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Generalized epilepsies
Handbook of Clinical Neurology, Vol. 161 (3rd series) Clinical Neurophysiology: Diseases and Disorders K.H. Levin and P. Chauvel, Editors https://doi.org/10.1016/B978-0-444-64142-7.00038-2 Copyright © 2019 Elsevier B.V. All rights reserved
Chapter 1
Generalized epilepsies RENZO GUERRINI*, CARLA MARINI, AND CARMEN BARBA Neuroscience Department, Children’s Hospital A. Meyer-University of Florence, Florence, Italy
Abstract Idiopathic generalized epilepsies (IGE) are characterized by normal background EEG activity and generalized interictal spike-and-wave discharges in the absence of any evidence of brain lesion. Absence epilepsies are the prototypes of IGEs. In childhood and juvenile absence epilepsies, by definition, all patients manifest absence seizures associated with an EEG pattern of generalized spike-wave (GSW) discharges. In juvenile myoclonic epilepsy, myoclonic jerks, usually affecting shoulders and arms bilaterally and appearing upon awakening, are the most characteristic clinical feature. Myoclonic jerks are accompanied on the EEG by generalized spike/polyspike-and-wave (GSW, GPWS) complexes at 3.5–6 Hz. Idiopathic generalized epilepsy with generalized tonic–clonic seizures only is a broad and nonspecific category including all patients with generalized tonic–clonic seizures and an interictal EEG pattern of GSW discharges. Despite the strong heritability and the recent advances in genetic technology, the genetic basis of IGEs remains largely elusive and only in a small minority of patients with classic IGE phenotypes is a monogenic cause identified. Early myoclonic encephalopathy (EME), early infantile encephalopathy with suppression bursts, West syndrome, and Lennox–Gastaut syndrome, once classified among the generalized epilepsies, are now considered to be epileptic encephalopathies. Among them, only Lennox–Gastaut syndrome is characterized by prominent generalized clinical and EEG features.
The International League Against Epilepsy (ILAE) classification of epilepsies and epileptic syndromes (ILAE, 1989) identified syndromes as groups of signs and symptoms that customarily occur in association, in a clinical context that included not just seizure types, but also the clinical background, neurophysiologic and neuroimaging findings, and, often, outcome. According to ictal symptoms, epilepsies were classified as generalized and partial (or focal). Generalized epilepsies were defined as characterized by generalized seizures, bilateral motor manifestations, and generalized interictal and ictal EEG discharges. From an etiological point of view, generalized epilepsies were subdivided into idiopathic, cryptogenetic, and symptomatic. Idiopathic epilepsies were characterized by normal background EEG activity and interictal generalized spike-and-wave (GSW) discharges in the absence of any brain lesion. The term cryptogenic was used to define syndromes that
were presumed to be symptomatic, whose etiology was unknown. Symptomatic epilepsies were considered the expression of a focal or diffuse brain abnormality as demonstrated by clinical history, structural neuroimaging, EEG findings, or biological tests. This etiological classification has been modified through the 2001 (Engel, 2001), 2006 (Engel, 2006), 2010 (Berg et al., 2010), and 2017 (Scheffer et al., 2017) ILAE reports. In particular, the term cryptogenetic has been discouraged in favor of the wording “probably symptomatic” (Engel, 2006), while the concept of symptomatic epilepsies has been stratified into several etiological categories: metabolic, structural, infectious, genetic, immune, and unknown (Berg et al., 2010; Scheffer et al., 2017). An additional new concept has identified most idiopathic generalized epilepsy syndromes as “genetic generalized epilepsies (GGEs)” (Berg et al., 2010), in order to distinguish them from the “secondary” lesional generalized
*Correspondence to: Renzo Guerrini, Neuroscience Department, Children’s Hospital A. Meyer-University of Florence, viale Pieraccini 24, 50139, Florence, Italy. Tel: +39-0555662573, E-mail: [email protected]
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epilepsies, such as Lennox–Gastaut syndrome. An example is represented by the familial epilepsy syndrome initially defined as “generalized epilepsy with febrile seizures plus (GEFS+)” (Scheffer and Berkovic, 1997). GEFS+ is a typically inherited disorder with autosomal dominance and variable penetrance. About one-third of affected family members only have febrile seizures, about one-third develop a few afebrile generalized tonic–clonic seizures in childhood with remission in adolescence, and the remaining one-third may have generalized epilepsies, including childhood absence and myoclonic astatic epilepsy (Camfield and Camfield, 2015). Recently, patients with focal epilepsy have also been described (Myers et al., 2017). Genetic studies of GEFS+ families found SCN1A gene mutations in some. Owing to the possible occurrence of focal seizures and the genetic etiology, the wording “generalized epilepsy with febrile seizures plus” has been changed to “genetic epilepsy with febrile seizures plus” (still GEFS+) (Zhang et al., 2017). However, in 2017, the ILAE Task Force for Classification and Terminology (Scheffer et al., 2017) considered that the term idiopathic generalized epilepsy (IGE) could still be acceptable for four well-characterized epilepsy syndromes: childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and IGE with generalized tonic–clonic seizures only (IGE-TCS).
ABSENCE EPILEPSIES Absence epilepsies are the prototypes of IGEs. Childhood and juvenile forms are recognized in which, by definition, all patients manifest absence seizures associated with an EEG pattern of GSW discharges (ILAE, 1989). Before the ILAE classification introduced the age-related partition of absence seizure syndromes into childhood and juvenile forms, this distinction was only
used in German publications (Janz and Christian, 1957; Doose et al., 1965). Doose, Janz, and colleagues had clearly recognized that absence epilepsy had a first peak of age of onset at 6–7 years, corresponding to the typical CAE, while a second peak was near age 12 years, corresponding to the juvenile form. Thus, JAE typically begins during puberty, between age 10 and 17 years (Wolf, 1992; Obeid, 1994).
Childhood absence epilepsy Childhood absence epilepsy has an estimated incidence of 6.3–8/100,000 in children aged 0–15 years (Loiseau, 1992); it accounts for 2%–12% of patients with epilepsy (Berg et al., 2000) and is definitely age related. Typical absence seizures are sudden and brief, lasting 5–15 s, with periods of loss of awareness with interruption of ongoing activities, followed by immediate and complete recovery (Fig. 1.1A). Although absences were initially described as staring spells, a minority of patients have simple absences with unresponsiveness and interruption of ongoing activity (Penry et al., 1975). Most children exhibit complex absences, with additional clinical phenomena such as automatisms (Fig. 1.1B) with tonic, atonic, or autonomic components (Penry et al., 1975; Holmes et al., 1987). Absences are very frequent, occurring up to 100 times per day. They occur spontaneously but are also influenced by various factors, especially hyperventilation. The age of onset of CAE is between 4 and 10 years with a peak at 5–7 years, and girls are more frequently affected than boys (Penry et al., 1975; Berkovic, 1996). There are no clear-cut boundaries in age of onset, and onset before 3 years or after 10 years has been described (Penry et al., 1975; Cavazzuti, 1980). Most children with CAE exhibit normal developmental skills and normal cognitive functions. However,
Fig. 1.1. (A) A 7-year-old child with CAE. EEG polygraphic recording of a “simple” absence seizure showing a high voltage 3-Hz generalized spike-wave discharge associated with unresponsiveness and irregular breathing. The child moves after the discharge ends (black arrow). (B) A 16-year-old girl with JAE. EEG polygraphic recording of a “complex” absence seizure showing a highvoltage 3–3.5 Hz generalized spike-wave discharge associated with unresponsiveness, oroalimentary, and gestural automatisms (the black arrow indicates chewing artifacts at the left temporal leads).
GENERALIZED EPILEPSIES children with borderline IQ or mild cognitive impairment are not rare. The lowest scores in neuropsychologic tests might be correlated with earlier onset and longer duration of seizures (Sato et al., 1983). CAE has a highly specific EEG pattern consisting of generalized, bilaterally synchronous and symmetrical GSW discharges. These bursts are usually frontocentral dominant; however, in some patients they are restricted to, or maximally expressed in, the occipital regions. The frequency is around 3.0–3.5 Hz at onset and slows to 2.5–3.0 Hz toward the end of the discharge. More irregular discharges of generalized polyspike-and-wave (GPWS), changing rhythm inside a discharge, can also be observed (Sadleir et al., 2009). Discharges arise suddenly from a normal background and the end is less abrupt than onset. Hyperventilation is the most effective activator of the GSW pattern, while photic stimulation precipitates absence seizures in only about 15% of cases (Sadleir et al., 2009). Background EEG activity is usually normal, although some degree of slowing may be seen in up to one-third of patients (Sato et al., 1983; Holmes et al., 1987). Transient focal epileptiform activity such as centrotemporal spikes may occur (Hedstrom and Olsson, 1991; Fig. 1.2). During sleep, spike-and-wave complexes become more fragmented, and bursts of polyspike-andwave activity may appear (Niedermeyer, 1965; Ross et al., 1966; Sato et al., 1983; Fig. 1.2B). The frequency of the complexes may slow to 1.5–2.5 Hz. Both simple and complex absence seizures are associated with bursts of generalized 3-Hz spike-andwave activity, which generally lasts less than 30 s. The general view is that CAE has a good or excellent prognosis. Absences disappear before adulthood in up to 90% of cases with which no other seizure types are associated (Guiwer et al., 2003). If absences persist, TCSs usually appear. Early and late onset (before 4 and after 10 years), initial drug resistance, and photosensitivity are at greater risk of having a less favorable prognosis (Guerrini, 2006).
