Pediatric Neurology 50 (2014) 205e212

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Topical Review

Current Advances in Childhood Absence Epilepsy Sara Matricardi MD a, *, Alberto Verrotti MD, PhD b, Francesco Chiarelli MD, PhD a, Caterina Cerminara MD c, Paolo Curatolo MD c a

Department of Pediatrics, University “G. D’Annunzio” of Chieti, Chieti, Italy Department of Pediatrics, University of Perugia, Perugia, Italy c Department of Neurosciences, Pediatric Neurology Unit Tor Vergata University, Rome, Italy b

abstract BACKGROUND: Childhood absence epilepsy is an age-dependent, idiopathic, generalized epilepsy with a characteristic seizure appearance. The disorder is likely to be multifactorial, resulting from interactions between genetic and acquired factors, but the debate is still open. We review recent studies on different aspects of childhood absence epilepsy and also to describe new concepts. METHODS: Data for this review were identified using Medline and PubMed survey to locate studies dealing with childhood absence epilepsy. Searches included articles published between 1924 and 2013. RESULTS: The diagnosis comprises predominant and associated seizure types associated with other clinical and electroencephalographic characteristics. Many studies have challenged the prevailing concepts, particularly with respect to the pathophysiological mechanisms underlying the electroencephalographic seizure discharges. Childhood absence epilepsy fits the definition of system epilepsy as a condition resulting from the persisting susceptibility of the thalamocortical system as a whole to generate seizures. This syndrome, if properly defined using strict diagnostic criteria, has a good prognosis. In some cases, it may affect multiple cognitive functions determining risk for academic and functional difficulties; the detection of children at risk allows tailored interventions. Childhood absence epilepsy is usually treated with ethosuximide, valproate, lamotrigine, or levetiracetam, but the most efficacious and tolerable initial empirical treatment has not been well defined. CONCLUSIONS: We review recent studies and new concepts on the electroclinical features and pathophysiological findings of childhood absence epilepsy in order to highlight areas of consensus as well as areas of uncertainty that indicate directions for future research. Keywords: childhood absence epilepsy, idiopathic generalized epilepsy, system epilepsy, thalamocortical system, neuropsychological aspects, treatment

Pediatr Neurol 2014; 50: 205-212 Ó 2014 Elsevier Inc. All rights reserved.

Introduction

Childhood absence epilepsy (CAE) is a common form of pediatric idiopathic generalized epilepsy, accounting for 10% to 17% of all cases of epilepsy diagnosed in school-aged children.1 It is characterized by multiple typical absence seizures, accompanied with bilateral, symmetrical, and synchronous discharges of 3-Hz generalized spike and waves Article History: Received 20 July 2013; Accepted in final form 12 October 2013 * Communications should be addressed to: Dr. Matricardi; Department of Pediatrics; University “G. D’Annunzio” of Chieti; Via dei Vestini 5; 66100 Chieti, Italy. E-mail address: [email protected] 0887-8994/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2013.10.009

on electroencephalography (EEG). There is a new increased interest in the cognitive, behavioral, and genetic aspects, but also in the neuroimaging studies in these patients. The purpose of this report is to review recent studies on clinical features of CAE. Data for this review have been identified on Medline and PubMed survey for studies dealing with CAE, references from relevant articles, and searches of the authors’ file. Searches were done by considering articles published between 1924 and 2013. We considered reports in English, French, and Spanish. Specific review articles, systematic reviews, textbooks, and case reports were examined for any further publications, as were the reference sections of all articles identified by the literature search.

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Epidemiology

CAE has been variously reported to occur between 5.8 and 7.1 times per 100,000 persons.2,3 In children’s cohorts, the prevalence has been estimated to range from 0.4 to 0.7 per 1000 persons.4 CAE, with some exceptions, is clearly more frequent in girls than in boys (11.4% vs. 2.5%).5 CAE usually begins between 4 and 10 years with a peak at 5-7 years.6 Clinical and EEG presentation Clinical presentation

