Childhood Absence Epilepsy

Abstract

Childhood absence epilepsy (CAE) is a common epilepsy syndrome characterized by absence seizures affecting young children and representing 18% of all diagnosed cases of epilepsy in school-age children. Absence seizures are classically very frequent during the day and each seizure lasts a short time, from about 10 to 20 seconds, it ends abruptly, and awareness and responsiveness are severely impaired. The typical EEG pattern in CAE is a bilateral, synchronous, and symmetrical discharge of complex spike-wave rhythms at 3 Hz (range of 2.5–4 Hz), with sudden onset and termination. CAE is genetically determined, the mode of inheritance and genes involved remain not fully clarified but the final outcome is the dysregulation of cortico-thalamic-cortical circuit that plays a crucial role in the pathophysiology of absence seizures. CAE may have an impact on patients’ lives in terms of negative consequences in neurocognitive and neuropsychological aspects that should always be considered during a global evaluation of a child with epilepsy.

1. Introduction

Childhood absence epilepsy (CAE) is a common form of idiopathic generalized epilepsy of childhood, corresponding to 18% of all diagnosed cases of epilepsy in school-age children. CAE is characterized by multiple typical absence seizures, together with, on the electroencephalogram, synchronous and symmetrical bilateral discharges of 2.5–4 Hz generalized spike-waves [1].

In 2017, the International League Against Epilepsy (ILAE) classification [2] CAE was included in the group of idiopathic generalized epilepsy (IGE) together with juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and epilepsy with generalized tonic–clonic seizures alone (GTCA). In 2022, the Task Force on Nosology and Definitions defined IGE as a distinct subgroup of Genetic Generalized Epilepsies because they generally have a good prognosis, a polygenic inheritance, an overlap symptomatology, similar EEG findings, and they do not evolve in epileptic encephalopathy but can evolve into each other [3].

2. Epidemiology

CAE incidence is 6.3–8.0 cases per 100,000 per year [4], and it represents 18% of epilepsy in school-aged children. In a cohort study of children, the CAE prevalence was estimated between 0.4 and 0.7 per 1000 people [5]. CAE, with some exceptions, is more frequent in girls than in boys (75 vs. 60%) [6]. Usual CAE onset is between 4 and 10 years of age with a peak at 5–7 years [7].

3. Clinical presentation

CAE is characterized by frequent absence seizures, up to 100 daily seizures, in otherwise typically developmental children although comorbid neurodevelopmental disorders may be present [1, 8, 9]. The sudden loss of awareness is the essential characteristic of CAE absence seizures, with loss of contact with the surrounding environment, lack of response to calls, and psychomotor arrest [10].

Absence seizures are typically multiple during the day and can be often underrecognized.

Many children stop their activities, but some may continue to carry out their tasks in an impaired manner, and at the end of the seizure, there is an immediate return to normal activity [11]. Another important ictal-associated clinical feature consists of fixed gaze, regular eye movements at 3 Hz, and eyes opening in cases where they are initially closed [11]. Frequently, automatisms can be observed, especially in longer crises and during hyperventilation.

The automatisms are mostly oro-alimentary or gestural movements and are repeated in a similar way in the same child. In any case, these movements may not be present in all absence seizures even in the same child, and their presence is not influenced by age or state of vigilance [12].

Mild clonic and tonic movements may also be present during the first seconds of the absence seizure, while tonic drops are never mentioned. Pallor is also common.

Urine incontinence occurs in exceptional cases [13]. Furthermore, some studies report perioral myoclonus and arrhythmic and single myoclonic jerks of the limbs, head, or trunk present during seizures in some children [11, 14]. These are mostly retropulsive movements of the head [9].

The duration of seizures is influenced by various factors: induction (hyperventilation or intermittent light stimulation), the state of arousal, sleep deprivation, pharmacological treatment, and individual factors [12, 15]. The typical duration of absence seizure is 3–20 seconds; a seizure duration of less than 4 seconds or more than 30 seconds is not typical of CAE [7]. Generalized tonic–clonic may rarely occur in the period of a high frequency of seizures and sometimes during adolescence, they can underline the evolution to another IGE [16].

4. Electroencephalogram

The typical EEG pattern of CAE is a bilateral, synchronous, and symmetrical discharge of complex spike-wave rhythms at 3 Hz (range 2.5–4 Hz), with sudden onset and termination. Often, a recovery of function is observed towards the end of the crisis and sometimes functions can be spared (Figure 1) [10]. However, EEG discharges sometimes have maximum frontal amplitude or may exhibit initial unilateral focal spikes [17].

Figure 1.

EEG example of patient with CAE with typical 3 Hz spike and wave discharges.