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Juvenile absence epilepsy Absence seizures are clinically similar to those seen in CAE; however, loss of awareness is less pronounced and attacks have a much lower frequency, usually occurring a few times per day. Tonic–clonic seizures are common in JAE, occurring in 80% of patients, and they begin at the same time or even prior to the onset of absences (Wolf, 1992). Sleep deprivation is the main precipitant. In our experience, absence seizures are at times detected for the first time during an EEG performed after a first tonic–clonic seizure, which has occurred after sleep deprivation. About 16% of patients will also have myoclonic seizures, especially early in the morning (Thomas et al., 2002). On EEG recordings, absences may have a faster rhythm of GSW at 4–5 Hz, especially at the onset of the attack. Background EEG activity is also normal and interictal GSWs are seen. Photosensitivity is rare. Absences tend to disappear over time, but in rare cases they may persist through adult life. Generalized tonic– clonic seizures (GTCSs) are common, even in early adulthood and especially after sleep deprivation; episodes of absence status can occur. Only about 60% of patients have a long-term remission (Trinka et al., 2004).
Juvenile myoclonic epilepsy Juvenile myoclonic epilepsy is estimated to account for 3%–12% of all epilepsies (Thomas et al., 2002). The characteristic clinical feature of JME are myoclonic jerks, usually affecting shoulders and arms bilaterally, but not always symmetrically, usually appearing upon awakening, in the morning. Jerks can sometimes involve muscles in the face or the legs and rarely may cause a sudden fall. The patient is usually aware of such symptoms. Myoclonic jerks are single or repetitive and vary in intensity. Subtle jerks are perceived as an
Fig. 1.2. A 7-year old child with CAE. (A) Polygraphic EEG recording while awake, showing high-voltage 3-Hz generalized spike-wave discharge, followed by bilateral fronto-temporal spikes (black arrow). (B) Sleep recording showing frequent, irregular, SW discharges (black arrowheads) and bilateral fronto-temporal spikes (black arrows).
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internal body electric sensation with no exterior movement; more severe jerks cause objects to be dropped or launched. The age at seizure onset varies between 8 and 26 years, but the great majority of patients exhibit the first manifestations between 12 and 18 years. Males and females are equally affected (Delgado-Escueta et al., 1996). Background EEG activity is normal. There are interictal bursts of frontocentral dominant GSW and GPWS. The frequency of these bursts tends to be more irregular than the typical 3-Hz spike-and-wave bursts and varies between 3 and 5 Hz (Janz, 1955, 1985; Tsuboi, 1977; Delgado-Escueta and Enrile-Bascal, 1984). Polyspikes may occur without the slow wave afterward. Frequently, these bursts are fragmentary in appearance and restricted to the frontal regions. During sleep, the bursts of spike-and-wave and polyspikeand-wave may decrease, particularly during deep slow-wave sleep, and be markedly diminished, or absent, during REM sleep. The characteristic EEG patterns during myoclonic jerks are GPWS complexes or GSW at 3.5–6 Hz (Fig. 1.3). Photosensitivity is found in about 30% of males and 40% of females (Asconape and Penry, 1984; Appleton et al., 2000). Generalized tonic–clonic seizures occur in 90%–95% of patients, more frequently in the morning and often preceded by a crescendo of myoclonic jerks (Delgado-Escueta et al., 1996). Myoclonic seizures and GTCSs may be precipitated by sleep deprivation, awakening, photic stimulation, and excess of alcohol. Infrequent, short absences are reported in 10%–33% of patients, who are unaware of their occurrence
(Thomas et al., 2002). During absences, EEG usually shows irregular 3–4 Hz GSW. It has been suggested that 5%–15% of patients with CAE will evolve into JME (Janz and Christian, 1957; Wirrell et al., 1996). We have not observed such a transition in our cohort. A consensus on JME (Kasteleijn-Nolst Trenite et al., 2013) proposed two sets of criteria for the diagnosis of this syndrome. Class I criteria encompass myoclonic jerks without loss of consciousness exclusively occurring on or after awakening and associated with typical generalized epileptiform EEG abnormalities, with an age of onset between 10 and 25 years. Class II criteria allow the inclusion of myoclonic jerks predominantly occurring after awakening, generalized epileptiform EEG abnormalities, with or without concomitant myoclonic jerks, and a greater time window for age at onset (6–25 years). Juvenile myoclonic epilepsy is described as the prototype of pharmacodependent epilepsies, assuming that treatment will be lifelong (Baruzzi et al., 1988), although about 10% appear to have permanent remission in adolescence (Camfield and Camfield, 2005).
Other possible syndromes with typical absence seizures Absences with a mild clonic component, often manifesting as flickering of the eyelids, are well recognized in CAE and JAE. However, no clear-cut boundaries exist in severity, frequency, and distribution of the jerking component, with the consequence that a confusing nomenclature and several subtypes of absence seizures
Fig. 1.3. Polygraphic EEG recording showing a high-voltage generalized spike (black arrowhead) associated with a myoclonic jerk (black arrow), in a 14-year-old girl with JME. A generalized spike and wave discharge at 2 Hz is detectable after the myoclonic jerk.
GENERALIZED EPILEPSIES and epilepsies have been proposed. Whether or not all proposed syndromes represent distinct clinical and genetic entities is still debated.
EYELID MYOCLONIA WITH ABSENCES The hallmark of eyelid myoclonia with absences (Appleton et al., 1993), initially described as a form of photosensitive epilepsy by Jeavons (1977), is eyelid myoclonia somewhat different from the flickering of the eyelids seen in typical absence epilepsies. Age at onset is between 3 and 7 years. Tonic–clonic seizures are infrequent and usually precipitated by sleep deprivation or photic stimulation. EEG changes associated with eyelid myoclonia are GPWS discharges at 3–5 Hz, following eye closure (Fig. 1.4). It has been suggested that eyelid myoclonia would be, at least in some photosensitive patients, a sort of subconscious eye blinking performed in order to self-induce the related absence component (Binnie et al., 1980). However, the reverse is also possible in that physiologic blinking might act in highly photosensitive individuals as a photic trigger, by virtue of the contrast in brightness it generates, activating as a consequence a cascade of reflex “epileptic” blinking and a microabsence. The whole population of patients exhibiting such seizure type is extremely heterogeneous, varying from otherwise healthy individuals, who share all the characteristics of an idiopathic generalized epilepsy, to patients with severe cognitive impairment and an obviously symptomatic disorder (Guerrini et al., 2005).
Perioral myoclonus with absences It has been proposed that jaw and lip myoclonus, associated with typical absences, represent the distinctive feature of a syndrome (Panayiotopoulos et al., 1995) with onset in childhood or adolescence, a high risk for absence status, and possible subsequent GTCS. However, insufficient evidence has been gathered to consider this clinical phenomenon as a distinct epilepsy syndrome separated from classic CAE or JAE.
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TYPICAL ABSENCE SEIZURES IN SYMPTOMATIC EPILEPSIES
Absence seizures, sometimes typical, may occasionally occur in symptomatic epilepsies, arising as a consequence of a known disorder. Typical absences have been reported following encephalitis, lysosomal storage disorders, and metabolic encephalopathies (Andermann, 1967; Berkovic, 1996). Hypothalamic hamartomas have also been associated with GSW and with absence attacks (Scherman and Abraham, 1963).
ABSENCE EPILEPSY ASSOCIATED WITH NONEPILEPTIC PAROXYSMAL DISORDERS
Absence epilepsies and more broadly IGEs can sometimes co-occur with paroxysmal movement disorders. Families and sporadic patients in which affected individuals have absence epilepsy or paroxysmal movement disorders, or both, have been described (Guerrini et al., 2002; Bing et al., 2005; Suls et al., 2008). Age of onset of absences in some of such patients is usually early, before age 2 years. One recognized cause of early onset absence epilepsy and paroxysmal dyskinesia is the glucose transporter 1 (GLUT1) deficiency syndrome, caused by mutations of the SLC2A1 gene (Suls et al., 2009; Fig. 1.5).
IGE with generalized tonic–clonic seizures only IGE-TCS, previously referred to as grand mal epilepsy (Temkin, 1971), is a broad and nonspecific category including all patients with GTCS and an interictal EEG pattern of GSW discharges. The initial defining feature of IGE-TCS was GTCS predominantly on awakening or in the evening period of relaxation (ILAE, 1989). However, subsequent studies have shown that, in almost half of the patients, seizures do not occur in relation to awakening or relaxation (Reutens and Berkovic, 1995). Some authors have instead proposed to recognize
Fig. 1.4. A 16-year-old girl with eyelid myoclonia with absences. (A) Polygraphic EEG recording showing a GPWS discharge during photic stimulation at 21 Hz at eye closure, associated with eyelid myoclonia. (B) The same 21-Hz photic stimulation does not provoke any response when the eyes are closed throughout.
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Fig. 1.5. Polygraphic EEG recording showing a high-voltage 2.5–3 Hz generalized spike-wave discharge associated with unresponsiveness in a 1-year-old patient with SLC2A1 gene mutation.
two separate entities, depending upon whether GTCSs occur on awakening or not (Unterberger et al., 2001). Age of onset ranges from late childhood to early adulthood, without clear boundaries. Seizures are infrequent in most patients, and often occur in relation to sleep deprivation or excessive alcohol. Some studies have described patients with GTCS immediately preceded by 3-Hz GSW or by an absence seizure (Mayville et al., 2000). The EEG shows normal background and interictal discharges of GSW or GPWS.
