age of 12 years with less than 10% of patients developing infrequent GTCS in adolescence or adult life.33 As in all IGEs, VGB, TGB, CBZ, and GBP can produce worsening of absences. CAE is not the only IGE absence syndrome in the first decade of life, and meticulous differentiation from other absence syndromes of worse prognosis is clinically important.

EPILEPSY WITH MYOCLONIC ABSENCES (E-MA)34,35

This rare type of generalized epilepsy was described by Tassinari36,37 and is characterized by myoclonic absences that are associated with 3-Hz regular GSW activity like the typical absences in childhood or juvenile absence epilepsies, but also with bilateral myoclonic jerks of the arms and legs that are time locked to the spike component of the ictal discharge and have a superimposed tonic contraction resulting in a characteristic stepwise upward abduction of the arms. Other seizure types may include GTCS, clonic seizures, and rarely simple absences without myoclonus. It affects less than 1% of children with epileptic disorders, mostly boys (70%), between 5 months and 13 years (median 7 years). Etiology is heterogeneous, and only one-third of patients are of normal neurological and mental state (idiopathic form). These retain normal EEG background. The others are symptomatic, with learning difficulties manifested before or after seizure onset. Early control of absences may secure normal development. The main task of differential diagnosis here is to distinguish between idiopathic and symptomatic cases (see later discussion).

JUVENILE MYOCLONIC EPILEPSY (JME)2,4144

JME is the quintessence of myoclonic IGE and affects 8 to 10% of patients with epilepsies without any sex difference. Inheritance is probably complex and polygenic with susceptibility loci in chromosomes 6p11-12 (EJM1) and 15q14 (EJM2). MS are the defining seizure, as they occur in all patients, typically on awakening. They start between 8 to 26 years (with peak in early teens), may occur in volleys preceding a GTCS, and are typically activated by sleep deprivation, awakening, fatigue and mental stress and excitement, and excessive alcohol intake. Triggers include photosensitivity (present in one-third of patients) and less frequently movements or intension of movement (praxis-induced), whereas reading-induced jerks are rare but well documented. TA occur in around one-third of patients between 5 and 16 years of age (peak at 10 years) and are usually mild and inconspicuous, therefore detectable mainly by video EEG. The combination of more prolonged and frequent TA and random MS favor. JAE rather than JME. GTCS occur in nearly all patients, usually months after onset of myoclonic jerks. In untreated patients, interictal EEG is usually abnormal, with generalized discharges of irregular 3- to 6-Hz spike/polyspike waves. Focal abnormalities occur in 30 to 40% of patients. A normal EEG in a patient suspected of having JME should prompt an EEG during sleep and on awakening. MS are associated with generalized, frequently asymmetrical, multiple spikes, and TA are brief with 3- to 6-Hz GSW and multiple spikes and irregular intradischarge frequency with fragmentations. Susceptibility to all seizures is probably permanent, although patients show improvement after the age of 40. Despite appropriate treatment, seizures become intractable in about 20% of patients, with those who have all three types of seizures being more likely to show pharmacoresistance. Misdiagnosis is common resulting in avoidable morbidity. Factors responsible for misdiagnosis include lack of familiarity with JME, failure to elicit a history of jerks, misinterpretation of absences or jerks as focal seizures, and high prevalence of focal EEG abnormalities. An uncertain number of patients with MS only may escape diagnosis, as they do not seek medical advice. Optimal management includes appropriate education and advice, focusing mainly on seizure precipitants. VPA is the most effective AED but with significant concerns regarding women. Control and open studies indicate that LEV is probably one of the most promising new AEDs. Clonazepam is effective for persistent myoclonic jerks, but may deprive patients from the early morning volley that alerts for an impending GTCS.45

IGE WITH GTCS ONLY (IGE/GTCS)2,46,47

By definition, this syndrome manifests with GTCS only without TA and MS throughout the history on clinical and EEG basis, but many accept rare MS or brief TA. Therefore, the true prevalence is uncertain. EEG-wise, the interictal occurrence of GSW discharges should also be a diagnostic prerequisite. The age at onset ranges from 6 to 47 years with a peak around 16 to 17 years. GTCS can occur on awakening (usual pattern), during relaxation or leisure, during sleep, and randomly. Seizure precipitants include sleep deprivation, fatigue, and excessive alcohol consumption, whereas about 15% show EEG photosensitivity. IGE with GTCS on awakening is probably a lifelong disorder with high rate of relapse on withdrawal of treatment. GTCS become rarer and more random with time, either as a result of the evolution of the disease or drug-induced modifications, and precipitants less potent. Differential diagnosis includes JME (if one accepts rare MS), with which shares the typical circadian distribution, and the syndrome of phantom absences (if one accepts TA). Differentiation from cryptogenic generalized and focal epilepsies with secondarily GTCS or secondary bilateral synchrony employs clinical and EEG criteria, and patients with poorly understood nocturnal seizures and without clear EEG indicators should not be included here. CBZ, OXC, PB, and PHT can be helpful in some patients provided that TA and MS are not part of the clinical picture. If these seizures also occur, only VPA, LEV, TPM, and LTG are recommended.