Sadleir and colleagues meticulously described the electroclinical characteristics of absence seizures and analyzed videos of 339 absence seizures from a cohort of 47 children with a recent diagnosis of AIH. The authors demonstrated that the mean seizure duration was 9.4 seconds (ranging from 1 to 44 seconds), shorter than the 12.4 seconds previously reported. In 50% of CAE seizures, the initial generalized discharge is characterized by a typical spike-wave, while others are characterized by single spikes, polyspikes, or an atypical irregular generalized slow wave.

Seizures without a regular slow wave discharge are rare. The majority of discharges consist of spike-wave complexes with one or two spikes per wave. Children with photosensitivity are more likely to have three or four spikes per wave. The discharge may show a degree of variability at the end of the seizure, especially coinciding with drowsiness, sleep, or hyperventilation. In these circumstances, the regular ictal discharge can be interrupted by slow waves, complexes of different frequencies and/or morphology, or brief and transient interruptions of the ictal discharge [18].

Hyperventilation induces absence seizures in 83% of patients while intermittent light stimulation induces absence seizures in 21% of patients [11].

The interictal electroencephalographic activity of CAE is characterized by normal background activity but in 92% of cases, it is possible to document paroxysmal interictal activity consisting of bursts of generalized spike-wave discharges. However, focal epileptiform interictal discharges could be present not only in central areas but also in frontal, temporal, and parietal areas [11, 18].

Delta, rhythmic, intermittent occipital activity, also described as delta, rhythmic, bilateral, posterior activity is another interictal abnormality of CAE. This activity is characterized by rhythmic bursts at 2.5–4 Hz over the occipital regions, and it is enhanced by hyperventilation and drowsiness while attenuated by eye opening and deep sleep [11, 19]. The presence of multiple spikes (more than three), 3–4 Hz spike-wave paroxysms of less than 4 seconds, or segmentation of the ictal discharge are not typical of CAE and suggest a worse prognosis [7].

5. Pathophysiology of CAE

Theories on epileptogenesis. The mechanisms underlying the generalized spike-and-wave discharges of absence seizures have been analyzed in many studies, for more than 7 decades, but the debate continues [1]. Absence seizures evidently involve bilateral cortical and subcortical networks that are part of the default state system [20]. In 1941, Jasper and Kershman, analyzing the electroencephalograms of patients suffering from childhood petit mal, proposed a subcortical origin of absence seizures, imagining a thalamic pacemaker that projected simultaneously to both cerebral hemispheres. Subsequently, a second thalamo-cortical projection system was hypothesized to contribute to the spread of spike-wave discharges originating from the intralaminar nucleus of the thalamus [21].

These results led Jasper and Droogleever Fortujn, in 1947, to the first experimental model of spike-and-wave: the cat thalamic stimulation model. A stimulation of 3 cycles/sec in the intralaminar nucleus of the thalamus can produce a bilateral and synchronous 3 Hz spike-and-wave EEG discharge, associated with an absence-like behavioral modification [22].

In 1954, Penfield introduced the expression “centrencephalic epilepsy”, to indicate the genesis in the trunk and diencephalon, responsible for the origin of generalized seizures with initial loss of consciousness and bilateral onset synchronous on the EEG [23].

In 1952, Gibbs and Gibbs questioned the centrencephalic theory, hypothesizing instead that a diffuse cortical process was at the origin of spike-and-wave discharges. Data in favor of these hypotheses were produced by administering proconvulsant substances via the arterial route: the intracarotid injection determined the appearance of bilateral and synchronous spike-and-wave -type EEG discharges; the same substances were ineffective when administered into the vertebral arteries. Further data in support of a cortical origin of the absences were obtained through depth recordings carried out in patients suffering from lesional epilepsy of the frontal lobe and generalized EEG anomalies [24]; the latter led Luders and Niedermeyer to formulate the hypothesis of a fronto-mesial origin of absences and, more generally, of idiopathic generalized epilepsies [25, 26].

At the end of the 1960s, Gloor proposed a reticulocortical mechanism, attributing an essential role to the genesis of bilateral and synchronous POs to both the cortex and the thalamus and trunk. The theory was based on the stimulation of the thalamus in the cat, capable of inducing PO discharges only after the application of penicillin in the cortex. This led to the belief that the factor necessary for the genesis of PO discharges was in the condition of cortical hyperexcitability [27, 28].

The intrathalamic network. In 1991, Buzsaki studied the thalamo-cortical system in a strain of rats with spontaneous PO discharges, hypothesizing a “thalamic clock”, initially responsible for discharges, located in the thalamic reticular nucleus. In this nucleus, one would find the cells capable of triggering the recruitment of the intrathalamic network and the thalamo-cortical connections, at the basis of the origin of the physiological spindle figures.

PO discharges would be the result of an abnormal rhythmic oscillation of the intrathalamic network, which would impose its own rhythm on the cortex [29]. This theory, which revived the concept of “centrencephalic epilepsy”, was subsequently supported by further studies on different strains of epileptic rats (GAERS, WAG, Rij). In these animals, both lesions to the reticular nucleus of the thalamus and deactivation of the cortex resulted in the disappearance of spontaneous PO discharges, demonstrating that both structures are necessary for the generation of absences [30].

