Co‐occurrence of childhood absence epilepsy and self‐limited focal epilepsy interictal discharges: Differences from childhood absence epilepsy alone

Abstract

Objective

Some children with Childhood Absence Epilepsy (CAE) exhibit focal abnormalities similar to those observed in Self‐Limited Focal Epilepsies of Childhood (SeLFEs). It remains unclear whether this subgroup of patients may present distinct clinical characteristics or prognoses compared to those with CAE and generalized discharges alone. In this study, we retrospectively evaluated the electroclinical features of patients with CAE plus focal abnormalities and compared them with those with CAE lacking focal abnormalities.

Methods

We included children diagnosed with absence epilepsy with onset before the age of 10 years and normal neuropsychomotor development prior to seizure onset. These patients were evaluated and followed up at our Institute between January 2013 and January 2023.

Results

Fifteen out of 100 patients with CAE (15%) exhibited focal epileptiform abnormalities characteristic of SeLFEs. In 6 cases (40%), focal interictal epileptiform discharges (IEDs) emerged only after the resolution of absences during routine electroencephalograms (EEGs), while in 9 cases (60%), they occurred concurrently with generalized discharges in the same EEG. Three patients experienced clinical seizures associated with both syndromes, and one of them displayed during the same recording a focal seizure immediately followed by an absence seizure. Patients with both generalized and focal epileptiform abnormalities (CAE plus SeLFE‐IEDs/SeLFEs) showed similar outcomes compared to those with generalized abnormalities alone, but they had an earlier age at absence onset (4.3 years vs. 5.7 years, p = 0.03), an increased occurrence of automatisms during absence seizures (50% vs. 17.5%, p = 0.02), and required a higher number of antiepileptic drugs to control absences (average 2.1 vs. 1.4, p = 0.002).

Significance

CAE and SeLFEs share several features, and their coexistence or sequential evolution in clinical practice is not uncommon. This overlap may suggest common pathophysiological mechanisms involving cortico‐thalamo‐cortical circuits.

Abbreviations

AED

antiepileptic drugs

AS

absence seizures

BOLD

blood oxygenation level‐dependent

CAE

childhood absence epilepsy

CBZ

carbamazepine

CGH

comparative genomic hybridization

COVE

childhood occipital visual epilepsy

CT

centro‐temporal

DEE‐SWAS

developmental/epileptic encephalopathy with spike–wave activation in sleep

EEG

electroencephalogram

ETS

ethosuximide

FS

febrile seizures

Gen

generalized

GS

global intelligent score

IEDs

interictal epileptiform discharges

IGEs

Idiopathic Generalized Epilepsies

ILAE

International League Against Epilepsy

IPS

intermittent photic stimulation

L

left

LEV

levetiracetam

LTG

lamotrigine

MRI

magnetic resonance imaging

NGS

next‐generation sequencing

OXC

oxcarbazepine

PO

parieto‐occipital

R

right

SeLEAS

self‐limited epilepsy with autonomic seizures

SeLECTS

self‐limited epilepsy with centro‐temporal spikes

SeLFEs

Self‐Limited Focal Epilepsies

SWDs

generalized spike–wave discharges

TCS

tonic–clonic seizures

TO

temporo‐occipital

VPA

valproic acid

WES

trio exome sequencing

Key points.

• The literature rarely reports the coexistence of Childhood Absence Epilepsy (CAE) and Self‐limited Focal Epilepsies (SeLFEs). More commonly, there is copresence with focal interictal epileptiform discharges typical of Self‐limited Focal Epilepsy (SeLFE‐IEDs).

• We evaluated the electroclinical features of a cohort of patients diagnosed with CAE at our Institute, who also exhibited SeLFE‐IEDs or SeLFEs, and compared their course and outcome to patients with CAE alone.

• CAE and SeLFEs may be pathophysiologically related, potentially sharing an underlying genetic pathogenesis that alters functionally cortico‐thalamo‐cortical networks.