CAE is characterized by very frequent (often dozens per day) absence seizures. Information from retrospective studies might be a source of confusion, and many authors have incorrectly classified as CAE any type of epilepsy with onset of absences seizures during childhood. The striking impairment of consciousness is the essential feature of absence seizures in CAE, with loss of awareness, unresponsiveness, and behavioral arrest.7 Most children have a complete arrest of their activity, but a few can continue activities in an altered fashion.8 In the periods immediately before and after seizures, mild impairment has been reported, but transient peri-ictal deficits are still debatable.9 Another important feature of absence seizures is variation in consciousness deficits from one seizure to another, within and between patients.10 Other associated ictal clinical features in CAE consisted of staring, 3-Hz regular eyelid movement, and eye opening that usually occur in an inconsistent manner during seizures in which eyes are initially closed.8 Automatisms occur frequently in CAE and are more likely to be observed in longer seizures and during hyperventilation; they are predominantly oral and similar for the same child. However, these repetitive motor activities are not present in all absence seizures even in the same child, and their presence is not influenced by age or state of alertness.11 Mild clonic or tonic movements often occur during the first seconds of the absence seizure, whereas atonic falls never occur. Pallor is common. Incontinence of urine is exceptional.12 Some studies report perioral myoclonia and single or arrhythmic myoclonic jerking of limbs, head, or trunk during seizure in a small number of children with CAE.8,13 Seizure duration is influenced by factors such as provocation (hyperventilation and intermittent photic stimulation), state of arousal, sleep deprivation, medication, and individual factors.14,15 Seizure duration of less than 4 seconds or more than 30 seconds is not typical of CAE.16 However, all children with absence seizures with focal onset also had other seizures with generalized onset.8,17 Therefore, exclusion criteria have been proposed16: the presence of seizures other than typical absence seizure such as generalized tonic-clonic seizure (GTCS) or myoclonic jerks before or during the active stage of absences. Eyelid and perioral myoclonia and single violent jerks may also be an exclusion criterion.18 Furthermore, the International League Against Epilepsy (ILAE), by accepting myoclonic absence epilepsy and juvenile myoclonic epilepsy as separate syndromes, probably excludes absence seizures with myoclonic and mild typical absence

seizures from CAE; ILAE also defines reflex absence seizures that are, triggered by specific stimuli (such as photic stimulation), as a distinct category, indicating that these also may not be part of CAE.19 Other precipitating or facilitating factors are emotional, intellectual, nyctohemeral, and metabolic stimuli.20 EEG aspects

The typical pattern is a bilaterally synchronous and symmetrical discharge of rhythmic 3-Hz spike-wave complexes that start and end abruptly; often, a recovery of functions can be observed toward the end of the seizure and sometimes functions can be initially spared.7 Sadleir and colleagues detailed the electroclinical features of absence seizures and analyzed the video monitoring of characteristics of 339 absence seizures in a cohort of 47 children with newly diagnosed, untreated CAE.8 These authors showed that an average seizure duration was 9.4 seconds (range, 1 to 44 seconds), a bit shorter than the 12.4 seconds previously reported.21 In 50% of seizures in CAE, the initial generalized discharge consisted of typical spike-wave morphology, whereas in others it consisted of single spike, polyspikes, or an atypical, irregular generalized spike wave. Seizures without regular spike-wave discharges are rare. The majority of the discharges consisted of spike-wave complexes with one or two spikes per wave; however, children with a photoparoxysmal response are more likely to have three or four spikes per wave. The discharge can develop some degree of irregularity at the end of the seizure, particularly during drowsiness, sleep, and hyperventilation. In these circumstances, slow waves or complexes of different frequency and/or morphology or brief, transient interruptions of seizure discharges can disrupt the regular ictal discharges.22 Hyperventilation and intermittent photic stimulation induce absence seizures in 83% and 21% of patients, respectively.8 The interictal EEG in CAE is characterized by a normal background activity, but an interictal paroxysmal activity consisting of fragments of generalized spike-wave discharges can be documented in up to 92% of patients. Focal epileptiform interictal discharges may be present not only in the bicentral areas, but also in the frontal, temporal, and parietal areas.8,22 Occipital intermittent rhythmic delta activity, described also as rhythmic posterior bilateral delta activity, is another interictal abnormality of CAE. It is characterized by rhythmic bursts at 2.5-4 Hz over the occipital regions, which is enhanced by hyperventilation and drowsiness and attenuated by eye opening and deep stages of sleep.8,22 Multiple spikes (more than three), 3-4 Hz spike-wave paroxysms of less than 4 seconds, or ictal discharge fragmentations are not typical of CAE and may suggest a worse prognosis.16 Neuropsychological/cognitive aspects