In recent studies, the temporal relationships between thalamic and cortical structures during spike-and-wave discharges have been clarified with nonlinear signal analysis methods.

The result is evidence of a cortical “focus” at the level of the perioral region of the somato-sensory cortex, from which the discharges then propagate to other areas of the cortex, for example, to the thalamus [31].

Conversely, some studies have shown that the onset of spike-wave activity is in the thalamus [32, 33]. According to other researchers, these findings would be false representations of cortical activities occurring in sites distant from the typical focus of the somatosensory cortex [34].

Based on this conflicting evidence, the general consensus is that although some forms of spike-and-wave activity may originate from the cortex or thalamus, the entire thalamocortical circuit is required to generate typical spike-and-wave discharges [20].

In particular, one hypothesis is that the initiation of the discharge is induced by the cortex, and that the thalamic structures are subsequently responsible for its amplification and maintenance through the thalamo-cortical connections. In this way, the theory of the “cortical focus” underlying absence seizures appears to be a synthesis between the cortical and reticulocortical theories [34].

Today, the cortico-thalamic-cortical circuit is considered to play a crucial role in the pathophysiology of absence seizures. Neurons of the thalamic nucleus reticularis can fire in an oscillatory pattern or continuously in single spikes. Changes in the type of firing patterns depend on low-threshold transient calcium channels known as T-type channels neurons from the thalamic nucleus reticularis. After depolarization, T-type channels before becoming inactive allow a little calcium inflow. The reactivation of these channels requires a long hyperpolarization facilitated by GABA-B receptors. Therefore, T-type channel abnormalities or GABA-B hyperactivation can provoke abnormal oscillatory rhythms. Similarly, mutation in genes coding for T-type calcium channels and GABA receptors has been related to CAE etiopathogenesis [35].

6. EEG-fMRI studies

Associated EEG-fMRI studies have shown changes in activity in all components of the default state system [20, 31]. Many studies describe activation of the thalamus, as well as inactivation of the medial frontal cortex, medial parietal cortex, anterior and posterior cingulate cortex, lateral parietal cortex, and simultaneous activation-inactivation of the lateral frontal cortex [36, 37, 38].

Increased activity in the primary motor, somatosensory, visual and auditory cortex, and cerebellum are also reported on fMRI, while decreased activity is often observed in the basal ganglia and pons [36, 37, 39].

Only a few studies have attempted to relate fRMI in absence seizures to reduced behavioral performances [36, 37]: The results suggest widespread changes as behavior deteriorates. An important challenge appears to be represented by fMRI studies that simplify the analysis of hemodynamic response functions related to brain activity.

Time-course analyses have shown that an activation in fMRI begins in the medial frontal and parietal cortex 10 seconds before the onset of the absence seizure on the EEG [40, 41]. These early changes in fMRI are followed by complex sequences of activation and inactivation with different time courses in cortical and subcortical structures, most of which cannot be measured by standard hemodynamic functional responses used for conventional fMRI analysis [10].

Furthermore, new approaches are indispensable to detect these important fMRI changes that may be related to the deterioration of consciousness. All studies support the conclusion that spike-and-wave discharges are the result of epileptic activity generated within the cortico-thalamocortical circuit. Therefore, the EAI sticks to the definition of an epileptic system understood as a condition underlying a persistent susceptibility of the thalamic-cortical system, capable in its fullness of generating seizures. The epileptic system hypothesis postulates that the propensity to generate seizures depends on a specific susceptibility of a specific neural system to an epileptogenic factor.

Available data support the idea of a trigger zone within a specific area of the thalamo-cortical system that has a genetically determined epileptogenic susceptibility [1], a pretreatment topological disruption is present and primarily affects the prefrontal-thalamocortical circuit underlining that an alteration brain network topology and structural–functional connectivity is an intrinsic feature of CAE [42].

7. Spike and wave discharges pathophysiology

Spike and wave discharges are the electrographic hallmarks of CAE. On the intracellular microelectrode level, cortical neurons show depolarization coinciding with the spikes and hyperpolarization corresponding to the wave of the EEG spike-wave complexes. Very briefly, the rhythmicity of the spike-wave complexes is the consequence of intrathalamic and thalamo-cortical oscillatory electrical activity [43], which would be generated in genetically predisposed subjects [1].

Key components of this circuit include cortical pyramidal neurons, relay nuclei neurons of the thalamus, and the reticular nucleus of the thalamus [1]. The intrathalamic and thalamo-cortical oscillatory circuits would depend on the activation of trans-membrane calcium currents, defined as transient T, on which the genesis, at the cortical level, of the rhythmic discharges of spike-wave complexes at 3 Hz would depend.