In 1989 the ILAE Commission on Classification and Terminology considered epilepsy with myoclonic astatic seizures and epilepsy with myoclonic absences (EMA) to possibly be cryptogenic or symptomatic, due to their less favorable outcome and the co-occurrence of cognitive impairment. Concepts have evolved and at present both syndromes are recognized as IGE phenotypes, at least in some patients.
Myoclonic absences manifest with rhythmic myoclonic jerks of the head, shoulders, and arms, time locked with spike-and-wave discharges, often associated with a background tonic muscle contraction. They usually last from 10 to 60 s and can be easily precipitated by hyperventilation or tend to cluster upon awakening. Frequency, calculated in a selected epilepsy population at the Centre Saint Paul, is around 0.5%–1% of all epilepsies, but the prevalence is probably lower among unselected epilepsies (Bureau and Tassinari, 2005). Myoclonic absences as a seizure type are by no means limited to a homogeneous syndrome in that they have also been described in association with variable etiologies and in different clinical contexts (Guerrini et al., 2005). There is a male preponderance and intellectual disability is present in 45% of patients before the onset of epilepsy (Bureau and Tassinari, 2005). Myoclonic absences are associated with 3-Hz GSW similar to those observed in CAE. The prognosis is variable but resistant cases are encountered much more frequently than in CAE and JAE, from which this syndrome is clearly distinct despite EEG similarities.
Epilepsy with myoclonic absences
Myoclonic astatic epilepsy
EMA is the only syndrome with 3-Hz GSW absences, other than CAE and JAE, which is recognized in the international classification of the generalized epilepsies (ILAE, 1989). EMA is a childhood epilepsy—mean age at onset 7 years—with daily myoclonic absences, and with other infrequent seizure types such as TCS, drop attacks, and atypical absences (Bureau and Tassinari, 2005).
Myoclonic astatic epilepsy epitomizes a spectrum of IGEs with prominent myoclonic seizures, appearing in previously healthy children. It represents about 2% of all childhood epilepsies (Guerrini, 2006). Onset is between 2 and 6 years of age. Myoclonic seizures and atonic falls may be repeated many times daily and are often associated with episodes of nonconvulsive status
OTHER GENERALIZED SYNDROMES TYPICAL OF CHILDHOOD
GENERALIZED EPILEPSIES epilepticus and GTCS. Background EEG activity may be normal at seizure onset, although a characteristic 4- to 7-Hz monomorphic theta activity with diffuse distribution and centroparietal prevalence is often observed. Interictal abnormalities consist of bursts of 2- to 3-Hz GSW and GPWS discharges, sometimes asymmetrical (Doose, 1992). Sleep is accompanied by an increase in discharges. Myoclonic seizures are accompanied by a generalized (poly)spike-and-wave complex, which may be isolated or repeated rhythmically at 3–4 Hz, lasting for 2–6 s (Oguni et al., 1992). Myoclonic jerks, involving mostly the proximal upper limbs, are timelocked to a spike-and-wave complex (Fig. 1.6). The electromyographic (EMG) correlate of each jerk is a burst lasting around 100 ms, followed by a longer (200–500 ms) postmyoclonic silent period. A single jerk or a series of two to three jerks is observed most commonly. Neurophysiologic analysis of myoclonic seizures (Guerrini et al., 2002) showed that spike-and-wave discharges and myoclonic jerks are bilateral and synchronous, thus supporting a thalamocortical origin of myoclonic jerks. The atonic component of seizures is characterized by a rhythmic discharge of (poly)spikeand-slow wave complexes at 3–4 Hz, accompanied by
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EMG inhibition, lasting 60–400 ms, synchronous in the recorded muscles, and time-locked to the onset of the slow wave (Oguni et al., 1992, 1997). Tonic seizures are accompanied by 10- to 15-Hz polyspike discharges lasting as long as the tonic contraction on EMG. Myoclonic status is associated with a very irregular and chaotic EEG with independent spike-and-wave discharges, sometimes resembling hypsarrhythmia (Doose, 1992). Focal, erratic, myoclonic jerks are recorded on distal and facial muscles. They are brief (30–100 ms) and are not time-locked to individual spikes on EEG (Guerrini et al., 2002). Outcome is unpredictable. Remission within a few months or years with normal cognition is possible even after a severe course. About 30% of children experience an epileptic encephalopathy with long-lasting intractability and cognitive impairment (Guerrini, 2006).
Genetic etiology of IGE IGEs have a predominant genetic etiology and current data are in favor of a complex model of inheritance with the interaction of two or more genes (Berkovic and Scheffer, 2001). Data from twin studies show that
Fig. 1.6. A 2-year-old child with EMA. Polygraphic EEG recording showing a high-voltage generalized spike and wave (black arrowhead) associated with a myoclonic–atonic seizure (black arrow).
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monozygous twins concordant for epilepsy have the same IGE subsyndrome and similar EEG patterns (Berkovic et al., 1998). Family studies have estimated the risk of developing epilepsy in close relatives of IGE probands to be between 4% and 10% (Annegers et al., 1982; Marini et al., 2004). The risk is comparable for the subsyndromes of CAE, JAE, and JME (Janz et al., 1992). The risk is higher in siblings and offspring and lower in second-degree relatives (Tsuboi, 1989). Analysis of epilepsy phenotypes in families with several affected family members shows that, usually, relatives also have an IGE, with about 30% phenotypic concordance (affected relatives have the same IGE subsyndrome as the proband), both for absence epilepsies and JME (Marini et al., 2004). In contrast, very few affected relatives of probands with absence epilepsies have JME and vice versa, suggesting that absence epilepsies and JME tend to segregate separately. These findings suggest that, within a polygenic model of inheritance, absence epilepsies are both closely related and genetically distinct from JME. Febrile seizures and GTCS are equally distributed in affected individuals of all IGEs, perhaps representing the expression of a nonspecific susceptibility to seizures. Rare large IGE families, with a predominant autosomal dominant inheritance, have been reported (Cossette et al., 2002; Marini et al., 2003). Other models of inheritance have been suggested for IGEs, including twolocus models and autosomal recessive. The two-locus models would imply two genes, one dominantly and the other recessively inherited or both recessively inherited (Greenberg et al., 1989). Possible autosomal recessive inheritance was observed in consanguineous families (Panayiotopoulos and Obeid, 1989). Rare families with mutations in genes encoding subunits of voltage- or ligand-gated ion channels have been described (Helbig et al., 2008). Genome-wide linkage analyses of large numbers of families with IGEs have shown several loci with putative genes for IGEs (Sander et al., 2000; Durner et al., 2001; Hempelmann et al., 2006). Modern technologies, including high-throughput and targeted next generation sequencing (NGS) using panels of genes and whole exome sequencing (WES), have increased the number of patients undergoing genetic analyses. This process has made genotype–phenotype correlations even more complex and challenging. For instance, novel mutations in the GABRA1 gene, coding for the a1 subunit of the GABAA receptor, originally associated with JME (Cossette et al., 2002) have also been identified in patients with Dravet syndrome or other epileptic encephalopathies (EE) (Carvill et al., 2014; Johannesen et al., 2016; Kodera et al., 2016). Similarly, CACNA1A mutations historically found in patients with
intermittent ataxia, migraine, and generalized epilepsies including CAE are also associated with EE with refractory seizures and cognitive impairment. Such findings give rise to the challenging discussion of whether IGE and EE are discrete entities or might, in some patients, represent a biological continuum in which severity of the disorder might be due to additional genetic variants controlling drug response. Recently WES of an IGE family with eyelid myoclonia with absences uncovered a genomic variant in the RORB gene on chromosome 9q21.13; additional variants were subsequently identified enlarging the screening to sporadic IGE patients (Rudolf et al., 2016). The authors discussed the hypothesis that mutation in the RORB gene might cause IGEs but also highlighted the occurrence of intellectual disability in some of such patients, placing the doubt that mutations in this gene might cause generalized seizures and not the well-known and historically described IGEs. This concept is supported, for instance, by the clinical evidence that also SYNGAP1 gene mutations cause an epilepsy phenotype predominantly represented by childhood onset absences with eyelid myoclonia and tonic–clonic seizures in patients with cognitive and behavior impairment (Klitten et al., 2011; Mignot et al., 2016). Structural genomic variants or copy number variants (CNVs) have increasingly been recognized in the IGEs and, combining the results from several studies, it appears that microdeletions at 15q13.3, 15q11.2, and 16p13.11 are genetic risk factors that can be identified in 3% of patients with IGE, including JME (Helbig et al., 2013). However, these microdeletions also represent genetic risk factors for a broad range of other neurodevelopmental disorders. Patients with IGEs, especially early onset absence epilepsy and myoclonic astatic epilepsy, might carry SLC1A2 or GLUT1 gene mutations (Mullen et al., 2011; Striano et al., 2012). This finding, although rare, has a high relevance with the potential of immediate translation into treatment with the ketogenic diet, and the power to modify disease progression and outcome. In conclusion, despite the strong heritability and the recent advances in genetic technology, the genetic basis of IGEs remains largely elusive. Table 1.1 summarizes current relevant genetic findings concerning IGEs.