1. INTRODUCTION

Childhood Absence Epilepsy (CAE), also known as “petit mal seizures,” is one of the four Idiopathic Genetic Generalized Epilepsies (IGEs) identified by the 2017 International League Against Epilepsy (ILAE) classification, ¹ with an annual incidence of 8 cases per 100 000 children. ² CAE accounts for approximately 18% of epilepsy cases in school‐aged children. ¹ It is characterized by daily absence seizures in otherwise healthy children, associated with 2.5–4 Hz generalized spike–wave discharges, often facilitated by hyperventilation. ³ The interictal wake electroencephalogram (EEG) typically shows normal background activity, though occasional generalized spike–wave discharges or focal abnormalities may be present. ⁴ Notably, the updated classification of epilepsy syndromes has moved consistently unilateral focal spikes from the “exclusionary” to the “alert” category for CAE diagnosis, as some children with CAE also exhibit centro‐temporal spikes or sharp waves. ¹

A few reports have described the rare coexistence of CAE and Self‐Limited Focal Epilepsies of childhood (SeLFEs), with rare ictal EEG recordings available. ⁵ , ⁶ , ⁷ , ⁸ , ⁹ , ¹⁰ , ¹¹ The co‐presence of CAE and focal interictal epileptiform abnormalities typical of Self‐Limited Focal Epilepsy (SeLFE‐IEDs)—high‐amplitude sharp and slow‐wave complex activated during sleep ¹² —appears to be more frequent, ranging from 1.4% to 14.8%. ⁷ , ⁸

In this article, we describe a retrospective series of patients with co‐occurrence of CAE and SeLFE‐IEDs or SeLFEs and compare their evolution to a group of children with CAE alone.

2. METHODS

We conducted a retrospective review of patients diagnosed with CAE with onset before age 10 and normal neuropsychomotor development prior to seizure onset. These patients were evaluated at the Giannina Gaslini Institute, a tertiary hospital center, between January 2013 and January 2023 (Figure 1). The objective of our study was to describe patients with CAE who also presented interictal epileptiform abnormalities or clinical seizures characteristic of SeLFEs.

FIGURE 1.

Study design.

In accordance with the ILAE's Position Statement on Nosology and Definitions, CAE was diagnosed through wake EEGs performed with hyperventilation and intermittent photic stimulation (IPS), identifying cases where EEG recordings displayed typical 2.5–4 Hz generalized spike–wave discharges (SWDs) corresponding to clinical absence seizures. ¹ Patients were excluded if ictal EEG recordings were unavailable or if follow‐up was less than two years since onset. Additionally, children with structural Magnetic Resonance Imaging (MRI) abnormalities suggestive of potential epileptogenic lesions, those with neurodevelopmental issues prior to epilepsy onset, and subjects harboring a pathogenic variant in SLC2A1 were excluded by the study.

All patients underwent follow‐up visits and wake EEGs every 6 to 8 months. For all patients, we had at least a 20‐minute wake EEG with hyperventilation and IPS. We classified the appearance of focal abnormalities (high‐amplitude sharp and slow‐wave complexes) as “further” if SeLFE‐IEDs emerged only after complete control of absence seizures, during routine control EEGs, regardless of ongoing antiseizure medications. Conversely, we classified SeLFE‐IEDs as “concomitant” if focal abnormalities—either mono‐ or plurifocal—were present on the same EEG recording showing generalized SW discharges with clinically correlated absences.

Data collected included age of onset, treatment response to antiepileptic drugs (AEDs), later emergence of neurodevelopmental issues, additional instrumental evaluations, and follow‐up outcomes.

3. RESULTS

We identified 100 patients with CAE (46 males, 54 females; mean age of onset 5.1 years, range 1–10 years) who underwent a median follow‐up of 7.8 years (range 2–18 years).

Among our sample, 15 children (15%) exhibited interictal epileptiform discharges (IEDs) typical of SeLFEs at absence onset or during follow‐up. Specifically, in 6 cases (40%), SeLFE‐IEDs appeared after the resolution of absence seizures: 5 during treatment with AEDs and 1 after AEDs withdrawal. Five of these patients had centro‐temporal focal abnormalities, while 1 case showed migration of the epileptogenic focus from centro‐temporal to temporo‐occipital regions. In the remaining 9 patients (60%), SeLFE‐IEDs occurred concomitantly with generalized spike–wave discharges and absences, with 8 showing a centro‐temporal distribution and 1 a temporo‐occipital distribution.