On a neurotransmitter level, the ideal condition for the genesis of these discharges is given by a high level of both glutamate-asparthaergic excitation and GABA A-mediated inhibition [44]. Furthermore, the role of GABA B receptors appears crucial at the level of the thalamic relay nuclei, the activation of which would facilitate the genesis of spike-wave discharges [43].

In particular, the main synaptic connections of the thalamic-cortical circuit include glutamatergic fibers extending from the neocortical pyramidal cells to the thalamic reticular nucleus (NRT) and GABAergic fibers extending from the thalamic reticular nucleus to the thalamic relay neurons. The cellular events that guarantee the maintenance of oscillatory rhythms are ensured by the presence of Ca ++ channels and T-Transient at the level of the neurons of the reticular nucleus of the thalamus (NRT) [1].

According to the cortical focus theory, spike-and-wave activity rapidly propagates through cortico-cortical networks from the cortical focus of origin. Oscillatory circuits of the thalamic-cortical network amplify and sustain discharges [45]. The origin of the ictal discharge is characterized by the activation of the dorsolateral frontal and orbital frontal regions [45].

8. Genetics

Although CAE is genetically determined, the mode of inheritance and genes involved remain not fully clarified. In most cases, CAE susceptibility is likely due to the influence of multiple genes and only a few genes confer a monogenic risk for CAE.

The calcium channel genes are associated with CAE especially CACNA1H and CACNG3 genes [46]. Also, GABA A and B receptor genes such as GABRG2, GABRA1, GABRB3, GABAB1, and GABAB2 genes have been implicated in the epileptogenesis of CAE [47]. Moreover, there is literature evidence of the involvement of chloride channels genes (CLCN2) as a susceptibility locus in CAE [48]. If there are atypical clinical features such as early onset, drug resistance, intellectual disability, and movement disorders, a glucose transporter 1 deficiency (SLC2A1 gene) should be suspected [49].

Mutations in patients with CAE were sometimes described in SLC2A1 gene coding for glucose transporter type 1 although the mutation rate in patients with CAE seems to be low [50].

Lastly, there are also recurrent CNVs that must be considered within the multiple possible genetic causes of CAE such as 15q11.2, 15q13.3, and 16p13.11 microdeletion [51].

9. Pharmacological treatment of CAE

The first-line antiseizure medications (ASMs) commonly used for CAE is ethosuximide (ETX), valid alternatives as initial treatment for CAE, valproic acid (VPA), and lamotrigine (LTG). VPA has more adverse effects, and LTG is less effective compared to ETX [52].

Topiramate, zonisamide, and levetiracetam [53, 54, 55] can be considered when other treatments fail.

Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, tiagabine, and vigabatrin may worsen absence seizures or cause absence status epilepticus and should not be administered [56].

10. The evolution and prognosis of CAE

Studies on the evolution and prognosis of CAE are relatively incomplete due to the inaccuracy of diagnosis, definitions, and inclusion and exclusion criteria. Furthermore, the variability of the prognosis depends on the duration of follow-up [1]. CAE, if correctly recognized using correct diagnostic criteria recently revised in 2022 by ILAE (Table 1), has an excellent prognosis for seizure remission and for successful treatment with ASMs. The rate of remission cases reported in literature varies in the range of 56–84% [57, 58].

	Mandatory	Alerts*	Exclusionary
Seizures	Typical absence; Seizures	GTCS prior to or during the peak of absence seizures; seizures duration >30 s or with postictal confusion; Absences rarely occur in untreated patients	Prominent myoclonic, Myoclonic–absence, or eyelid myoclonia seizures; Presence of atonic, tonic, atypical absence, focal impaired awareness seizures
EEG	Synchronous and symmetrical discharge of complex spike-wave rhythms at 3 Hz (range 2.5–4 Hz). An ictal EEG is not required for diagnosis	Unilateral epileptiform discharges; Lack of hyperventilation activation; Recording a typical staring spell without EEG correlate; Slowing of the EEG background	Diffuse background slowing
Age at onset	between 4 and 10 years, peak at 5–7 years	2–3 or 11–13 years	<2 or > 13 years
Development at onset	Normal	Mild intellectual disability	Moderate to profound intellectual disability
Neurological Exam	Normal	Potentially relevant neurological examination abnormalities, excluding incidental findings
Imaging	Normal (An MRI is not required for diagnosis)	Potentially relevant abnormal neuroimaging, excluding incidental findings

Table 1.

Diagnostic criteria for CAE.

*

Alert criteria are absent in most CAE patients, but they may be rarely present. Alerts do not exclude CAE diagnosis but their presence should lead to a rethink of the diagnosis or to make further investigations.

Source: Modified from Hirsch et al. [3].

Note: CAE, childhood absence epilepsy; CSF, cerebrospinal fluid; EEG, electroencephalogram; and GTCS, generalized tonic–clonic seizures.