Neuropsychological studies have demonstrated that, even during childhood and at diagnosis, patients affected by CAE have cognitive and linguistic impairment as well as behavioral disorders.23,24 The cognitive difficulties involve particularly the attentional domain and the executive

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functions25,26 as well as verbal and visuospatial memory27,28 even when the seizures are controlled by medications. Language and reading disabilities are also widely reported.23,29 Some studies have demonstrated attention deficit hyperactivity disorder in children with CAE27,28 as well as affective disorders such as depression and anxiety disorders.23,30 Neuroimaging studies demonstrate significant modification in attention networks as a decreased activation of anterior insula of the medial frontal cortex. Moreover, a functional magnetic resonance imaging (fMRI) study, carried out while a CAE patient performed a sustained attention task, revealed impaired functioning of an attention network that included the anterior insula/frontal operculum and medial frontal cortex.31 One report compared executive functions and attention dysfunction in CAE patients treated with valproic acid to healthy children. The study showed significant group differences in the performance of sustained and divided attention tasks. Children with absence epilepsy are also found to end the task more slowly than healthy children, suggesting that attention problems in patients with CAE appear to be a core feature of the syndrome. In a recent study, the authors investigated the attentional function of children with clinically diagnosed CAE from a multicomponent perspective using several test procedures that measure different aspects of attention. Individuals with CAE were markedly impaired in some measures of alertness, divided attention, impulsivity, and selective attention.31 With regard to focused attention, however, no differences were observed between the two groups. Furthermore, other epilepsyrelated factors, such as longer duration of the disease, high frequency of seizures, and treatment with one or more antiepileptic drugs (AEDs) have also been associated with increased cognitive difficulties.27,28 The effect of CAE on neuropsychological and behavioral function is still unclear. These functions may be influenced by unique factors of the epileptic syndrome itself, but it is difficult to examine them separately. Moreover, there is still debate about whether behavioral problems are part of the epileptic syndrome or develop as a consequence of disease-related factors. The presence of these comorbidities may contribute to social difficulties and poor scholastic achievement in patients with CAE. Early evaluation and detection of these comorbidities can lead to specific interventions such as cognitive behavioral therapy, educational and didactic support, and psychosocial assistance. Pathophysiology

The mechanisms underlying generalized spike-wave discharges in absence seizures have been analyzed in many studies for more than 7 decades, but the debate continues. Absence seizures evidently involve bilateral cortical and subcortical networks which are part of the default state system.9 In this regard, genetic animal models of absence epilepsy and EEG-fMRI studies have provided useful insights. Animal models have provided fundamental insights into the pathophysiology of absence seizures.32,33 In the Wistar Albino Glaxo/Rijswijk model, a cortical focus within the