EYELID MYOCLONIA WITH ABSENCES (ELMA OR JEAVONS SYNDROME)2,4952

This is the most distinctive reflex IGE syndrome, characterized by (a) eyelid myoclonia with and without absences; (b) eye closure-induced seizures, EEG paroxysms, or both; and (c) photosensitivity. The age at onset ranges between 2 and 14 years (with peak at 6 to 8 years), and its prevalence is around 3% of adults with epileptic disorders and 13% of those with absence IGE syndromes. There is a twofold female preponderance. Eyelid myoclonia, the clinical hallmark of this syndrome, includes brief but marked, episodic jerking of the eyelids, the eyebrows, and often of the eyeballs and head, which may be time locked to GSW and polyspike discharges, and may or may not be associated with clinically apparent impairment of awareness (eyelid myoclonia with or without absences). These seizures are brief (3 to 6 sec) and occur mainly after eye closure, many times per day, and especially on awakening. Spontaneous or photically induced GTCS are probably inevitable in the long term and are easily provoked by sleep deprivation, alcohol, and inappropriate AED modifications. Myoclonic jerks of the limbs may occur. Absence Status Epilepticus (ASE) occurs in one-fifth of patients with prominent but discontinuous eyelid myoclonia and usually mild impairment of consciousness. Video-EEG is important for the diagnosis. Photoparoxysmal responses occur in all untreated young patients, but photosensitivity declines in adulthood. ELMA is particularly resistant to AED treatment (VPA, LEV, and CLZ are the main choices), and prognosis is guarded. Despite the sometimes extreme photosensitivity, self-induction is rare.

THE SYNDROME OF “DE NOVO ABSENCE-LIKE STATUS OF LATE ONSET”

De novo absence-like status is a form of nonconvulsive status epilepticus that occurs for the first time in nonepileptic patients of middle or old age as a result of an exogenous trigger and bears electroclinical resemblance to idiopathic absence status epilepticus.5961 Distinction from idiopathic ASE is clinically important, as biological substrates and by implication management and prognosis are different. Patients with idiopathic ASE need appropriate prophylactic treatment with AED; for those with de novo absence-like status, elimination of the offending factor may suffice, and the overall prognosis is excellent with little risk for recurrence.60 Triggers include acute withdrawal of chronic psychotropic medication (mainly benzodiazepines60,62), but also tricyclic antidepressants,63 major neuroleptics and lithium, acute or chronic alcoholism and metabolic imbalance, and toxic or other pharmacological agents.60 However, relying only on apparent triggers may be misleading, and one has to bear in mind that in some patients with IGE, episodes of true absence status may be precipitated after discontinuation of a benzodiazepine (taken as antiepileptic medication such as clobazam) or moderate alcohol consumption. The underlying pathophysiology of de novo absence-like status is uncertain, and therefore its nosological taxonomy has been controversial. It appears that the triggering or facilitating potential of these factors becomes particularly effective when acting on brains compromised already by vascular or degenerative processes, as is more frequently the case in elderly people. A contribution of a genetically determined liability cannot be excluded.

Other Epileptic Syndromes and Conditions Associated with GSW Activity

CRYPTOGENIC/SYMPTOMATIC GENERALIZED EPILEPTIC SYNDROMES AND EPILEPTIC ENCEPHALOPATHIES

Common characteristics that distinguish this group of epilepsies from IGE include varying etiology and multiple seizure types, frequent developmental delay, and a general reluctance to respond to treatment. From the EEG viewpoint, background is usually abnormal, and GSW discharges are slower, 2.5 Hz or less. Absences here are associated with slow GSW and milder, with not always sharp onset and termination, and are called atypical absence seizures.