In a prospective study, Callenbach et al. observed that the total duration of epilepsy and the average age at the end of remission corresponded to 3.9 years and 9.5 years, respectively; the two criteria studied increased in children who presented seizures 6 months after enrollment. Few children, equal to 7%, of those who presented crises after 12–17 years of follow-up showed a good prognosis [57].

Retrospective studies highlight the possibility that patients in remission were under-reported and this contributed to an apparently lower remission rate. Grosso et al., however, demonstrated that the inclusion criteria had a notable influence on the outcomes of these results [59].

Patients were classified into two groups: the first with a diagnosis based on the ILAE classification and the second with a diagnosis established on more rigid diagnostic criteria proposed by Loiseau and Panayiotopoulos [7]. The second group showed a higher remission rate defined by the percentage of seizure-free patients in the absence of ASMs treatment for a period of ≥1 year (82 vs. 51%), a lower incidence of generalized tonic–clonic seizures (8 vs. 30%), and absence of relapse upon discontinuation of AEDs (0 vs. 22%).

The estimated percentage of patients developing generalized tonic–clonic seizures range from 8 to 69%, as can be seen from the literature [45, 57]. Most often, generalized tonic–clonic seizures occur 5–10 years after the onset of the absence seizure. Some patients develop a refractory syndrome known as juvenile myoclonic epilepsy [58]. However, all these observations relating to the evolution of the syndrome and/or the earlier onset of generalized tonic–clonic seizures remain controversial. Furthermore, the development of myoclonic seizures also suggests a worse prognosis. Other negative prognostic factors include: type of absence, late onset of absence seizures (after age 8), abnormal EEG background activity, multiple spikes, and presence of focal abnormalities [58, 59].

On the contrary, a favorable prognostic factor is the early remission of the seizure following the introduction of an appropriate antiepileptic treatment [60]. EEG abnormalities can persist even in adults and even in seizure-free subjects [1].

11. Differential diagnoses

Differential diagnosis includes other IGE syndromes. Epilepsy with myoclonic absences (EMA) is characterized by an alteration of contact with the environment of variable extent (from mild to complete); bilateral myoclonus (prevalent in the limbs) constitutes the constant characteristic of this type of crisis and is often associated with a tonic contracture, especially proximal. Seizures begin and end abruptly, and their duration varies from 10 to 60 seconds. The frequency is high and absences often occur 10 times a day; in 14% of cases, they can be induced by SLI or occur during slow sleep, awakening the patient. The interictal EEG is usually normal. In a third of cases, generalized PO sequences and rarer focal or multifocal PO bursts can be observed. The critical EEG is characterized by a discharge of bilateral, synchronous, and symmetric 3 Hz PO complexes. Polygraphic recordings document that myoclonias are closely correlated with the tips of the complex. The prognosis appears to be closely correlated with the presence of associated generalized tonic–clonic (CGTC) seizures (worse if present) [9].

The juvenile absence epilepsy (JEA) has the same characteristics as CAE, but the age of onset is pubertal (9–13 years), and its frequency is lower: 1–10 per day.

Seizures are often associated with CGTC and more rarely, with sporadic myoclonia. Absence-type status epilepticus (SE) is also described. The interictal EEG is normal or with short bursts or groups of PO and PPO. PO discharges, predominantly frontal, are generally faster than 3 Hz (3.5–4 Hz), the first complex is often faster, and PPOs are frequent. However, seems to be very difficult to exactly define a certain border between these CAE and JAE, and there always remains a gray area between the two syndromes [61].

However, studies relating to this syndromic group are few. In a video-EEG study, Panayiotopoulos et al. [62], reported the characteristics of the absence seizures of patients with EAG, compared to those typical of EAI: Contact breaking is less important, eyes opening during the absence is less common, crises last longer, and discharges can become fragmented [9].

Reflex absences. They are classified based on the stimulus capable of causing them. According to the ILAE classification, reflex syndromes can be caused by visual, proprioceptive, and somatosensory stimuli and there are seizures caused by music, reading, contact with hot water, etc. However, the ILAE specifically mentions only idiopathic photosensitive occipital epilepsy, primary reading epilepsy, and startle epilepsy as reflex epilepsies. Seizures are usually of a generalized type on a clinical level (absences, myoclonia, generalized tonic–clonic seizures) [9].

Juvenile myoclonic epilepsy is a syndrome that begins in the pubertal period (12–18 years) and is typically characterized by massive, bilateral, single, arrhythmic, irregular myoclonic seizures, predominant in upper limbs, without alteration of contact with the environment. Myoclonias are more frequent after waking up at night and cause objects to fall from the hands. In addition to myoclonic seizures, subjects present CGTC (preceded by myoclonic seizures) in 85% of cases and absence seizures in approximately a third of cases. The critical EEG is characterized by generalized bursts of PP at 10–16 Hz, of medium voltage, followed by short sequences of slow waves at 1–3 Hz. Absence seizures are short and generally not associated with automatisms and from an EEG point of view, they correlate with discharges of irregular PO and PPO complexes at 3–4 Hz (with inscriptions of components at 2–7 Hz). The interictal EEG is characterized by normal background activity, with the possibility of recording short groups of generalized and irregular PO and PPO complexes [1].