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perioral region of the somatosensory cortex leads the thalamus by a mean time of 8.1 ms during the first 500 ms of an absence seizure.34 Concordant findings were reported in the Genetic Absence Epilepsy Rats from Strasbourg model.35 Conversely, some animal studies have demonstrated initiation of spike-wave activity in the thalamus.36,37 According to other researchers, these findings could be a misrepresentation of the cortical recordings having being performed at distant sites from the typical facial focus in the somatosensory cortex.38 Studies involving the feline generalized penicillin epilepsy model39 as well as Genetic Absence Epilepsy Rats from Strasbourg model40 have demonstrated that both the thalamus and cortex, with their interconnections, are needed to generate spike-wave complexes. On the basis of this wide-ranging evidence, the emerging consensus is that, although some forms of spike-wave activity can originate from the cortex or thalamus, an intact thalamocortical circuitry is required for the generation of typical spike-wave discharges.9 The spectrum of inherited epilepsies resulting from such mutations ranges from monogenic epilepsies to those with complex inheritance. A positive family history of epilepsy was found in 15% to 44% of CAE cases12dparticularly with regard to epilepsy in parents and in siblings, the frequency is respectively 42.6% and 20.7%.20 In two series, epilepsy was found in 17% of first-degree relatives of patients affected by CAE.41,42 In studies on twins, 84% of monozygotic twins showed typical spike-wave discharges on EEG recordings and 75% developed absence seizures.12,20 Other studies of epilepsy in twins confirmed a concordance rate significantly higher in developing the same epileptic syndrome, particularly in idiopathic generalized epilepsy as CAE.43,44 Although CAE is genetically determined, the precise mode of inheritance and the genes involved remain largely unidentified.32 The genes implicated in epileptogenesis in absence seizures include the g-aminobutyric acid (GABA) A and B receptors (GABRG2, GABRA1, GABRB3, GABA(B1), GABA(B2)),45,46 which are involved in the generation of spike wave discharges. Above all, calcium channels (CACNA1 A, CACNA1 H, CACNA1 G, CACNA1I, and CACNG3) contribute to “thalamocortical dysrhythmia,” and mutations in genes encoding these channels may be highly implicated in CAE.46 In particular, CACNA1 H seems to be a susceptibility gene in the Chinese Han population, but it is not sufficient to cause epilepsy on its own in Caucasians; CACNG3 could be a susceptibility locus in a subset of patients with CAE.47 There is now evidence of mutations involving sodium channels (SCN1B, SCN1A) as result of studies on the phenotype of families with “febrile seizures plus,” in which febrile seizures may represent the first manifestation of an epileptic diathesis.48 Furthermore, gene mutations in chloride channels (CLCN2) may be a susceptibility locus in a subset of CAE.49 In some cases of early-onset absence epilepsy, other authors have reported SLC2A1 mutations, showing that GLUT1 defects can be a rare cause of a classic idiopathic generalized epilepsy.50,51 However, mutations of GLUT1 gene seem to be related to a worse prognosis. EEG-fMRI studies have shown changes in activity in all components of the default state system.9,34 Most studies describe activation of the thalamus, besides inactivation in the medial frontal, medial parietal, anterior and posterior

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cingulate, lateral parietal cortices, and a mixture of activation-inactivation in the lateral frontal cortex.10,52,53 Increased activity on fMRI has also been reported in primary motor, somatosensory, visual, and auditory cortices as well as the cerebellum, and decreases are often observed in the basal ganglia and pons.54,55 Only a few studies have attempted to relate changes on fMRI in absence seizures to impaired behavioral performance10,56; the results suggest extensive fMRI changes when behavior is impaired. One important challenge is that most fMRI studies oversimplify the hemodynamic response function related to brain activity. Time-course analyses have shown that fMRI increases begin in the medial frontal and parietal cortex up to 10 seconds before the electroencephalographic onset of absence seizures.54,57 These early fMRI changes are followed by a complex sequence of increases and decreases with different time courses in cortical and subcortical structures, most of which cannot be measured by the standard hemodynamic response function used for conventional fMRI analyses.7 Therefore, new approaches are needed to detect these important fMRI changes, which could be related to impairment of consciousness. All these studies support the conclusion that the spike-wave discharges are the result of epileptic activity generated within the cortico-thalamocortical circuitry. Therefore, CAE complies with the definition of system epilepsy as a condition resulting from the persisting susceptibility of the thalamocortical system as a whole to generate seizures. The system epilepsy hypothesis postulates that the propensity to generate seizures depends on a specific susceptibility of a given neural system to epileptogenic factors. The phenomenology associated is determined by a contextual involvement of the contributing structures not obtainable by an element of the system alone. The available data support the idea of a trigger zone within a given area of thalamocortical system that has a particular genetically determined epileptogenic susceptibility; the trigger area becomes a part of the oscillating network during absence seizures and the oscillations constitute an emergent property of the whole system (as in dynamic, nonlinear systems).58 Key components of the circuitry include cortical pyramidal neurons, thalamic relay neurons, and the nucleus reticularis thalami (NRT). The principal synaptic connections of the thalamocortical circuit include glutamatergic fibers between neocortical pyramidal cells and the NRT and GABAergic fibers from NRT neurons to the thalamic relay neurons. In addition, recurrent collateral GABAergic fibers from the NRT activate GABA(A) receptors on adjacent NRT neurons. The NRT plays a pivotal role in modifying the flow of information between the thalamus and cerebral cortex. The NRT cells oscillate rhythmically during sleep, whereas during wakefulness their spiking behavior is tonic firing. The cellular events that underlie the ability of NRT neurons to shift between an oscillatory and tonic firing mode are related to the low-threshold Ca2þ spikes. The presence of low-threshold, transient Ca2þ channels (T-channels) is key for changing from oscillatory to burst firing in thalamocortical cells. Mild depolarization activates these channels, allowing the influx of extracellular Ca2þ. Further depolarization produced by Ca2þ inflow exceeds the threshold for firing a burst of action potentials. After

