Sleep, cognitive functions, behavioral, and emotional disturbance in self-limited focal childhood epilepsies

Self-limited focal epilepsies of childhood are electroclinical syndromes of unknown or genetic cause that occur in developmentally and neurologically normal children and have a benign course, remitting prior to adulthood [1].

The best described syndromes are self-limited epilepsy with centrotemporal spikes (SeLECTS) previously known as benign childhood epilepsy with centrotemporal spikes, idiopathic childhood occipital epilepsy of Gastaut (ICOE-G), and self-limited epilepsy with autonomic seizures (SeLEAS) formyl known as Panayiotopoulos syndrome [2].

Sleep disorders are common and may coexist with a variety of neurological diseases, including epilepsy [3]. On the other hand, one-third of patients with epilepsy have seizures during sleep [4]. The relationship between epilepsy and sleep is both complex and bidirectional. While sleep states modulate the expression of epileptic seizures and interictal epileptiform discharges, epileptic discharges alter sleep regulation and provoke sleep disruption [5].

Despite of abundant literatures addressing the sleep and epilepsy, the relation between benign focal epilepsies of childhood and sleep disturbance is unclear, as few studies investigated the effect of SeLECTS on sleep [6].

Traditionally, SeLECTS was thought to cause no neurological or cognitive deficits, with seizures stopping spontaneously after puberty. However, recent research challenges this benign view, finding evidence of cognitive impairment, especially in speech and executive functions, as well as higher rates of behavioral, social problems, and psychiatric comorbidities like psychosis. The severity of these deficits appears to be correlated with the frequency and duration of epileptiform discharges during non-rapid eye movement (NREM) sleep [7].

Unfortunately, most previous studies focused on SeLECTS and ignoring other type of self-limited focal childhood epilepsy. In our study, we tried to study the possible effect of epilepsy on sleep architecture, cognitive functions, behavior, and emotional disturbance in non-medicated children with self-limited focal epilepsies.

The current study is a cross-sectional one that was conducted on 46 newly diagnosed epileptic children (self-limited focal epilepsies) aged from 6 to 12 years of both genders over a period of 12 months from attending the outpatient clinic in the department of Neuropsychiatry. After taking informed written consent from the patients' parent, patients were classified into 3 subgroups as follows:

Group I A: included 22 patients with SeLECTS, diagnosed on clinical and EEG basis according to International League against Epilepsy, all of them were newly diagnosed and drug naive. Group IB: included 12 patients with ICOE-G, diagnosed on clinical and EEG basis according to International League against Epilepsy, all of them were newly diagnosed and drug naïve. Group IC: included 12 patients with SeLEAS diagnosed on clinical and EEG basis according to International League against Epilepsy, all of them were newly diagnosed and drug naïve.

Another 20 healthy age- and sex-matched children sex matched healthy were recruited from complex school’s compound who severed as a control group (group II).

Magnetic resonance imaging of the brain (in suspected secondary epileptic cases). Routine laboratory tests were done, such as fasting and post prandial blood sugar level, and liver and kidney function tests to exclude diabetic patients or patients with liver or kidney diseases.

Patients with endocrinal, cardiac, renal, hepatic problems, symptomatic epilepsy, patients on antiepileptic drugs or medications influencing sleep such as benzodiazepines, patients with psychiatric illness, and body mass index > 30 were excluded from the study.

All patients were subjected to: Thorough neurological examination and clinical assessment of epilepsy severity was done using Hague seizure severity scale (HASS) [8]

All participants were subjected to one night polysomnography (PSG), and PSG parameters were scored using Somon Medics GmbH (Am SonnenstuhL63, D-97236 Rander Sacker, Type: SOMNO screen TM plus, SN: 4259, kw45: 2014, Germany). The PSG parameters were scored according to The American Academy of Sleep Medicine Manual for the Scoring of Sleep and Associated Events: Rules, Terminology and Technical Specifications, version 2.4 [9]. Measure for the quantification of epileptiform activity was done using spike frequency method consists in counting the total number of spikes per unit of time [10].