The epilepsy with eyelid myoclonia should be considered if there are rhythmic and fast (>4 Hz) jerks of the eyelids, with an upward deviation of the eyeballs and with possible subtle head extension; seizures can be very frequent and can be triggered by eye closure and photic stimulation [63].

12. Neurocognitive aspects in CAE

The impact of absence epilepsy on neurocognitive functions can vary widely. While some individuals may not experience significant cognitive difficulties, others may exhibit varying degrees of impairment in cognitive domains such as memory, attention, and executive functions.

Even in the absence of visible seizures (ictal events), individuals with absence epilepsy may exhibit abnormal electrical brain activity during interictal periods. These interictal discharges can disrupt cognitive processing and contribute to neurocognitive impairments [64].

Furthermore, cognitive difficulties may depend on cortical microdysplasias for example, on the characteristics of absence seizures themselves (aura, ictal phase, perictal phase) or on anticonvulsant pharmacological treatment [65].

In 2013, a double-blind randomized clinical trial conducted on 446 children affected by CAE showed a high rate of attention deficits in patients before treatments and even if seizures were well controlled. Despite average intellectual ability, 35% of untreated children demonstrated the presence of clinically significant attention problems. Attention deficits in children with CAE have an important impact on learning and achievement. Although children may become seizure-free with a normalized EEG, attention deficits persist even with the use of the most efficacious medication. Furthermore, in this study, valproic acid affects attention more than either lamotrigine or ethosuximide [66].

Various areas of cognitive domains may be compromised in CAE patients. Below, we will analyze some of the cognitive domains affected by alterations or impairment.

To explain CAE comorbidities, several studies have evaluated the intellectual functioning of affected subjects in relation to healthy patients or other types of epilepsy. For assessing cognitive problems in children, intelligence tests are considered a first-line instrument. The results of intelligence quotient (IQ) tests were largely analyzed in various studies. Despite being within the normal range, the average IQ scores in current studies were significantly lower than those in healthy controls [65, 67, 68]. IQ appeared to be related to the frequency and extent of seizures [69]. The common hypothesis in multiple studies is that IQ could reflect the impact of seizures, considering lower age of onset and not well-controlled seizures, as negatively affecting cognition and language skills [70, 71]. Lower IQs in CAE children [72] are even related to social difficulties and behavioral problems. Performance analysis by testing found lower IQ scores in CAE subjects compared to those with partial or generalized seizures.

There is some evidence that a reduction of sleep spindle density in N2 sleep phase can represent a good EEG marker in predicting cognitive impairment in children with CAE [73].

The study of ASMs role on cognition has been widely debated in CAEs. Some studies have reported a significantly beneficial effect of AEDs, through seizure control, on various cognitive functions such as motor fluidity, memory, and attention [74]. However, Nolan et al. in 2003 [70] showed that the use of more than two anticonvulsant drugs was associated with lower IQ scores.

Pavone et al. conducted a study on 16 children suffering from an epileptic syndrome defined by clear diagnostic criteria: epilepsy with absences. All patients had negative neuroimaging and were under pharmacological treatment with ethosuximide, valproate, or both [65]. The researchers excluded all children with generalized tonic–clonic seizures. The abilities of these patients were compared with a control group of the same number. The study showed that global cognitive abilities appeared average (with total IQ between 71 and 120), although significantly deficient compared to the control group.

Visuospatial skills were moderately deficient in subjects with absence seizures. Furthermore, a selective deficit in non-verbal memory was observed, while language functions were generally preserved.

Studies conducted on surface-based morphometry in CAE patients have shown that the average intellectual functioning of these children reflects the neuropathology underlying CAE and is linked to plasticity and reorganization of brain development. In fact, CAE patients did not have cortical morphometric measures in line with age or related to other variables such as age of onset, seizure frequency, or AED intake. In particular, an increase in sulcal depth was found at the level of the superior temporal gyrus, the somatosensory region, and the left frontal lobe [75]. This suggests widespread neurocognitive deficits in patients with absence seizures involving multiple brain systems.

Several studies investigating verbal IQ in children with CAE, such as those conducted by Jones et al., Caplan et al., or Henkin et al. [8, 76, 77] revealed worse performances than normal children especially in verbal fluency [78].

Children affected by absence epilepsy often experience attention-related problems [69].

During absence seizures, individuals often experience a sudden and temporary loss of awareness or consciousness. This means their attention to their surroundings, ongoing activities, and conversations are interrupted [79].

Attention appears particularly vulnerable to epileptic activity [80]. At the same time, seizures themselves are typically very brief (usually lasting only a few seconds), these interruptions can disrupt attention and concentration, especially if they occur frequently throughout the day [81].