T channels are activated, they become inactivated rather quickly; hence, the name transient. De-inactivation of T channels requires a relatively lengthy hyperpolarization through GABA(B) receptors. When thalamocortical oscillations become aberrant, generalized spike-wave activity ensues; therefore, the generalized spike-wave discharges are the final common output of this aberrant oscillatory rhythm. Although the same cortico-thalamocortical network underlies both spike-wave discharges and sleep spindles, the “initiation site” is different for spike-wave discharges and sleep spindles, which are the cortex and the thalamus, respectively.59 According to the cortical focus theory, spike-wave activity is rapidly synchronized by propagating via cortico-cortical networks from the focal cortical site of origin. The oscillatory thalamocortical network amplifies and sustains the discharges.60 There is evidence for selective involvement of certain thalamocortical networks during spike-wave discharges. The ictal onset is characterized by activation of dorsolateral frontal or orbital frontal regions based on EEG source analysis.60 Evolution and prognosis

Studies of the evolution and prognosis of CAE are relatively inconclusive because they differ in diagnostic accuracy, definitions, and inclusion and exclusion criteria. The prognosis may reflect these selection biases. The variable prognosis at different stages also depends on the length of follow-up. All these aspects should be kept in mind when comparing results from different studies. CAE, if properly defined using strict diagnostic criteria, has an excellent prognosis for remission of seizures and successful AED withdrawal.12,16 The reported remission rate ranges from 56% to 84%.61-63 Callenbach et al., noted in their prospective study that the total duration of epilepsy and mean age at final remission were 3.9 and 9.5 years, respectively, being longer and higher in children still having seizures more than 6 months after enrolment. Children affected by CAE showed an overall good prognosis with only a few children (7%) still having seizures after 12-17 years of follow-up.63 In retrospective studies, it is possible that patients in remission may be underrepresented in retrospective studies, contributing to an apparent lower remission rate. Grosso et al. demonstrated the strong influence of inclusion criteria on the outcome.62 They classified patients with CAE into two groups, the first based on the ILAE classification19 and the second on more strict criteria proposed by Loiseau and Panayiotopoulos.16 The second group showed a higher rate of terminal remission defined as 1 year seizure freedom off AEDs (82% vs. 51%), lower GTCS (8% vs. 30%), and no relapses on AED withdrawal (0% vs. 22%). The estimated percentage of patients who develop GTCS ranges from 8% to 69% among the studies.61-63 Most often, GTCS occurs 5-10 years after onset of absence seizures. Some patients may develop a more refractory syndrome such as juvenile myoclonic epilepsy.61 All of these observations related to syndrome evolution or earlier age of onset of GTCS remain controversial. Furthermore, the development of myoclonic seizures also suggests a bad prognosis. Other poor prognostic features include absence status, late onset of

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absence seizures (more than 8 years), an abnormal background activity on EEG, multiple spikes, and focal abnormalities61,62; the latter likely correspond to misdiagnoses. On the contrary, a favorable prognostic sign is prompt seizure control after introduction of an appropriate AED treatment.20 EEG abnormalities may persist into adulthood even in individuals who are seizure free. Because retrospective studies in adults sometimes lack accurate initial data, individuals with CAE should be followed beyond 18 or 20 years of age in a prospective analysis before drawing final conclusions. Although CAE is historically believed to be a “benign” disorder, children affected by CAE may have poor psychosocial adaptation.64 Social functioning, academic achievement, and behavioral aspects of patients having had CAE would be poor in one-third of children, even when in remission. Outcome data are more significant when compared with reference groups such as other idiopathic generalized epilepsy syndromes, people without epilepsy, and individuals affected by other chronic diseases.64-66 Treatment