We collected clinical data for all patients (Table 1). CAE plus SeLFE‐IEDs/SeLFEs group is analyzed in Table 2. Comparison of the two groups (Table 1, N = 15; N = 85) revealed that some clinical features were more frequent in the CAE plus SeLFE‐IEDs/SeLFEs group. These included an earlier onset of absence seizures (4.3 years vs. 5.7 years, p = 0.03) and a higher number of AEDs used to treat absences (average 2.1 vs. 1.4, p = 0.002). Moreover, we observed a slight predominance of males and a higher incidence of febrile seizures in the CAE plus SeLFE‐IEDs/SeLFEs group, although these differences were not statistically significant (Table 1). In addition, when evaluating absence characteristics at onset (video or descriptive report available in 69 patients), we observed that subjects with CAE plus SeLFE‐IEDs/SeLFEs had a higher incidence of automatisms during absence seizures (50% vs. 17.5%, p = 0.02).

TABLE 1.

Comparison between CAE alone (no focal abnormalities) and CAE with further or concomitant focal abnormalities typical of SeLFEs.

	CAE alone (sample 1) (N = 85 pt)	CAE with further SeLFE‐IEDs (sample 2) (N = 6 pt)	CAE with concomitant SeLFE‐IEDs (sample 3) (N = 9 pt)	CAE with further + concomitant SeLFE‐IEDs (sample 2 + 3) (N = 15 pt)	P value (comparison between sample 1 and sample 2 + 3)
Gender					0.37
M	38 (44.7%)	3 (50%)	5 (55.6%)	8 (53.3%)
F	47 (55.3%)	3 (50%)	4 (44.4%)	7 (46.7%)
Age of CAE onset (years)					0.03
Mean ± SD	5.7 ± 2.2	4.2 ± 2.0	4.4 ± 2.1	4.3 ± 1.9
Median (min, max)	6 (1, 10)	5 (1.5, 6)	4 (1, 8)	4 (1, 8)
Absence seizure duration (sec) a					0.81
Mean ± SD	10.1 ± 7.0 (of 57 pt)	9.8 ± 7.0 (of 4 pt)	9.8 ± 7.1 (of 8 pt)	10.3 ± 6.7 (of 12 pt)
Median (min, max)	7 (2, 30)	9 (3, 18)	11.5 (3, 25)	11.5 (3, 25)
Presence of automatisms a	10 (17.5%) (of 57 pt)	1 (25%) (of 4 pt)	5 (62.5%) (of 8 pt)	6 (50%) (of 12 pt)	0.02
Positive family history for epilepsy/FS	34 (40%)	3 (50%)	2 (22.2%)	5 (33.3%)	0.78
Febrile seizures	7 (8.2%)	1 (16.7%)	2 (22.2%)	3 (20%)	0.17
Tonic–clonic seizures	11 (12.9%)	0 (0%)	1 (11.1%)	1 (6.7%)	0.69
Number of AEDs tried					0.002
Mean ± SD	1.4 ± 0.6	2 ± 0.6	2.1 ± 1.2	2.1 ± 0.9
Median (min, max)	1 (0, 3)	2 (1, 3)	2 (1, 4)	2 (1, 4)
Absence drug resistance b	6 (7.1%)	1 (16.7%)	2 (25%) (of 8 pt)	3 (21.4%) (of 14 pt)	0.11
Follow‐up from CAE onset (years)					0.77
Mean ± SD	7.4 ± 3.3 (of 81 pt)	10.5 ± 4.7 (of 6 pt)	6.7 ± 4.2 (of 9 pt)	8.2 ± 4.7 (of 15 pt)
Median (min, max)	7 (2, 17)	9 (5, 18)	5 (3, 14)	8 (3, 18)
Drug withdrawal at follow‐up	66 (77.6%)	5 (83.3%)	6 (66.7%)	11 (73.3%)	0.74
Drug withdrawal (years)					0.27
Mean ± SD	5.6 ± 2.8 (of 68 pt)	7.2 ± 2.9 (of 5 pt)	5.8 ± 3.3 (of 6 pt)	6.5 ± 3.0 (of 11 pt)
Median (min, max)	5 (2, 14)	7 (4, 12)	6 (2, 11)	7 (2, 12)
Follow‐up from AEDs withdrawal (years)					0.93
Mean ± SD	1.8 ± 1.3 (of 68 pt)	1.8 ± 1.3 (of 5 pt)	2.2 ± 2.4 (of 6 pt)	2 ± 1.9 (of 11 pt)
Median (min, max)	1 (1, 6)	1 (1, 4)	1 (1, 7)	1 (1, 7)
Time between last seizure‐drug withdrawal (years)					0.19
Mean ± SD	3.3 ± 1.7 (of 78 pt)	4.8 ± 1.9 (of 5 pt)	3.8 ± 2.6 (of 6 pt)	4.3 ± 2.2 (of 11 pt)
Median (min, max)	3 (1, 7)	5 (2, 7)	2.5 (2, 8)	4 (2, 8)
Neurodevelopmental issues during the follow‐up	23 (27.1%)	1 (16.7%)	3 (30%)	4 (26.7%)	1