A study by Cerminara et al. [82] assessed the attentional characteristics of children with CAE using tests that measure attention and discovered that patients with CAE had lower scores in the areas of vigilance, selective attention, and impulsivity compared to healthy controls.

Neuroimaging studies demonstrate significant changes in brain networks underlying attention, such as, for example, decreased activity in the anterior insula of the medial frontal cortex [1, 80].

Regarding how treatment affects attentional abilities, several studies agree that VPA can cause a worsening of attentional abilities more than other antiepileptic drugs [83].

Visual memory is impaired in children with CAE, as evidenced by multiple studies [75], while others have found no significant differences with children with other epileptic syndromes [84]. The presence of epileptic seizures in children and adolescents for several years can lead to problems with consolidating knowledge, which can negatively impact school results [85].

A deficit of executive functions is frequently found in subjects with epilepsy, as demonstrated by several studies [72, 84], even in CAE children compared to healthy controls [86]. The affected children showed difficulties in those domains of frontal executive functions such as decision-making skills, problem-solving, and planning, in particular, the difficulty they had concerned knowing how to change responses based on external requests.

13. Comorbidities

Studies focused on CAE have shown the presence of learning disabilities in this group of patients. Frequent absence seizures, if uncontrolled, can interfere with the learning process, particularly in school-aged children. These seizures can disrupt the continuity of lessons and affect the ability to retain information [8].

Vanasse et al., in a 2005 study [87], demonstrated that even children suffering from generalized seizures, specifically absence seizures, had difficulties in reading. Many children struggle to acquire the phonological strategies that underlie learning to read.

The involvement of both the temporal and frontal lobes in the phonological reading processes has largely been demonstrated; about this, patients with complex partial epilepsy show difficulties in reading skills [88, 89].

Despite seizures per se, duration, age of onset, and other factors influencing cognitive abilities, and variables such as familial factors or neuropsychological comorbidities are often significant in influencing underperformance at school in epileptic children [77].

Attention deficit hyperactivity disorder (ADHD) may co-occur with epilepsy in some cases, especially in children. The presence of both conditions can complicate diagnosis and management.

ADHD is the most common disorder in preschool and school-age children with epilepsy [90]. It has a negative impact on the quality of life and represents a significant risk factor for academic performance [91].

There is evidence pointing to a complex relationship between ADHD and seizure disorders. Some literature studies have demonstrated the presence of ADHD, anxiety, and depression disorders in children affected by CAE [8, 92]. A close association between these pathologies has recently been postulated. The mechanisms underlying attention deficits are still unknown and appear to be different between generalized and focal epilepsies [93].

ADHD and selective attention deficits are more prevalent in children with CAE than in typically developing children. ADHD is reported to be comorbid in children with childhood epilepsy in about 12–17% of cases [94]. In several studies, comorbid ADHD was diagnosed in about 40% of CAE patients [95, 96].

In particular, some findings suggest that recurrent seizures and treatment may not be the main etiological factor underlying ADHD [97] and that attention deficit and hyperactivity symptoms start before the diagnosis of epilepsy [95, 97]. From most recent studies, it is therefore clear that the early diagnosis of ADHD in comorbidity with epilepsy is useful to correctly plan a pharmacological treatment.

Furthermore, a significant proportion of patients affected by epilepsy, between 10 and 15%, manifests intellectual disability [65].

The comorbidity between intellectual disability and epilepsy is well-documented and relatively common. Studies have shown that individuals with intellectual disabilities have a higher risk of developing epilepsy than the general population. Individuals with intellectual disabilities may have a higher predisposition to epilepsy due to underlying structural brain abnormalities or genetic factors [98]. As discussed, epilepsy can potentially lead to intellectual impairment, particularly if seizures are frequent, severe, or difficult to control.

In this regard, for example, a syndrome has been described as a phenotype of the 15q13.3 microdeletion syndrome, characterised by absence seizures and intellectual disability [99].

Regarding behavioral problems, there is an ongoing debate as to whether these problems are an integral part of epilepsy syndrome or whether they develop due to factors associated with the disease [100].

Some researchers argue that behavioral problems are intrinsic to certain epilepsy syndromes. They believe that abnormal electrical activity in the brain during seizures or interictal periods can directly affect mood and behavior [101].

In addition, the resulting psychosocial disruption of diagnosis in patients’ lifestyles or therapeutic interventions with AEDs can also cause behavioral effects [102]. Some AEDs may lead to mood swings, aggression, or other behavioral changes [103].

In this regard, we recall a 1997 study, in which Elaine et al. hypothesized that patients suffering from absence epilepsy could have more serious psychosocial disorders than patients suffering from chronic non-neurological pathologies [104].