In absence of well-accepted guidelines, although CAE typically is an age-dependent and self-limited epilepsy, prophylactic anticonvulsant treatment is recommended because the seizures can occur frequently throughout the day and consequently can impair quality of life and interfere with normal cognitive functioning. There is little class I evidence (randomized trials) to support management routines for CAE, and most of the available evidence for the clinical practice derives from case series and expert opinion. There is also variability in the methodology used to report seizures in the different studies, particularly among the older studies. However, in the majority of studies, seizure freedom is defined as lack of clinically observed seizures and, above all, the lack of electroclinical seizures during video EEG evaluation. Older AEDs continue to play a major role in the treatment of CAE. Ethosuximide

Ethosuximide (ESM) allows complete control of absence seizures in 70% of treated patients, but it is considered undesirable as monotherapy when other generalized seizures coexist.67 Its mechanisms of action are not well elucidated; the prevailing hypothesis is that it may modify the thalamic low-threshold calcium channels involved in absence seizures. ESM, at therapeutic concentrations, can either reduce the number or conductance of these channels, reducing calcium influx into synaptic terminals. Valproate

Valproate (VPA) has been assessed in several open, noncomparative studies, with seizure-free rates varying from 88% to 95%.68 There are rare reports of VPA leading to paradoxical aggravation of absence seizures, probably related to a genetic heterogeneity of CAE.69 VPA is a broad-spectrum AED, raises brain level of GABA, and affects sodium and calcium channels. None of the identified

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actions are widely accepted as the predominant relevant mechanism in absence seizures. Ethosuximide with Valproate

Increased efficacy with ESM-VPA combination treatment was also widely demonstrated. This effect was due to the pharmacokinetic interaction because VPA can decrease the clearance of ESM, increasing its plasma level.70,71 ESM and VPA have been demonstrated to be equally effective as monotherapy for absence seizures72; among the older AEDs they are considered first-choice drugs for this seizure type. Other AEDs

Among older AEDs, acetazolamide, clonazepam, and clobazam are second-line drugs for CAE, sharing risks of tolerance and adverse effects.73 They may be also useful as adjunctive agents.74 In contrast, carbamazepine, phenytoin, and phenobarbital are contraindicated in absence seizures.6,75,76 Blockade of voltage-gated sodium channels by these AEDs exacerbates seizures and epileptiform discharges in CAE because they are associated with slowing in background activity. Generalized slow waves on EEG may be generated by the same thalamocortical network responsible for spike-and-wave generation; therefore, action on the thalamocortical network by these drugs may result in facilitation of generalized epileptogenesis.76 In the last two decades, the introduction of new AEDs has raised the hope that at least some of these drugs will prove useful not only for partial seizures but also for idiopathic generalized epilepsy. Lamotrigine (LTG), levetiracetam (LEV), topiramate (TPM), and zonisamide (ZSM) have been suggested for a broad spectrum of seizure types. Lamotrigine

A small, open-label randomized trial found that LTG was equivalent to VPA for the initial treatment of CAE, although equivalent seizure control was not seen until a year after beginning treatment.77 The delayed effect of LTG, compared with VPA’s faster onset of action, was attributed to the slow dose titration of LTG. LTG controls absence seizures in 50% to 56% of treated patients, but it may cause hypersensitivity immune reaction.78 LTG acts as a use-dependent blocker of voltage-sensitive sodium channels. Lamotrigine versus Ethosuximide and Valproate

Two double-blind, randomized controlled clinical trials comparing the efficacy, tolerability, and neuropsychological effects of ESM, VPA, and LTG in children with newly diagnosed CAE showed that VPA and ESM were more effective than LTG and that ESM was associated with fewer cognitive side effects. These studies indicate that ESM is the optimal initial empiric monotherapy for CAE.79,80 Levetiracetam

LEV mechanisms of action may be related to modulation of a synaptic vesicle protein. A recent study assessed the efficacy, safety, and tolerability of LEV monotherapy in

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absence seizures and demonstrated more than a 50% reduction in seizures in newly diagnosed patients with CAE. No adverse events occurred in any patient during the treatment.81 Another recent randomized controlled trial showed that, although better than placebo, LEV had moderate efficacy for absence seizure control.82 Auvin et al., however, reported six children with CAE who showed an aggravation of absence seizures after starting LEV.83

receptors. GABA-induced hyperpolarization of thalamic neurons enhances oscillatory thalamocortical activity, leading to more prominent and prolonged EEG discharges.76 In the Table, we summarize the AEDs that are most commonly prescribed for individuals with CAE.