Abbreviations: AEDs, antiepileptic drugs; CAE, childhood absence epilepsy; CBZ, carbamazepine; IEDs, interictal epileptiform discharges; SeLFEs, self‐limited focal epilepsies; OXC, oxcarbazepine. Bold: statistically significant results.

^a These data were available for 69 patients.

^b Drug resistance defined by the persistence of seizure, despite 2 appropriately chosen AEDs at adequate dosage.

TABLE 2.

Clinical data of patients with CAE and SeLFE‐IEDs/SeLFEs.

Case, gender	CAE onset (years)	Family history for FS/epilepsy	Seizure type	Focal abnormalities (SeLFE‐IEDs)	Timing AS/SeLFE ‐IEDs	Brain MRI	AEDs	Absence resolution with AEDs withdrawal (years)	Drug‐resistance	Neuropsychiatric comorbidities after epilepsy onset	Follow‐up (years)
1, M	6	No	FS, AS	Bilateral CT	Concomitant	Normal	VPA	8	No	No	9
2, F	5	Yes	AS	R CT	Further	Normal	VPA, ETS	12	No	Learning disorder	13
3, F	8	Yes	AS, TCS	Bilateral CT	Concomitant	NP	VPA, TPM	15	No	No	16
4, M	5	No	AS	L CT	Concomitant	NP	VPA, ETS	16	No	No	18
5, F	4	No	AS, Focal seizure	L CT	Concomitant	NP	VPA	Unknown	–	Eating disorder	9
6, F	5	No	AS	Bilateral CT	Further	Normal	VPA	9	No	No	10
7, F	4	No	AS	Bilateral CT	Concomitant	Normal	VPA, LEV	7	No	No	8
8, M	6	No	AS	L CT	Concomitant	NP	VPA	11	No	No	12
9, M	1	No	AS	Bilateral TO	Concomitant	NP	VPA, LEV, ETS, LTG	–	Yes	No	4
10, F	2.5	Yes	FS, AS, Focal seizures	R CT	Concomitant	Normal	VPA, ETS, LEV, LTG	–	Yes	Decline of cognitive performance	6.5
11, M	1.5	No	AS, Focal seizure	Bilateral CT	Further	Normal	VPA, ETS, LEV	8.5	No	No	15.5
12, F	2	Yes	FS	Bilateral TO	Further	NP	VPA, LEV	–	Yes	No	20
13, M	6	Yes	AS	R CT	Further	Normal	ETS, VPA	12	No	No	16
14, M	6	No	AS	L CT	Further	Normal	ETS, VPA	13	No	No	14
15, M	4	No	AS	L PO then bilateral CT	Concomitant	Normal	ETS, VPA	11	No	Learning disorder	18