Ring Chromosome 20 Syndrome (r20S)

This rare chromosomal syndrome is characterized by variable psychomotor delay, behavioral disturbance, and frequent episodes of nonconvulsive status epilepticus (NCSE), but there are no dysmorphisms, and this may delay the diagnosis. Some patients may have normal intelligence. Focal seizures with affective symptomatology (usually terror), frontal discharges, and atypical absences with 2- to 3-Hz bilateral rhythmic slow activity and some autonomic features66 may be part of the clinical picture, which becomes typical after the age of 8 years.67 As a rule, seizures are resistant to treatment. Interictal EEG may be normal or show bilateral frontocentral theta activity. The NCSE in r20S is mainly an absence state with an associated myoclonic component. Differentiation from IGE may be difficult in patients with regular spike-wave activity, mild retardation or normal intellect, and normal or almost normal interictal EEG. Middle-aged patients may be misdiagnosed as de novo absence-like status if previous episodes are not identified, and frontal lobe status should also be considered in view of the affective and autonomic symptomatology.

Severe Myoclonic Epilepsy in Infancy—Dravet Syndrome

First described by Dravet in 1978,68 this syndrome is a genetically determined channelopathy69 and a syndromic phenotype that can occur within the frame of GEFS+.70 The first seizure is typically triggered by fever during infancy and is prolonged unilateral or generalized clonic or tonic-clonic; other nonfebrile convulsive seizures follow soon. Generalized myoclonic seizures associated with brief 3Hz GSW with polyspikes and segmental myoclonus appear in the 2nd or 3rd year, and atypical absences occur in up to 80 to 90% of the children, either concurrently with the myoclonic seizures or later. Focal and tonic seizures also occur. Episodes of absence status occur in at least 30 to 40% of cases and may persist for hours and even days (obtundation status). Photosensitivity occurs in up to 42% of children and may persist.71

Cryptogenic/Symptomatic Form of Epilepsy with Myoclonic-Astatic Seizures

As opposed to the idiopathic form of MAE (see in IGE section earlier), the cryptogenic variant is characterized by frequent (up to 90% of children) episodes of generalized myoclonic/absence status associated with chaotic EEG with asynchronous SW discharges that resemble hypsarrhythmia,29 tonic seizures during sleep, progressive slowing of the EEG background, and unfavorable outcome. These children continue with seizures, severe cognitive impairment, and behavioral abnormalities, whereas ataxia and motor and linguistic disturbances may emerge. Treatment is similar to the idiopathic form with intravenous benzodiazepines being used for nonconvulsive status epilepticus. In general, myoclonic astatic seizures occur in many childhood epilepsies, particularly epileptic encephalopathies, and differential diagnosis includes benign or progressive myoclonic epilepsies, Dravet syndrome, Lennox-Gastaut syndrome, atypical benign focal epilepsy of childhood, atypical evolutions of rolandic epilepsy, Panayiotopoulos syndrome, and nonepileptic myoclonus of various neurological disorders.

EPILEPTIC ENCEPHALOPATHY WITH CONTINUOUS SPIKE-AND-WAVE DURING SLEEP (CSWS) INCLUDING LANDAU-KLEFFNER SYNDROME (LKS)

This is an age-related and partly reversible childhood disorder characterized by generalized and partial seizures mainly occurring during sleep and typical or atypical absences during awake state, global or selective regression of high cognitive functions, motor impairment. The EEG is characteristic with diffuse or regional spike-wave activity which is nearly continuous and occurs during non-REM sleep.2 There are no tonic seizures, and the kind of neuropsychological impairment relates to the topography of the continuous discharges. CSWS becomes apparent a couple of years after the onset of epilepsy and is associated with seizure worsening including also diurnal episodes of absence status. Seizures and CSWS gradually resolve, but only 25% of the children attain acceptable social and professional levels. In LKS, focal spike-wave activity heavily involves the “speech cortex” and cannot be considered generalized.

IDIOPATHIC FOCAL EPILEPSIES OF CHILDHOOD

Due perhaps to the very nature of “idiopathic focal or system epileptogenesis”, both benign rolandic epilepsy with centrotemporal spikes (BECTS) and Panayiotopoulos syndrome (PS) manifest with bilateral regional or diffuse epileptogenicity, distinctly different to the focal ictogenesis of the symptomatic focal epilepsies.72 GSW discharge may occur, sometimes associated with mild impairment of consciousness (absences). In addition, both BECTS and PS may occasionally evolve into atypical electroclinical forms that include continuous spike-wave during sleep, absences with inhibitory phenomena, and episodes of atypical absence status, with favorable outcome in most children.7378

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