In the study, two groups of patients were compared: one group was made up of young adults who had been diagnosed with CAE, and the other group was affected by juvenile rheumatoid arthritis. The study found that patients suffering from CAE had many more psychosocial problems than those suffering from arthritis. Patients with CAE, in fact, had greater scholastic difficulties, increased need for scholastic support, major behavioral problems, and relationship difficulties with peers and family members.

Psychiatric and emotional disorders were reported in both groups but were more common in subjects with CAE. Furthermore, remission of epileptic seizures did not lead to an improvement in the psychosocial condition, although subjects whose seizure remission was not observed showed a remarkable worsening and a higher risk of psychiatric and emotional disorders.

Furthermore, the presence of these comorbidities can contribute to causing difficulties in socialization and poor academic results in patients with CAE.

Individuals with epilepsy may also have comorbid psychiatric disorders, such as depression, anxiety, or ADHD [105]. At least 50–60% of patients with epilepsy develop psychiatric disturbances.

Depression is one of the most common psychiatric disorders in people with epilepsy. The physical and emotional impact of seizures, as well as the social stigma associated with epilepsy, can contribute to feelings of sadness and hopelessness [106].

Depressive and anxiety syndromes are the most frequent disorders in adults with epilepsy [107], and there is much literature evidence that epilepsy and depression share a bidirectional relationship, although the nature of this relationship remains unclear at present [108].

Anxiety disorders, including generalized anxiety disorders and specific phobias, are more prevalent in individuals with epilepsy. The unpredictability of seizures can lead to heightened anxiety [109, 110].

A study on 45 subjects with CAE and 41 healthy controls, between the ages of 6 and 16 years specifically examined anxiety and depression symptoms, revealing that children with CAE demonstrated higher rates of anxiety and depression symptoms and greater general psychosocial problems, while intractability, disease duration, and medication effects were not associated with higher rates of affective problems [99], although an iatrogenic role in this context cannot be ruled out.

However, Ott et al., in 2001 [111], administrating the Diagnostic Interview for the Evaluation of Psychopathological Disorders in Children and Adolescents (K-SADS-PL) reported mood disorders, specifically anxiety and depression disorders, in 12% of 48 children suffering from complex partial seizures and in 18% of 40 children suffering from CAE.

Caplan et al., in a 2005 study [92] conducted on 171 children, of which 100 with complex partial epilepsy, 71 with absence epilepsy, and 93 healthy children, demonstrated that 33% of children affected by complex partial epilepsy and absence epilepsy suffer from affective disorders, especially anxiety disorders. Individuals with epilepsy, particularly those with comorbid psychiatric disorders, may be at a higher risk of suicide [112].

In conclusion, we can state that although CAE is historically considered a benign disorder, children affected may present several difficulties in psychosocial adaptation [1].

An early diagnosis and evaluation of comorbidities can favor the implementation of specific interventions such as cognitive-behavioral therapy, school and educational approaches, and psychological support [1] that help to contain and reduce negative prognostic outcomes related to neurodevelopmental disorders.

14. Iatrogenic effects of treatment

Antiepileptic drugs (AEDs) are a common cause of cognitive and behavioral effects in children with CAE.

Cognitive functions, including vigilance, attention, psychomotor speed, memory, and mood, are also the domains affected. Despite iatrogenic effects, epilepsy treatment may positively affect patients’ cognitive performances by stopping or decreasing seizures [113, 114].

Some common cognitive side effects associated with certain AEDs include memory problems, attention and concentration, language and verbal skills [114].

Certain AEDs may affect language abilities, leading to difficulties with speech or comprehension.

New antiepileptic drugs generally produce fewer cognitive effects, although topiramate may impair attention, memory, and language.

Most studies agree that high doses of antiepileptic drugs and polytherapy compromise concentration, motor skills, and memory functions [65].

The effects of valproate have not yet been carefully studied in children, but we know that the drug has mild effects on cognitive abilities [101, 115].

A more recent study reports that valproic acid does not cause consequences on cognitive abilities if the ammonia level is controlled [116] and that ethosuximide does not cause cognitive deterioration, although the available data are still sketchy [116].

In some cases, cognitive side effects may be dose-dependent, meaning that higher doses of medication are more likely to cause cognitive impairment [66].

A targeted therapy evaluating the benefits and potential side effects of AEDs is recommended, searching for the best way to control seizures with minimal cognitive side effects [102].

15. Conclusion

CAE is a common epilepsy syndrome whose diagnosis is not difficult, and it should be considered in every child with normal development and multiple daily absence seizures associated with 3 Hz generalized spike-and-wave. Seizures are usually drug-responsive, and it is possible to retain first-line monotherapies: ethosuximide followed by valproate. CAE may be associated with impairments in executive function, attention, and concentration, and it may be correlated with learning disabilities, language disorders, and neuropsychological problems such as anxiety and depression. According to this perspective, taking care of patients with CAE may require a multispecialty approach especially when it is necessary to treat cognitive-behavioral disorders or drug-resistant seizures.