Abbreviations: AEDs, antiepileptic drugs; AS, absence seizures; CAE, childhood absence epilepsy; CT, centro‐temporal; ETS, ethosuximide; FS, febrile seizures; Gen, generalized; IEDs, interictal epileptiform discharge; L, left; LEV, levetiracetam; LTG, lamotrigine; n/a, not available; NP, not performed; PO, parieto‐occipital; R, right; SeLFEs, self‐limited focal epilepsies; TCS, tonic–clonic seizures; TO, temporo‐occipital; VPA, valproic acid.

None of the patients with CAE and SeLFE‐IEDs/SeLFEs were treated with carbamazepine or oxcarbazepine. The median follow‐up from the onset of absence seizures (7 years vs. 8 years) and after AEDs withdrawal (1 year) was similar between the two groups (Table 1). No significant differences were found in terms of the possibility of drug withdrawal (p = 0.74) or the presence of neurodevelopmental issues at follow‐up (p = 1). The time from the last seizure and AEDs withdrawal was longer for patients with CAE plus SeLFE‐IEDs/SeLFEs compared to those with CAE and no focal abnormalities, but this difference was not statistically significant.

Two children demonstrated electroclinical characteristics of both syndromes at different ages (SeLFEs after CAE), while one girl presented with concurrent features of both syndromes at the same time (patient 10). Specifically, one male patient (patient 11) experienced a single focal seizure 10 years after the onset of CAE, diagnosed at 18 months old, several years after withdrawal of valproate and ethosuximide. One female (patient 5), diagnosed with CAE at the age of 4, developed a single focal motor seizure at 9 years of age during AED (valproate) treatment (continued after unsuccessful attempt to withdraw and transient recurrence of absences when 8 years old). Both patients are now seizure‐free, off therapy, and exhibit normal development and cognition.

3.1. Case report

G.I. (Patient 10, Table 2) is the first‐born child of non‐consanguineous parents. Her pregnancy and delivery were uneventful. She experienced two episodes of simple febrile seizures (FS) at ages 18 and 30 months. Both her mother and brother have a history of febrile seizures, too.

At 30 months of age, G.I. began having episodes of daily psychomotor arrest. Her first EEG showed a typical electrographic pattern with generalized 3.5 Hz spike–wave discharges, correlating with clinical absence seizures (Figure 2A). She was diagnosed with early‐onset CAE, and treatment with valproate (VPA) was initiated, providing transient seizure control.

FIGURE 2.

Patient 10. Panel A. Two years of age. Absence seizure (3 Hz spike–waves synchronous bilateral discharge) recorded at onset. Panel B. Three years of age. Ictal recording of a somatosensitive seizure associated with a focal right centro‐temporal discharge followed by a clinical absence during a 3 Hz bilaterally synchronous spike–wave discharge. SI 10–20 system, 30 sec/pg, Sens 14 uV/mm, HF 50 Hz.

One year later, following an infection, absence seizures recurred, and focal epileptiform abnormalities were observed over the right centro‐temporal (CT) regions. Subsequent EEG recorded a somatosensitive seizure with a focal discharge over the right CT area, followed by a generalized absence seizure (Figure 2B). Clinically, she reported a sensation starting on the left side of her body and extending to the left side of her face, without awareness of the generalized seizures.

A few weeks later, focal motor seizures developed, characterized by twitching of the left or right hemiface, drooling, and anarthria. Add‐on treatment with ethosuximide (ETS) was only partially effective for the generalized seizures, while adding levetiracetam (LEV) improved control of the focal seizures. At the age of 4, treatment with lamotrigine (LTG) was started, resulting in fluctuating seizure control. A worsening of the sleep EEG was observed, showing subcontinuous centro‐temporal activity. Consequently, steroid pulse therapy with prednisone (1.5 mg/day for 3 months, followed by a 6‐month taper) was administered, yielding only minimal improvement.