Symptomatic generalized epilepsies The ILAE international classification of the epilepsies considered the following four syndromes as symptomatic generalized epilepsies: early myoclonic encephalopathy (EME), early infantile encephalopathy with suppression bursts, West syndrome, and Lennox–Gastaut syndrome
GENERALIZED EPILEPSIES
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Table 1.1 Summary of the genetic defects identified in some IGE patients or families Gene
Locus
Protein
Phenotype
GABRG2 5q31–33 GABAA receptor g2-subunit GABRA1 5q34–35 GABAA receptor a1-subunit CLCN2 3q26 ClC-2 voltage-gated Cl channel EFHC1 6p11–12 Myoclonin1 CACNA1H 16p13.3 T-type Ca2+ channel a1H-subunit CACNB4 2q22–23 Ca2+ channel b4-subunit CACNA1A 19p13 P/Q-type Ca2+ channel a1A-subunit RORB 9q21.13 Transcriptional factors List of loci from genome-wide linkage analyses of small multiplex families 1p, 2q36, 3q26, 5q12-q14, 5q34, 6p21, 8q24, 8p, 9q32–33; 10q25–26, 10p11, 11q13, 13q22–31, 14q23, 15q14, 18q21, 19q13 List of CNVs, risk factors of IGE Microdeletions: 15q13.3, 15q11.2, 16p13.11 Duplication: 1q21.3
CAE and FS JME, CAE CAE, JAE, JME, EMA JME CAE JME, JAE CAE with ataxia Eyelid myoclonia with Ab IGE, CAE, JME
IGE, JME Early onset CAE
CAE, childhood absence epilepsy; EMA, myoclonic–astatic epilepsy; FS, febrile seizures; IGE, idiopathic generalized epilepsy; JAE, juvenile absence epilepsy; JME, juvenile myoclonic epilepsy.
(ILAE, 1989). In 2001 these syndromes were reclassified as epileptic encephalopathies, i.e., conditions in which the epileptic processes themselves are believed to contribute to the disturbance in cerebral function (Engel, 2001). Seizures associated with a suppression burst electroencephalographic pattern are relatively common in the neonatal period, especially in association with hypoxic–ischemic encephalopathy. However, in Ohtahara syndrome and in EME this pattern remains relatively protracted and stable for more than 2 weeks. Both syndromes present with seizures in the first 3 months of life with multiple seizure types. Differentiating between the two syndromes can be difficult but is based on the specific electroclinical pattern (Cross and Guerrini, 2013). Both have an extremely poor prognosis with regard to seizure control and neurodevelopmental outcome; whether more successful treatment of seizures leads to a more optimal developmental outcome has not been fully established (Howell et al., 2015; Pisano et al., 2015). In many patients the underlying etiology is metabolic or structural, although genetic factors are increasingly recognized (Parrini et al., 2017). Infantile spasms are typical in the first year of life, are usually resistant to conventional antiepileptic drugs, and are associated with developmental delay or deterioration. A cumulative incidence of 2.9 per 10,000 live births and an age-specific prevalence of 2.0 per 10,000 in 10-year-old children were observed in the United States (Trevathan et al., 1999). Infantile spasms are etiologically heterogeneous and can be caused by focal structural brain lesions
(for example, in focal cortical dysplasia), extensive bilateral lesions (for example, in tuberous sclerosis), or by genetic conditions causing in turn widespread structural brain changes that can be visible or undetectable by imaging. Infantile spasms that occur as a consequence of localized epileptogenic lesions are to be considered as a focal epilepsy and as such can be eligible for surgical treatment (Barba et al., 2016). The EEG of children with spasms often reveals a hypsarrhythmic pattern, which is characterized by very high-voltage (up to 500 mV) slow waves, irregularly interspersed with spikes and sharp waves that occur randomly in all cortical areas (Guerrini and Pellock, 2012). The abnormal discharges are not synchronous over both hemispheres, so the general appearance is that of a chaotic disorganization of electrogenesis. Hypsarrhythmia is an interictal pattern and is observed mainly while the child is awake. During slow sleep, bursts of more synchronous polyspikes and waves often appear. In West syndrome, spasms, hypsarrhythmia, and cognitive deterioration occur together. However, infantile spasms might occur without the typical EEG or developmental features. Infantile spasms are manifested as clusters of increasing plateau–decreasing intensity brisk (0.5–2.0 s) flexions or extensions of the neck, with abduction or adduction of the upper limbs. Clusters include a few units to several dozens of spasms and are repeated many times per day. After a series, the child is usually exhausted. Asymmetrical spasms are often associated with a lateralized brain lesion (Kramer et al., 1997), although unilateral lesions may cause symmetrical spasms. Lateralized
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motor phenomena, including lateral or upward eye deviation and eyebrow contraction, and abduction of one shoulder, may sometimes constitute the entire series of spasms or initiate a series that will eventually develop into bilateral phenomena. Such lateralized manifestations are usually accompanied by unilateral or asymmetric ictal EEG changes. Other seizure types can coexist. Prognosis depends more on the cause than on treatment. Unfavorable prognostic factors include manifest symptomaticity, early onset (before 3 months), preexisting seizures other than spasms, asymmetrical EEG, and relapse after initial response to treatment (Guerrini, 2006). Adequate resolution requires the cessation of clinical spasms and normalization of the EEG (Pellock et al., 2010). Good prognostic indicators include cryptogenicity, normal findings on brain magnetic resonance imaging (Saltik et al., 2002), typical hypsarrhythmia, rapid response to treatment, and no regression after onset of spasms or its short duration (Kivity et al., 2004). Lennox–Gastaut syndrome is characterized by brief tonic and atonic seizures, atypical absences, and a generalized interictal EEG pattern of spike-and-slow wave discharges. It accounts for 2.9% of all childhood epilepsies (Berg et al., 2000). Incidence peaks between 3 and 5 years of age. About 30% of cases occur in previously healthy children; most result from neuronal migration disorders and hypoxic brain damage. About 40% of children have previous infantile spasms (Guerrini, 2006). The core seizure types of the syndrome, including tonic, atonic seizures, atypical absences, and episodes of nonconvulsive status, are not always present at onset, nor is the interictal EEG pattern of slow spikeand-wave. Some authors consider the presence of fast (10 Hz) rhythms associated with tonic seizures or occurring with minimal manifestations, especially during NREM sleep, to be an essential diagnostic criterion (Beaumanoir, 1985; Genton et al., 2000). Tonic seizures are particularly frequent during sleep. Patients who have tonic and atonic seizures when they are awake can violently collapse. Atypical absences might translate into nonconvulsive status, which can worsen cognitive deterioration. The classic EEG feature of Lennox–Gastaut syndrome is the slow spike-and-wave pattern, often repeated in bilaterally synchronous complexes at 1–2 Hz. Although slow spike-and-wave discharges are often associated with staring, confusion, or, at times, with an atonic fall, they can be interictal in many cases. Generalized bursts of polyspikes or fast rhythms (>10 Hz), also called generalized paroxysmal fast activity, are recorded during slow sleep, lasting from a few seconds to 15 s and recurring at relatively brief intervals (Blume et al., 1973). They occur as an interictal manifestation or are accompanied by a graded range of clinical
manifestations, ranging from opening and upward deviation of the eyes, brief apnea or a mild EMG axial contraction to a typical tonic seizure. Sleep EEG recordings may be necessary to elicit their presence (Arzimanoglou et al., 2009). About 80% of patients continue to have seizures later in life, with symptomatic origin and early onset having the poorest outcome. Cognitive and psychiatric impairment are frequent. Long-term follow-up reports mortality rates of up to 17% (Guerrini, 2006).
CONCLUSIONS IGEs are the most common group of epilepsies in children and adolescents. IGE syndromes are defined by distinct age at onset, seizure types and characteristic EEG abnormalities, without structural brain lesions and with normal developmental skills. Most IGEs are classified among the pharmacosensitive epilepsies in which appropriate drug treatment leads to seizure control, followed after a few years by spontaneous remission. Despite the strong heritability and the recent advances in molecular genetics, the genetic bases of IGEs remain largely elusive and only in a small minority of patients with classic IGE phenotypes is a monogenic cause identified.