Topiramate

There are a very few studies on medically refractory CAE, and they are particularly perplexing in terms of the inclusion criteria. Some cases of refractory CAE may be caused by mutations in the SCL2A1 gene, which bring on GLUT1 deficiency; an early identification of patients with this mutation may lead to a targeted treatment represented by the ketogenic diet.50,51 Some reports highlight the possible efficacy of vagus nerve stimulation for medically refractory absence seizures,89 but these data are based on a small number of patients and on short-term follow-up to draw evidence-based treatment in these patients.

TPM has multiple mechanisms of action, including ion-channel blockade, inhibition of excitatory responses, and enhancement of GABAergic inhibitory synaptic transmission; this may explain its efficacy on absence seizures. There is only class III and IV evidence to support the use of TPM in absence seizures. Biton et al., in their open-label portion of the study, showed 48% of patients with absence seizures were responders.84 In another small, open-label pilot study, no significant improvement in seizure control occurred in five children.85 Furthermore, in a recent pilot study of TPM in CAE, Piña-Garza et al. showed that, although well-tolerated, TPM monotherapy was ineffective for absence seizures.86 Zonisamide

ZSM acts by blocking voltage-sensitive sodium, as well a T-type calcium channel. Although some authors have suggested that ZSM is effective for absence seizures,87 there are no well-controlled studies evaluating its efficacy and tolerability in these types of seizures. Contraindicated AEDs

Gabapentin proved to be ineffective in CAE in a doubleblind trial.88 Moreover, it is well known that other drugs, such as oxcarbazepine, vigabatrin, and tiagabine, are ineffective and contraindicated in CAE.6,76 Oxcarbazepine is similar to carbamazepine and acts by blocking voltagegated sodium channels, and, like carbamazepine, it may lead to absence seizure exacerbation with the same mechanisms. In animal models of absence seizures, GABAB agonists produce an increase in seizure frequency by facilitating the deinactivation of low-threshold transient calcium channels, whereas GABAA agonist reduces absence seizures frequency. The facilitation of thalamic oscillatory activity by GABAergic drugs (gabapentin, vigabatrin, and tiagabine) appears to be mediated partly by GABAB

Other treatments

Conclusion

CAE is a common pediatric epileptic syndrome, and the correct diagnosis comprises the predominant and associated seizure types associated with other clinical and EEG characteristics. CAE is probably genetically heterogeneous, but the precise mode of inheritance and the genes involved are incompletely understood. The clinical expression of this syndrome is likely to depend on both genetic and acquired factors. CAE is a good example of system epilepsy in which the propensity to generate seizures is due to the specific susceptibility of the thalamocortical system, which is endowed with oscillating properties. CAE can impair multiple cognitive functions and lead to academic and other functional difficulties. Therefore, the early detection of children at risk of developing neuropsychological problems to make the tailored interventions that address their specific needs might prevent worse school achievement and psychosocial functioning. Cognitive side effects should be an important factor in the selection of a specific AED among medications that are equally effective. CAE is usually treated with ESM, VPA, LTG, or LEV. The most efficacious and tolerable initial empirical treatment has not been well defined, although ESM is considered the drug of choice. None of these drugs can be considered ideal.

TABLE. Antiepileptic drugs most commonly prescribed for childhood absence epilepsy

Drug

Mechanism of Action

Efficacy

Reported Side Effects

Ethosuximide

Diminishes low-threshold (T-type) calcium current in thalamic cells Different mechanisms not completely known (raises brain level of g-aminobutyric acid and also affects sodium and calcium channels) Blockage of use-dependent voltage sensitive sodium channels Modulation of a synaptic vesicle protein

Complete control in 70% of patients

Nausea, headache, drowsiness

Seizure-free from 88% to 95% of patients

Weight gain, hair loss, hepatitis, polycystic ovaries

Seizure free in 50% to 56% of patients

Skin rash, drowsiness, dizziness, headache Dizziness, fatigue, irritability

Valproate

Lamotrigine Levetiracetam

Reduction of seizure in 50% of patients

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A systematic approach is needed to improve our understanding of the genetic and pathophysiological aspects of the pharmacological trials. Therefore, there is a need for more systematic studies to try to improve the management and diminish the social impact of this important pediatric epileptic syndrome.

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