Over the course of the disease, G.I. showed a worsening of cognitive performance on neurodevelopmental scales, at first in normal ranges, with a global intelligence score (GS) of 69 at seven years of age, accompanied by slight deficits in working memory and processing speed. Genetic testing was inconclusive, with a normal 180 K array‐CGH (Comparative Genomic Hybridization), NGS (Next‐Generation Sequencing) epilepsy gene panel, and trio exome sequencing (WES). Two variants of uncertain significance (GABRG2 c259 G>A pVal87Met and NTRK2 c1976 C>T pPro659Leu) inherited from the healthy father were identified but were not considered causative. Brain MRI and neurological examination remained normal.

4. DISCUSSION

CAE and SeLFEs are the most frequent epileptic syndromes in childhood, accounting for 18% and 23% of cases in school‐age children, respectively. ¹ , ¹³ Data from the literature support a polygenic inheritance pattern in both cases. ⁴ , ¹⁴ First‐ and second‐degree relatives of patients with IGE experience seizures in approximately 13% of cases, a figure that rises to 41–48.6% in the specific case of CAE. ¹⁴ , ¹⁵ , ¹⁶ Moreover, CAE is also often associated with febrile seizures in 10–15% of cases. ¹ Genetic factors are believed to play a significant role in SeLFEs too, as evidenced by the higher incidence of a positive family history of epilepsy. ¹⁴ Similar to CAE, background activity and sleep architecture are generally normal in SeLFEs, although some cases may develop electrical status epilepticus during sleep. ¹⁷ In both syndromes, the majority of patients achieve seizure resolution by puberty. ¹⁸

Very often, a precise syndromic diagnosis is possible since seizure onset both in CAE and SeLFEs. ¹⁹ Clinical or electroencephalographic clues observed at onset or during routine evaluations may be relevant for identifying prognostic factors, as some rare cases can be difficult to treat, persist into adulthood, or even evolve into different syndromes.

While the coexistence of CAE and SeLFEs within the same patient is rarely reported in the literature, the occurrence of IEDs typical of SeLFEs in children with CAE is relatively common. ⁵ , ⁶ , ⁷ , ⁸ , ⁹ , ¹⁰ , ¹¹ Our analysis supports this finding, with 15% of our sample of children with CAE showing SeLFE‐IEDs during routine wake EEGs (Figure 1). Among them, only 3% of patients exhibited focal seizures indicative of SeLFEs, occurring either following or concomitantly with absence seizures. None of the patients in our sample were treated with carbamazepine or oxcarbazepine, so drug‐induced effects can be ruled out.

In most cases, the abnormalities were localized to the centro‐temporal regions, either unilaterally or bilaterally. Consistent with this, focal seizures were somato‐motor in all three patients with SeLFEs. The length of follow‐up was similar in both groups.

When comparing patients with CAE plus SeLFE‐IEDs/SeLFEs to those with CAE alone, we observed an earlier onset of absence seizures in the former group (4.3 years vs. 5.7 years, p = 0.03), as well as a higher number of antiepileptic drugs (AEDs) used to treat absences (average 2.1 vs. 1.4, p = 0.002) and a higher incidence of automatisms during absence seizures at onset (video or descriptive reports available for 69 patients: 50% vs. 17.5%, p = 0.02). Additionally, there was a slight predominance of males and a higher incidence of febrile convulsions in the first group, though these differences were not statistically significant. Interestingly, the time from the last absence seizure and drug withdrawal was longer for patients with CAE plus SeLFE‐IEDs/SeLFEs, suggesting that the presence of focal abnormalities may prompt greater caution in reducing therapy and extending treatment duration.

From a clinical perspective, since the final outcomes in terms of drug withdrawal and the risk of neurodevelopmental issues did not differ between the two groups, a different approach to maintenance of therapy does not appear to be justified.