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Obeid T (1994). Clinical and genetic aspects of juvenile absence epilepsy. J Neurol 241: 487–491. Oguni H, Fukuyama Y, Imaizumi Y et al. (1992). Video-EEG analysis of drop seizures in myoclonic astatic epilepsy of early childhood (Doose syndrome). Epilepsia 33: 805–813. Oguni H, Uehara T, Imai K et al. (1997). Atonic epileptic drop attacks associated with generalized spike-and-slow wave complexes: video-polygraphic study in two patients. Epilepsia 38: 813–818. Panayiotopoulos CP, Obeid T (1989). Juvenile myoclonic epilepsy: an autosomal recessive disease. Ann Neurol 25: 440–443. Panayiotopoulos CP, Ferrie CD, Giannakodimos S et al. (1995). Perioral myoclonia with absences. In: JS Duncan, CP Panayiotopoulos (Eds.), Typical absences and related epileptic syndromes, Churchill Communications, London, pp. 221–230. Parrini E, Marini C, Mei D et al. (2017). Diagnostic targeted resequencing in 349 patients with drug-resistant pediatric epilepsies identifies causative mutations in 30 different genes. Hum Mutat 38: 216–225. Pellock JM, Hrachovy R, Shinnar S et al. (2010). Infantile spasms: a U.S. consensus report. Epilepsia 51: 2175–2189. Penry JK, Porter RJ, Dreifuss FE (1975). Simultaneous recording of absence seizures with video tape and electroencephalography a study of 374 seizures in 48 patients. Brain 98: 427–440. Pisano T, Numis AL, Heavin SB et al. (2015). Early and effective treatment of KCNQ2 encephalopathy. Epilepsia 56: 685–691. Reutens DC, Berkovic SF (1995). Idiopathic generalized epilepsy of adolescence: are the syndromes clinically distinct? Neurology 45: 1469–1476. Ross JJ, Johnson LC, Walter R (1966). Spike and wave discharges during stages of sleep. Arch Neurol 14: 399–407. Rudolf G, Lesca G, Mehrjouy MM et al. (2016). Loss of function of the retinoid-related nuclear receptor (RORB) gene and epilepsy. Eur J Hum Genet 24: 1761–1770. Sadleir LG, Scheffer IE, Smith S et al. (2009). EEG features of absence seizures in idiopathic generalized epilepsy: impact of syndrome, age, and state. Epilepsia 50: 1572–1578. Saltik S, Kocer N, Dervent A (2002). Informative value of magnetic resonance imaging and EEG in the prognosis of infantile spasms. Epilepsia 43: 246–252. Sander T, Schulz H, Saar K et al. (2000). Genome search for susceptibility loci of common idiopathic generalised epilepsies. Hum Mol Genet 9: 1465–1472. Sato S, Dreifuss FE, Penry JK et al. (1983). Long-term followup of absence seizures. Neurology 33: 1590–1595. Scheffer IE, Berkovic SF (1997). Generalized epilepsy with febrile seizures +: a genetic disorder with heterogeneous clinical phenotypes. Brain 120: 479–490. Scheffer IE, Berkovic S, Capovilla G et al. (2017). ILAE classification of the epilepsies: position paper of the ILAE commission for classification and terminology. Epilepsia 58: 512–521. Scherman RG, Abraham K (1963). "Centrencephalic" electroencephalographic pattern in precocious puberty. Electroencephalogr Clin Neurophysiol 15: 559–567.
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Chapter 1
Generalized epilepsies RENZO GUERRINI*, CARLA MARINI, AND CARMEN BARBA Neuroscience Department, Children’s Hospital A. Meyer-University of Florence, Florence, Italy
Abstract Idiopathic generalized epilepsies (IGE) are characterized by normal background EEG activity and generalized interictal spike-and-wave discharges in the absence of any evidence of brain lesion. Absence epilepsies are the prototypes of IGEs. In childhood and juvenile absence epilepsies, by definition, all patients manifest absence seizures associated with an EEG pattern of generalized spike-wave (GSW) discharges. In juvenile myoclonic epilepsy, myoclonic jerks, usually affecting shoulders and arms bilaterally and appearing upon awakening, are the most characteristic clinical feature. Myoclonic jerks are accompanied on the EEG by generalized spike/polyspike-and-wave (GSW, GPWS) complexes at 3.5–6 Hz. Idiopathic generalized epilepsy with generalized tonic–clonic seizures only is a broad and nonspecific category including all patients with generalized tonic–clonic seizures and an interictal EEG pattern of GSW discharges. Despite the strong heritability and the recent advances in genetic technology, the genetic basis of IGEs remains largely elusive and only in a small minority of patients with classic IGE phenotypes is a monogenic cause identified. Early myoclonic encephalopathy (EME), early infantile encephalopathy with suppression bursts, West syndrome, and Lennox–Gastaut syndrome, once classified among the generalized epilepsies, are now considered to be epileptic encephalopathies. Among them, only Lennox–Gastaut syndrome is characterized by prominent generalized clinical and EEG features.
The International League Against Epilepsy (ILAE) classification of epilepsies and epileptic syndromes (ILAE, 1989) identified syndromes as groups of signs and symptoms that customarily occur in association, in a clinical context that included not just seizure types, but also the clinical background, neurophysiologic and neuroimaging findings, and, often, outcome. According to ictal symptoms, epilepsies were classified as generalized and partial (or focal). Generalized epilepsies were defined as characterized by generalized seizures, bilateral motor manifestations, and generalized interictal and ictal EEG discharges. From an etiological point of view, generalized epilepsies were subdivided into idiopathic, cryptogenetic, and symptomatic. Idiopathic epilepsies were characterized by normal background EEG activity and interictal generalized spike-and-wave (GSW) discharges in the absence of any brain lesion. The term cryptogenic was used to define syndromes that
were presumed to be symptomatic, whose etiology was unknown. Symptomatic epilepsies were considered the expression of a focal or diffuse brain abnormality as demonstrated by clinical history, structural neuroimaging, EEG findings, or biological tests. This etiological classification has been modified through the 2001 (Engel, 2001), 2006 (Engel, 2006), 2010 (Berg et al., 2010), and 2017 (Scheffer et al., 2017) ILAE reports. In particular, the term cryptogenetic has been discouraged in favor of the wording “probably symptomatic” (Engel, 2006), while the concept of symptomatic epilepsies has been stratified into several etiological categories: metabolic, structural, infectious, genetic, immune, and unknown (Berg et al., 2010; Scheffer et al., 2017). An additional new concept has identified most idiopathic generalized epilepsy syndromes as “genetic generalized epilepsies (GGEs)” (Berg et al., 2010), in order to distinguish them from the “secondary” lesional generalized
*Correspondence to: Renzo Guerrini, Neuroscience Department, Children’s Hospital A. Meyer-University of Florence, viale Pieraccini 24, 50139, Florence, Italy. Tel: +39-0555662573, E-mail: [email protected]
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epilepsies, such as Lennox–Gastaut syndrome. An example is represented by the familial epilepsy syndrome initially defined as “generalized epilepsy with febrile seizures plus (GEFS+)” (Scheffer and Berkovic, 1997). GEFS+ is a typically inherited disorder with autosomal dominance and variable penetrance. About one-third of affected family members only have febrile seizures, about one-third develop a few afebrile generalized tonic–clonic seizures in childhood with remission in adolescence, and the remaining one-third may have generalized epilepsies, including childhood absence and myoclonic astatic epilepsy (Camfield and Camfield, 2015). Recently, patients with focal epilepsy have also been described (Myers et al., 2017). Genetic studies of GEFS+ families found SCN1A gene mutations in some. Owing to the possible occurrence of focal seizures and the genetic etiology, the wording “generalized epilepsy with febrile seizures plus” has been changed to “genetic epilepsy with febrile seizures plus” (still GEFS+) (Zhang et al., 2017). However, in 2017, the ILAE Task Force for Classification and Terminology (Scheffer et al., 2017) considered that the term idiopathic generalized epilepsy (IGE) could still be acceptable for four well-characterized epilepsy syndromes: childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and IGE with generalized tonic–clonic seizures only (IGE-TCS).
ABSENCE EPILEPSIES Absence epilepsies are the prototypes of IGEs. Childhood and juvenile forms are recognized in which, by definition, all patients manifest absence seizures associated with an EEG pattern of GSW discharges (ILAE, 1989). Before the ILAE classification introduced the age-related partition of absence seizure syndromes into childhood and juvenile forms, this distinction was only
used in German publications (Janz and Christian, 1957; Doose et al., 1965). Doose, Janz, and colleagues had clearly recognized that absence epilepsy had a first peak of age of onset at 6–7 years, corresponding to the typical CAE, while a second peak was near age 12 years, corresponding to the juvenile form. Thus, JAE typically begins during puberty, between age 10 and 17 years (Wolf, 1992; Obeid, 1994).
Childhood absence epilepsy Childhood absence epilepsy has an estimated incidence of 6.3–8/100,000 in children aged 0–15 years (Loiseau, 1992); it accounts for 2%–12% of patients with epilepsy (Berg et al., 2000) and is definitely age related. Typical absence seizures are sudden and brief, lasting 5–15 s, with periods of loss of awareness with interruption of ongoing activities, followed by immediate and complete recovery (Fig. 1.1A). Although absences were initially described as staring spells, a minority of patients have simple absences with unresponsiveness and interruption of ongoing activity (Penry et al., 1975). Most children exhibit complex absences, with additional clinical phenomena such as automatisms (Fig. 1.1B) with tonic, atonic, or autonomic components (Penry et al., 1975; Holmes et al., 1987). Absences are very frequent, occurring up to 100 times per day. They occur spontaneously but are also influenced by various factors, especially hyperventilation. The age of onset of CAE is between 4 and 10 years with a peak at 5–7 years, and girls are more frequently affected than boys (Penry et al., 1975; Berkovic, 1996). There are no clear-cut boundaries in age of onset, and onset before 3 years or after 10 years has been described (Penry et al., 1975; Cavazzuti, 1980). Most children with CAE exhibit normal developmental skills and normal cognitive functions. However,
Fig. 1.1. (A) A 7-year-old child with CAE. EEG polygraphic recording of a “simple” absence seizure showing a high voltage 3-Hz generalized spike-wave discharge associated with unresponsiveness and irregular breathing. The child moves after the discharge ends (black arrow). (B) A 16-year-old girl with JAE. EEG polygraphic recording of a “complex” absence seizure showing a highvoltage 3–3.5 Hz generalized spike-wave discharge associated with unresponsiveness, oroalimentary, and gestural automatisms (the black arrow indicates chewing artifacts at the left temporal leads).
GENERALIZED EPILEPSIES children with borderline IQ or mild cognitive impairment are not rare. The lowest scores in neuropsychologic tests might be correlated with earlier onset and longer duration of seizures (Sato et al., 1983). CAE has a highly specific EEG pattern consisting of generalized, bilaterally synchronous and symmetrical GSW discharges. These bursts are usually frontocentral dominant; however, in some patients they are restricted to, or maximally expressed in, the occipital regions. The frequency is around 3.0–3.5 Hz at onset and slows to 2.5–3.0 Hz toward the end of the discharge. More irregular discharges of generalized polyspike-and-wave (GPWS), changing rhythm inside a discharge, can also be observed (Sadleir et al., 2009). Discharges arise suddenly from a normal background and the end is less abrupt than onset. Hyperventilation is the most effective activator of the GSW pattern, while photic stimulation precipitates absence seizures in only about 15% of cases (Sadleir et al., 2009). Background EEG activity is usually normal, although some degree of slowing may be seen in up to one-third of patients (Sato et al., 1983; Holmes et al., 1987). Transient focal epileptiform activity such as centrotemporal spikes may occur (Hedstrom and Olsson, 1991; Fig. 1.2). During sleep, spike-and-wave complexes become more fragmented, and bursts of polyspike-andwave activity may appear (Niedermeyer, 1965; Ross et al., 1966; Sato et al., 1983; Fig. 1.2B). The frequency of the complexes may slow to 1.5–2.5 Hz. Both simple and complex absence seizures are associated with bursts of generalized 3-Hz spike-andwave activity, which generally lasts less than 30 s. The general view is that CAE has a good or excellent prognosis. Absences disappear before adulthood in up to 90% of cases with which no other seizure types are associated (Guiwer et al., 2003). If absences persist, TCSs usually appear. Early and late onset (before 4 and after 10 years), initial drug resistance, and photosensitivity are at greater risk of having a less favorable prognosis (Guerrini, 2006).
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Juvenile absence epilepsy Absence seizures are clinically similar to those seen in CAE; however, loss of awareness is less pronounced and attacks have a much lower frequency, usually occurring a few times per day. Tonic–clonic seizures are common in JAE, occurring in 80% of patients, and they begin at the same time or even prior to the onset of absences (Wolf, 1992). Sleep deprivation is the main precipitant. In our experience, absence seizures are at times detected for the first time during an EEG performed after a first tonic–clonic seizure, which has occurred after sleep deprivation. About 16% of patients will also have myoclonic seizures, especially early in the morning (Thomas et al., 2002). On EEG recordings, absences may have a faster rhythm of GSW at 4–5 Hz, especially at the onset of the attack. Background EEG activity is also normal and interictal GSWs are seen. Photosensitivity is rare. Absences tend to disappear over time, but in rare cases they may persist through adult life. Generalized tonic– clonic seizures (GTCSs) are common, even in early adulthood and especially after sleep deprivation; episodes of absence status can occur. Only about 60% of patients have a long-term remission (Trinka et al., 2004).
Juvenile myoclonic epilepsy Juvenile myoclonic epilepsy is estimated to account for 3%–12% of all epilepsies (Thomas et al., 2002). The characteristic clinical feature of JME are myoclonic jerks, usually affecting shoulders and arms bilaterally, but not always symmetrically, usually appearing upon awakening, in the morning. Jerks can sometimes involve muscles in the face or the legs and rarely may cause a sudden fall. The patient is usually aware of such symptoms. Myoclonic jerks are single or repetitive and vary in intensity. Subtle jerks are perceived as an
Fig. 1.2. A 7-year old child with CAE. (A) Polygraphic EEG recording while awake, showing high-voltage 3-Hz generalized spike-wave discharge, followed by bilateral fronto-temporal spikes (black arrow). (B) Sleep recording showing frequent, irregular, SW discharges (black arrowheads) and bilateral fronto-temporal spikes (black arrows).
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internal body electric sensation with no exterior movement; more severe jerks cause objects to be dropped or launched. The age at seizure onset varies between 8 and 26 years, but the great majority of patients exhibit the first manifestations between 12 and 18 years. Males and females are equally affected (Delgado-Escueta et al., 1996). Background EEG activity is normal. There are interictal bursts of frontocentral dominant GSW and GPWS. The frequency of these bursts tends to be more irregular than the typical 3-Hz spike-and-wave bursts and varies between 3 and 5 Hz (Janz, 1955, 1985; Tsuboi, 1977; Delgado-Escueta and Enrile-Bascal, 1984). Polyspikes may occur without the slow wave afterward. Frequently, these bursts are fragmentary in appearance and restricted to the frontal regions. During sleep, the bursts of spike-and-wave and polyspikeand-wave may decrease, particularly during deep slow-wave sleep, and be markedly diminished, or absent, during REM sleep. The characteristic EEG patterns during myoclonic jerks are GPWS complexes or GSW at 3.5–6 Hz (Fig. 1.3). Photosensitivity is found in about 30% of males and 40% of females (Asconape and Penry, 1984; Appleton et al., 2000). Generalized tonic–clonic seizures occur in 90%–95% of patients, more frequently in the morning and often preceded by a crescendo of myoclonic jerks (Delgado-Escueta et al., 1996). Myoclonic seizures and GTCSs may be precipitated by sleep deprivation, awakening, photic stimulation, and excess of alcohol. Infrequent, short absences are reported in 10%–33% of patients, who are unaware of their occurrence
(Thomas et al., 2002). During absences, EEG usually shows irregular 3–4 Hz GSW. It has been suggested that 5%–15% of patients with CAE will evolve into JME (Janz and Christian, 1957; Wirrell et al., 1996). We have not observed such a transition in our cohort. A consensus on JME (Kasteleijn-Nolst Trenite et al., 2013) proposed two sets of criteria for the diagnosis of this syndrome. Class I criteria encompass myoclonic jerks without loss of consciousness exclusively occurring on or after awakening and associated with typical generalized epileptiform EEG abnormalities, with an age of onset between 10 and 25 years. Class II criteria allow the inclusion of myoclonic jerks predominantly occurring after awakening, generalized epileptiform EEG abnormalities, with or without concomitant myoclonic jerks, and a greater time window for age at onset (6–25 years). Juvenile myoclonic epilepsy is described as the prototype of pharmacodependent epilepsies, assuming that treatment will be lifelong (Baruzzi et al., 1988), although about 10% appear to have permanent remission in adolescence (Camfield and Camfield, 2005).
Other possible syndromes with typical absence seizures Absences with a mild clonic component, often manifesting as flickering of the eyelids, are well recognized in CAE and JAE. However, no clear-cut boundaries exist in severity, frequency, and distribution of the jerking component, with the consequence that a confusing nomenclature and several subtypes of absence seizures
Fig. 1.3. Polygraphic EEG recording showing a high-voltage generalized spike (black arrowhead) associated with a myoclonic jerk (black arrow), in a 14-year-old girl with JME. A generalized spike and wave discharge at 2 Hz is detectable after the myoclonic jerk.
GENERALIZED EPILEPSIES and epilepsies have been proposed. Whether or not all proposed syndromes represent distinct clinical and genetic entities is still debated.
EYELID MYOCLONIA WITH ABSENCES The hallmark of eyelid myoclonia with absences (Appleton et al., 1993), initially described as a form of photosensitive epilepsy by Jeavons (1977), is eyelid myoclonia somewhat different from the flickering of the eyelids seen in typical absence epilepsies. Age at onset is between 3 and 7 years. Tonic–clonic seizures are infrequent and usually precipitated by sleep deprivation or photic stimulation. EEG changes associated with eyelid myoclonia are GPWS discharges at 3–5 Hz, following eye closure (Fig. 1.4). It has been suggested that eyelid myoclonia would be, at least in some photosensitive patients, a sort of subconscious eye blinking performed in order to self-induce the related absence component (Binnie et al., 1980). However, the reverse is also possible in that physiologic blinking might act in highly photosensitive individuals as a photic trigger, by virtue of the contrast in brightness it generates, activating as a consequence a cascade of reflex “epileptic” blinking and a microabsence. The whole population of patients exhibiting such seizure type is extremely heterogeneous, varying from otherwise healthy individuals, who share all the characteristics of an idiopathic generalized epilepsy, to patients with severe cognitive impairment and an obviously symptomatic disorder (Guerrini et al., 2005).
Perioral myoclonus with absences It has been proposed that jaw and lip myoclonus, associated with typical absences, represent the distinctive feature of a syndrome (Panayiotopoulos et al., 1995) with onset in childhood or adolescence, a high risk for absence status, and possible subsequent GTCS. However, insufficient evidence has been gathered to consider this clinical phenomenon as a distinct epilepsy syndrome separated from classic CAE or JAE.
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TYPICAL ABSENCE SEIZURES IN SYMPTOMATIC EPILEPSIES
Absence seizures, sometimes typical, may occasionally occur in symptomatic epilepsies, arising as a consequence of a known disorder. Typical absences have been reported following encephalitis, lysosomal storage disorders, and metabolic encephalopathies (Andermann, 1967; Berkovic, 1996). Hypothalamic hamartomas have also been associated with GSW and with absence attacks (Scherman and Abraham, 1963).
ABSENCE EPILEPSY ASSOCIATED WITH NONEPILEPTIC PAROXYSMAL DISORDERS
Absence epilepsies and more broadly IGEs can sometimes co-occur with paroxysmal movement disorders. Families and sporadic patients in which affected individuals have absence epilepsy or paroxysmal movement disorders, or both, have been described (Guerrini et al., 2002; Bing et al., 2005; Suls et al., 2008). Age of onset of absences in some of such patients is usually early, before age 2 years. One recognized cause of early onset absence epilepsy and paroxysmal dyskinesia is the glucose transporter 1 (GLUT1) deficiency syndrome, caused by mutations of the SLC2A1 gene (Suls et al., 2009; Fig. 1.5).