In our study, only one child presented with clinical seizures indicative of both CAE and SeLFEs at the same time (self‐limited epilepsy with centro‐temporal spikes—SeLECTS), requiring polytherapy and demonstrating neurocognitive slowing during follow‐up. Video‐EEG revealed a centro‐temporal epileptiform discharge followed by 3 Hz bilaterally synchronous spike–wave discharges (SWDs) associated with a somatosensory seizure, followed by a typical absence seizure (Figure 2, Panel B). This pattern closely resembles the sequential seizures reported by Caraballo and colleagues (2005), ²⁰ where the authors proposed the possibility of secondary bilateral synchrony. It is important to note that a unique ictal pattern does not exist in SeLFEs; rather there is variability in both clinical and subclinical discharges with potential evolution of the same discharge into different patterns. ²¹ This was observed in our case; moreover, a generalized seizure immediately followed the focal one. Some years after CAE onset, this child developed an activation during sleep of her focal high‐amplitude sharp and slow‐wave complexes similar to a Developmental/Epileptic Encephalopathy with Spike–Wave Activation in Sleep (DEE‐SWAS) pattern. Since she was already on polytherapy for drug‐resistant absences, we are not able to define if the worsening observed during serial neurocognitive evaluations was related to the drug resistance itself, or to polytherapy, or to DEE‐SWAS.

The coexistence of CAE and SeLFEs has been rarely reported in the literature. Beaumanoir et al. described clinical and EEG evidence of typical absence seizures in 6 (23%) of 26 children diagnosed with SeLFEs, one of the highest reported percentages in the literature. ²² Later, Gastaut et al. observed 19 patients (38%) out of 50 subjects with occipital or centro‐temporal SeLFE‐IEDs who also exhibited bilaterally synchronous spike–wave discharges (SWDs) typical of Idiopathic Generalized Epilepsy (IGE). ¹¹ Notably, febrile seizures or a positive family history for febrile seizures were common in their cohort, suggesting a broader predisposition to seizures. Ramelli et al. described five children with co‐occurrence of 3 Hz generalized spike–wave discharges and SeLECTS‐IEDs, two of whom had both absence and focal motor seizures. ¹⁰

Caraballo et al. investigated the electroclinical features and evolution of 203 patients with CAE and reported that 30 of them had SeLFE‐IEDs, but only 7 suffered from clinical seizures. These seizures were all typical of occipital SeLFEs, 3 self‐limited epilepsy with autonomic seizures (SeLEAS) and 4 with childhood occipital visual epilepsy (COVE). ⁷

Verrotti et al. conducted a literature review and identified 19 patients with both CAE and SeLECTS. Among these, 3 children exhibited concurrent clinical manifestations of both syndromes (2 with onset of absences), while 16 had sequential manifestations. In the second group, three cases of SeLECTS developed absence seizures after initiating treatment with AEDs. Some authors have reported this occurrence in patients treated with Oxcarbazepine (OXC) or Carbamazepine (CBZ), suggesting that a drug‐induced mechanism in some cases cannot be excluded. ⁵

As observed in our sample, SeLFE‐IEDs are much more common than the clinical manifestation of SeLFEs. In fact, only 5% of individuals with SeLFE‐IEDs will develop a clinical SeLFE syndrome. Moreover, while absence seizures are frequently recorded due to their high frequency and daily occurrence, ictal recordings of focal seizures in SeLFEs are rare, despite their common occurrence in the pediatric population. This is because focal seizures typically occur infrequently and often during sleep, making them harder to capture. ¹² Given that we only performed wake EEG in our CAE sample, it is likely that we have underestimated the frequency of both SeLFE‐IEDs and SeLFEs.

On the contrary, we cannot exclude the possibility that we more frequently observed complex patterns with combined syndromes or both electrographic characteristics of CAE and SeLFEs since our study was conducted in a tertiary Epilepsy Centre, potentially introducing a selection bias.

Drawing from evolving theoretical frameworks, such as the “cortical focus” theory, it is recognized that absence seizures may originate from limited cortical areas, suggesting a potential pathophysiological link between SeLFEs and CAE. This link may involve a hereditary and multifactorial component. ²³ , ²⁴ , ²⁵ Blood oxygenation level‐dependent (BOLD) functional MRI has been employed in several studies to identify focal areas involved in the origin of absence seizures. ²⁶ , ²⁷ , ²⁸ , ²⁹ Additionally, recent research emphasizes the role of the thalamus in CAE; according to a “unified” perspective, neuronal activity occurs simultaneously in both the thalamus and cortex.