IGE with generalized tonic–clonic seizures only IGE-TCS, previously referred to as grand mal epilepsy (Temkin, 1971), is a broad and nonspecific category including all patients with GTCS and an interictal EEG pattern of GSW discharges. The initial defining feature of IGE-TCS was GTCS predominantly on awakening or in the evening period of relaxation (ILAE, 1989). However, subsequent studies have shown that, in almost half of the patients, seizures do not occur in relation to awakening or relaxation (Reutens and Berkovic, 1995). Some authors have instead proposed to recognize
Fig. 1.4. A 16-year-old girl with eyelid myoclonia with absences. (A) Polygraphic EEG recording showing a GPWS discharge during photic stimulation at 21 Hz at eye closure, associated with eyelid myoclonia. (B) The same 21-Hz photic stimulation does not provoke any response when the eyes are closed throughout.
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Fig. 1.5. Polygraphic EEG recording showing a high-voltage 2.5–3 Hz generalized spike-wave discharge associated with unresponsiveness in a 1-year-old patient with SLC2A1 gene mutation.
two separate entities, depending upon whether GTCSs occur on awakening or not (Unterberger et al., 2001). Age of onset ranges from late childhood to early adulthood, without clear boundaries. Seizures are infrequent in most patients, and often occur in relation to sleep deprivation or excessive alcohol. Some studies have described patients with GTCS immediately preceded by 3-Hz GSW or by an absence seizure (Mayville et al., 2000). The EEG shows normal background and interictal discharges of GSW or GPWS.
In 1989 the ILAE Commission on Classification and Terminology considered epilepsy with myoclonic astatic seizures and epilepsy with myoclonic absences (EMA) to possibly be cryptogenic or symptomatic, due to their less favorable outcome and the co-occurrence of cognitive impairment. Concepts have evolved and at present both syndromes are recognized as IGE phenotypes, at least in some patients.
Myoclonic absences manifest with rhythmic myoclonic jerks of the head, shoulders, and arms, time locked with spike-and-wave discharges, often associated with a background tonic muscle contraction. They usually last from 10 to 60 s and can be easily precipitated by hyperventilation or tend to cluster upon awakening. Frequency, calculated in a selected epilepsy population at the Centre Saint Paul, is around 0.5%–1% of all epilepsies, but the prevalence is probably lower among unselected epilepsies (Bureau and Tassinari, 2005). Myoclonic absences as a seizure type are by no means limited to a homogeneous syndrome in that they have also been described in association with variable etiologies and in different clinical contexts (Guerrini et al., 2005). There is a male preponderance and intellectual disability is present in 45% of patients before the onset of epilepsy (Bureau and Tassinari, 2005). Myoclonic absences are associated with 3-Hz GSW similar to those observed in CAE. The prognosis is variable but resistant cases are encountered much more frequently than in CAE and JAE, from which this syndrome is clearly distinct despite EEG similarities.
Epilepsy with myoclonic absences
Myoclonic astatic epilepsy
EMA is the only syndrome with 3-Hz GSW absences, other than CAE and JAE, which is recognized in the international classification of the generalized epilepsies (ILAE, 1989). EMA is a childhood epilepsy—mean age at onset 7 years—with daily myoclonic absences, and with other infrequent seizure types such as TCS, drop attacks, and atypical absences (Bureau and Tassinari, 2005).
Myoclonic astatic epilepsy epitomizes a spectrum of IGEs with prominent myoclonic seizures, appearing in previously healthy children. It represents about 2% of all childhood epilepsies (Guerrini, 2006). Onset is between 2 and 6 years of age. Myoclonic seizures and atonic falls may be repeated many times daily and are often associated with episodes of nonconvulsive status
OTHER GENERALIZED SYNDROMES TYPICAL OF CHILDHOOD
GENERALIZED EPILEPSIES epilepticus and GTCS. Background EEG activity may be normal at seizure onset, although a characteristic 4- to 7-Hz monomorphic theta activity with diffuse distribution and centroparietal prevalence is often observed. Interictal abnormalities consist of bursts of 2- to 3-Hz GSW and GPWS discharges, sometimes asymmetrical (Doose, 1992). Sleep is accompanied by an increase in discharges. Myoclonic seizures are accompanied by a generalized (poly)spike-and-wave complex, which may be isolated or repeated rhythmically at 3–4 Hz, lasting for 2–6 s (Oguni et al., 1992). Myoclonic jerks, involving mostly the proximal upper limbs, are timelocked to a spike-and-wave complex (Fig. 1.6). The electromyographic (EMG) correlate of each jerk is a burst lasting around 100 ms, followed by a longer (200–500 ms) postmyoclonic silent period. A single jerk or a series of two to three jerks is observed most commonly. Neurophysiologic analysis of myoclonic seizures (Guerrini et al., 2002) showed that spike-and-wave discharges and myoclonic jerks are bilateral and synchronous, thus supporting a thalamocortical origin of myoclonic jerks. The atonic component of seizures is characterized by a rhythmic discharge of (poly)spikeand-slow wave complexes at 3–4 Hz, accompanied by
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EMG inhibition, lasting 60–400 ms, synchronous in the recorded muscles, and time-locked to the onset of the slow wave (Oguni et al., 1992, 1997). Tonic seizures are accompanied by 10- to 15-Hz polyspike discharges lasting as long as the tonic contraction on EMG. Myoclonic status is associated with a very irregular and chaotic EEG with independent spike-and-wave discharges, sometimes resembling hypsarrhythmia (Doose, 1992). Focal, erratic, myoclonic jerks are recorded on distal and facial muscles. They are brief (30–100 ms) and are not time-locked to individual spikes on EEG (Guerrini et al., 2002). Outcome is unpredictable. Remission within a few months or years with normal cognition is possible even after a severe course. About 30% of children experience an epileptic encephalopathy with long-lasting intractability and cognitive impairment (Guerrini, 2006).
Genetic etiology of IGE IGEs have a predominant genetic etiology and current data are in favor of a complex model of inheritance with the interaction of two or more genes (Berkovic and Scheffer, 2001). Data from twin studies show that
Fig. 1.6. A 2-year-old child with EMA. Polygraphic EEG recording showing a high-voltage generalized spike and wave (black arrowhead) associated with a myoclonic–atonic seizure (black arrow).
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monozygous twins concordant for epilepsy have the same IGE subsyndrome and similar EEG patterns (Berkovic et al., 1998). Family studies have estimated the risk of developing epilepsy in close relatives of IGE probands to be between 4% and 10% (Annegers et al., 1982; Marini et al., 2004). The risk is comparable for the subsyndromes of CAE, JAE, and JME (Janz et al., 1992). The risk is higher in siblings and offspring and lower in second-degree relatives (Tsuboi, 1989). Analysis of epilepsy phenotypes in families with several affected family members shows that, usually, relatives also have an IGE, with about 30% phenotypic concordance (affected relatives have the same IGE subsyndrome as the proband), both for absence epilepsies and JME (Marini et al., 2004). In contrast, very few affected relatives of probands with absence epilepsies have JME and vice versa, suggesting that absence epilepsies and JME tend to segregate separately. These findings suggest that, within a polygenic model of inheritance, absence epilepsies are both closely related and genetically distinct from JME. Febrile seizures and GTCS are equally distributed in affected individuals of all IGEs, perhaps representing the expression of a nonspecific susceptibility to seizures. Rare large IGE families, with a predominant autosomal dominant inheritance, have been reported (Cossette et al., 2002; Marini et al., 2003). Other models of inheritance have been suggested for IGEs, including twolocus models and autosomal recessive. The two-locus models would imply two genes, one dominantly and the other recessively inherited or both recessively inherited (Greenberg et al., 1989). Possible autosomal recessive inheritance was observed in consanguineous families (Panayiotopoulos and Obeid, 1989). Rare families with mutations in genes encoding subunits of voltage- or ligand-gated ion channels have been described (Helbig et al., 2008). Genome-wide linkage analyses of large numbers of families with IGEs have shown several loci with putative genes for IGEs (Sander et al., 2000; Durner et al., 2001; Hempelmann et al., 2006). Modern technologies, including high-throughput and targeted next generation sequencing (NGS) using panels of genes and whole exome sequencing (WES), have increased the number of patients undergoing genetic analyses. This process has made genotype–phenotype correlations even more complex and challenging. For instance, novel mutations in the GABRA1 gene, coding for the a1 subunit of the GABAA receptor, originally associated with JME (Cossette et al., 2002) have also been identified in patients with Dravet syndrome or other epileptic encephalopathies (EE) (Carvill et al., 2014; Johannesen et al., 2016; Kodera et al., 2016). Similarly, CACNA1A mutations historically found in patients with
intermittent ataxia, migraine, and generalized epilepsies including CAE are also associated with EE with refractory seizures and cognitive impairment. Such findings give rise to the challenging discussion of whether IGE and EE are discrete entities or might, in some patients, represent a biological continuum in which severity of the disorder might be due to additional genetic variants controlling drug response. Recently WES of an IGE family with eyelid myoclonia with absences uncovered a genomic variant in the RORB gene on chromosome 9q21.13; additional variants were subsequently identified enlarging the screening to sporadic IGE patients (Rudolf et al., 2016). The authors discussed the hypothesis that mutation in the RORB gene might cause IGEs but also highlighted the occurrence of intellectual disability in some of such patients, placing the doubt that mutations in this gene might cause generalized seizures and not the well-known and historically described IGEs. This concept is supported, for instance, by the clinical evidence that also SYNGAP1 gene mutations cause an epilepsy phenotype predominantly represented by childhood onset absences with eyelid myoclonia and tonic–clonic seizures in patients with cognitive and behavior impairment (Klitten et al., 2011; Mignot et al., 2016). Structural genomic variants or copy number variants (CNVs) have increasingly been recognized in the IGEs and, combining the results from several studies, it appears that microdeletions at 15q13.3, 15q11.2, and 16p13.11 are genetic risk factors that can be identified in 3% of patients with IGE, including JME (Helbig et al., 2013). However, these microdeletions also represent genetic risk factors for a broad range of other neurodevelopmental disorders. Patients with IGEs, especially early onset absence epilepsy and myoclonic astatic epilepsy, might carry SLC1A2 or GLUT1 gene mutations (Mullen et al., 2011; Striano et al., 2012). This finding, although rare, has a high relevance with the potential of immediate translation into treatment with the ketogenic diet, and the power to modify disease progression and outcome. In conclusion, despite the strong heritability and the recent advances in genetic technology, the genetic basis of IGEs remains largely elusive. Table 1.1 summarizes current relevant genetic findings concerning IGEs.