This leads to a cascade of events originating in the Cortical Initiation Network, which results in bilateral generalized spike–wave discharges (SWDs), with the thalamus amplifying this activity through resonant cortico‐thalamic loops. ²⁰ , ³⁰ , ³¹ , ³² Experimental studies have demonstrated that spontaneous spindle waves during sleep, as well as evoked thalamo‐cortical or cortico‐thalamic responses mimicking spindle waves, can transform into bilateral spike–wave discharges under conditions of increased cortical excitability. ³³ , ³⁴ This highlights the role of thalamo‐cortical spindles and spindle‐like oscillations in promoting the generation and widespread synchronization of generalized spike–wave complexes.

Additionally, experimental models have described localized spike–wave discharges confined to a specific regional thalamo‐cortical circuit, involving a restricted pool of cortical neurons. ³⁵ In parallel, clinical studies have shown that thalamo‐cortical oscillations, which generate sleep spindles, can modulate the sleep‐related activation of spike and sharp waves in both CAE and focal self‐limited epilepsies. ³⁶ , ³⁷ , ³⁸ This suggests that the same thalamo‐cortical oscillatory mechanisms responsible for spindle occurrence may create a neurophysiological substrate that facilitates the activation and spread of interictal epileptiform discharges (IEDs) in an immature, hyperexcitable cortex. The observed correlation between IEDs and spindle oscillations in both CAE and SeLFE provides indirect evidence supporting a shared mechanism underlying these “systemic” epilepsies. ³⁶ , ³⁷ , ³⁹ , ⁴⁰ , ⁴¹ , ⁴² While definitive proof remains challenging, these findings suggest that CAE and SeLFEs may be pathophysiologically related, potentially sharing a genetic predisposition that affects cortico‐thalamo‐cortical network function. Furthermore, age‐dependent maturation processes likely influence the oscillatory properties of these circuits, contributing to distinct clinical phenotypes shaped by genetic and environmental factors. Taken together, while direct evidence of a common mechanism remains elusive, converging data from experimental and clinical studies support the hypothesis that thalamo‐cortical dynamics play a critical role in both CAE and SeLFEs. These shared oscillatory processes may explain the electroclinical overlap observed in some patients, further reinforcing the idea of a spectrum of epilepsy syndromes influenced by similar neurophysiological substrates. ⁴³ , ⁴⁴

5. CONCLUSION

CAE and SeLFEs share several common features, and SeLFE‐IEDs are frequently observed in children with CAE. However, patients experiencing both concomitant or sequential seizures typical of both syndromes are rare. Ictal patterns with focal seizures immediately followed by a generalized 3 Hz discharges are reported. The genetic connection and pathophysiological relationship between CAE and SeLFEs, likely involving cortico‐thalamo‐cortical circuits, require further investigations.

FUNDING INFORMATION

This study was not supported by any specific funding.

CONFLICT OF INTEREST STATEMENT

None of the authors has any conflict of interest to disclose.

INFORMED CONSENT STATEMENT

We have acquired the informed consent of the case described.

Test yourself

1. How do Childhood Absence Epilepsy (CAE) and Self‐Limited Focal Epilepsies (SeLFEs) overlap? Does it worsen prognosis?

2. How can CAE and SeLFEs be pathophysiologically related?

Answers may be found in the supporting information.

Supporting information

Appendix S1.

Barbagallo G, Nobile G, Calevo MG, Prato G, Nobili L, Canale E, et al. Co‐occurrence of childhood absence epilepsy and self‐limited focal epilepsy interictal discharges: Differences from childhood absence epilepsy alone. Epileptic Disord. 2025;27:648–659. 10.1002/epd2.70044

DATA AVAILABILITY STATEMENT

The original contributions presented in the study are included in the manuscript; further inquiries can be directed to the corresponding author.