Symptomatic generalized epilepsies The ILAE international classification of the epilepsies considered the following four syndromes as symptomatic generalized epilepsies: early myoclonic encephalopathy (EME), early infantile encephalopathy with suppression bursts, West syndrome, and Lennox–Gastaut syndrome
GENERALIZED EPILEPSIES
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Table 1.1 Summary of the genetic defects identified in some IGE patients or families Gene
Locus
Protein
Phenotype
GABRG2 5q31–33 GABAA receptor g2-subunit GABRA1 5q34–35 GABAA receptor a1-subunit CLCN2 3q26 ClC-2 voltage-gated Cl channel EFHC1 6p11–12 Myoclonin1 CACNA1H 16p13.3 T-type Ca2+ channel a1H-subunit CACNB4 2q22–23 Ca2+ channel b4-subunit CACNA1A 19p13 P/Q-type Ca2+ channel a1A-subunit RORB 9q21.13 Transcriptional factors List of loci from genome-wide linkage analyses of small multiplex families 1p, 2q36, 3q26, 5q12-q14, 5q34, 6p21, 8q24, 8p, 9q32–33; 10q25–26, 10p11, 11q13, 13q22–31, 14q23, 15q14, 18q21, 19q13 List of CNVs, risk factors of IGE Microdeletions: 15q13.3, 15q11.2, 16p13.11 Duplication: 1q21.3
CAE and FS JME, CAE CAE, JAE, JME, EMA JME CAE JME, JAE CAE with ataxia Eyelid myoclonia with Ab IGE, CAE, JME
IGE, JME Early onset CAE
CAE, childhood absence epilepsy; EMA, myoclonic–astatic epilepsy; FS, febrile seizures; IGE, idiopathic generalized epilepsy; JAE, juvenile absence epilepsy; JME, juvenile myoclonic epilepsy.
(ILAE, 1989). In 2001 these syndromes were reclassified as epileptic encephalopathies, i.e., conditions in which the epileptic processes themselves are believed to contribute to the disturbance in cerebral function (Engel, 2001). Seizures associated with a suppression burst electroencephalographic pattern are relatively common in the neonatal period, especially in association with hypoxic–ischemic encephalopathy. However, in Ohtahara syndrome and in EME this pattern remains relatively protracted and stable for more than 2 weeks. Both syndromes present with seizures in the first 3 months of life with multiple seizure types. Differentiating between the two syndromes can be difficult but is based on the specific electroclinical pattern (Cross and Guerrini, 2013). Both have an extremely poor prognosis with regard to seizure control and neurodevelopmental outcome; whether more successful treatment of seizures leads to a more optimal developmental outcome has not been fully established (Howell et al., 2015; Pisano et al., 2015). In many patients the underlying etiology is metabolic or structural, although genetic factors are increasingly recognized (Parrini et al., 2017). Infantile spasms are typical in the first year of life, are usually resistant to conventional antiepileptic drugs, and are associated with developmental delay or deterioration. A cumulative incidence of 2.9 per 10,000 live births and an age-specific prevalence of 2.0 per 10,000 in 10-year-old children were observed in the United States (Trevathan et al., 1999). Infantile spasms are etiologically heterogeneous and can be caused by focal structural brain lesions
(for example, in focal cortical dysplasia), extensive bilateral lesions (for example, in tuberous sclerosis), or by genetic conditions causing in turn widespread structural brain changes that can be visible or undetectable by imaging. Infantile spasms that occur as a consequence of localized epileptogenic lesions are to be considered as a focal epilepsy and as such can be eligible for surgical treatment (Barba et al., 2016). The EEG of children with spasms often reveals a hypsarrhythmic pattern, which is characterized by very high-voltage (up to 500 mV) slow waves, irregularly interspersed with spikes and sharp waves that occur randomly in all cortical areas (Guerrini and Pellock, 2012). The abnormal discharges are not synchronous over both hemispheres, so the general appearance is that of a chaotic disorganization of electrogenesis. Hypsarrhythmia is an interictal pattern and is observed mainly while the child is awake. During slow sleep, bursts of more synchronous polyspikes and waves often appear. In West syndrome, spasms, hypsarrhythmia, and cognitive deterioration occur together. However, infantile spasms might occur without the typical EEG or developmental features. Infantile spasms are manifested as clusters of increasing plateau–decreasing intensity brisk (0.5–2.0 s) flexions or extensions of the neck, with abduction or adduction of the upper limbs. Clusters include a few units to several dozens of spasms and are repeated many times per day. After a series, the child is usually exhausted. Asymmetrical spasms are often associated with a lateralized brain lesion (Kramer et al., 1997), although unilateral lesions may cause symmetrical spasms. Lateralized
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motor phenomena, including lateral or upward eye deviation and eyebrow contraction, and abduction of one shoulder, may sometimes constitute the entire series of spasms or initiate a series that will eventually develop into bilateral phenomena. Such lateralized manifestations are usually accompanied by unilateral or asymmetric ictal EEG changes. Other seizure types can coexist. Prognosis depends more on the cause than on treatment. Unfavorable prognostic factors include manifest symptomaticity, early onset (before 3 months), preexisting seizures other than spasms, asymmetrical EEG, and relapse after initial response to treatment (Guerrini, 2006). Adequate resolution requires the cessation of clinical spasms and normalization of the EEG (Pellock et al., 2010). Good prognostic indicators include cryptogenicity, normal findings on brain magnetic resonance imaging (Saltik et al., 2002), typical hypsarrhythmia, rapid response to treatment, and no regression after onset of spasms or its short duration (Kivity et al., 2004). Lennox–Gastaut syndrome is characterized by brief tonic and atonic seizures, atypical absences, and a generalized interictal EEG pattern of spike-and-slow wave discharges. It accounts for 2.9% of all childhood epilepsies (Berg et al., 2000). Incidence peaks between 3 and 5 years of age. About 30% of cases occur in previously healthy children; most result from neuronal migration disorders and hypoxic brain damage. About 40% of children have previous infantile spasms (Guerrini, 2006). The core seizure types of the syndrome, including tonic, atonic seizures, atypical absences, and episodes of nonconvulsive status, are not always present at onset, nor is the interictal EEG pattern of slow spikeand-wave. Some authors consider the presence of fast (10 Hz) rhythms associated with tonic seizures or occurring with minimal manifestations, especially during NREM sleep, to be an essential diagnostic criterion (Beaumanoir, 1985; Genton et al., 2000). Tonic seizures are particularly frequent during sleep. Patients who have tonic and atonic seizures when they are awake can violently collapse. Atypical absences might translate into nonconvulsive status, which can worsen cognitive deterioration. The classic EEG feature of Lennox–Gastaut syndrome is the slow spike-and-wave pattern, often repeated in bilaterally synchronous complexes at 1–2 Hz. Although slow spike-and-wave discharges are often associated with staring, confusion, or, at times, with an atonic fall, they can be interictal in many cases. Generalized bursts of polyspikes or fast rhythms (>10 Hz), also called generalized paroxysmal fast activity, are recorded during slow sleep, lasting from a few seconds to 15 s and recurring at relatively brief intervals (Blume et al., 1973). They occur as an interictal manifestation or are accompanied by a graded range of clinical
manifestations, ranging from opening and upward deviation of the eyes, brief apnea or a mild EMG axial contraction to a typical tonic seizure. Sleep EEG recordings may be necessary to elicit their presence (Arzimanoglou et al., 2009). About 80% of patients continue to have seizures later in life, with symptomatic origin and early onset having the poorest outcome. Cognitive and psychiatric impairment are frequent. Long-term follow-up reports mortality rates of up to 17% (Guerrini, 2006).
CONCLUSIONS IGEs are the most common group of epilepsies in children and adolescents. IGE syndromes are defined by distinct age at onset, seizure types and characteristic EEG abnormalities, without structural brain lesions and with normal developmental skills. Most IGEs are classified among the pharmacosensitive epilepsies in which appropriate drug treatment leads to seizure control, followed after a few years by spontaneous remission. Despite the strong heritability and the recent advances in molecular genetics, the genetic bases of IGEs remain largely elusive and only in a small minority of patients with classic IGE phenotypes is a monogenic cause identified.
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