All participants in the study were evaluated by cognitive, psychological, and behavioral battery including the following:

The child behavior checklist (CBCL) [11], a widely employed standardized tool designed to assess emotional, behavioral, and social problems in children and adolescents. The CBCL is a comprehensive questionnaire completed by parents or caregivers, providing a detailed profile of the child's functioning across various domains. It encompasses numerous items that evaluate a range of behavioral and emotional problems, including internalizing issues such as anxiety, depression, and somatic complaints, as well as externalizing problems like aggressive behavior and rule-breaking. Additionally, the CBCL assesses competencies in activities, social relationships, and school performance.

The controlled oral word association test (COWAT) [12, 13] is a neuropsychological test that evaluates verbal fluency and executive functioning. It requires patients to orally produce as many words as possible that begin with a given letter within a fixed time limit (usually 60 s). The test measures the spontaneous production of words under restricted search conditions. Performance requires cognitive flexibility, initiation, attention, and speed of verbal output. Impaired performance may indicate dysfunction in frontal systems that regulate executive functions like fluency, working memory, inhibition, and set shifting. The test has high utility in neuropsychological batteries evaluating executive dyscontrol and verbal function.

The Rey–Osterrieth complex figure (ROCF) [14] test is a neuropsychological assessment that evaluates visuospatial constructional ability and visual memory. It involves copying a complex geometric figure composed of multiple shapes and details. The accuracy and approach to copying the figure provides information on visuospatial and constructional skills. After a delay (often 30 min), the examinee is asked to redraw the figure from memory. This assesses visual and nonverbal memory ability. Impaired performance can indicate problems with visuospatial skills, nonverbal memory, executive functions like organization, and planning.

The Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS) [15] is a semi-structured psychiatric interview used to assess psychopathology in children and adolescents. It screens for a broad range of disorders including depression, anxiety, attention deficit hyperactive disorder (ADHD), conduct disorder, substance abuse, eating disorders, psychosis, and Oppositional defiant disorder (ODD).

The Wechsler intelligence scale for children (WISC-III-R) was utilized to measure intelligence quotient (IQ), providing scores for verbal IQ, performance IQ, and a combined full-scale IQ. This widely used test evaluates various aspects of intelligence in school-aged children and adolescents [16]. The Wisconsin card sorting test (WCST), a computerized version, was administered to evaluate executive functions such as set shifting, working memory, conceptual problem-solving ability, the use of feedback, the ability to modify incorrect strategies, flexibility, and the inhibition of prepotent but incorrect responses [17].

The Trail Making Test consisted of two parts. Part A measured visual search by requiring participants to draw lines in ascending order from 1 to 25 on a standard test sheet. The score was based on the number of seconds taken by the participant to solve the problem, with errors not corrected but the time continuing to run during corrections. Part B was similar but involved alternating between numbers (1 to 13) and letters (A to L) in ascending order. This part assessed distracted attention and set-shifting components of executive functions, with scoring done in the same manner as Part A. Additionally, the Digit Span (DS) subtest from the Wechsler scales was administered, comprising digits forward (DF) and digits backward (DB) components. DF assesses short-term auditory memory, sequencing, and simple verbal expression, while DB is more sensitive to deficits in verbal working memory. The DS scaled score, the longest digits forward raw score, and the longest digits backward raw score were analyzed in this study [17].

The reading disabilities were evaluated by test of reading disabilities which is composed of 80 sentences and each correct answer is given one degree. The child was considered to have reading disorder when the result of the test was below 85% of the total score [18, 19].

All cognitive assessments were conducted on participants in the interictal period, with a minimum duration of 1 week since their last seizure episode prior to participation in the current study. Participation was on a voluntary basis, and comprehensive information regarding the research objectives was provided to the parents of all prospective participants. Informed written consent was obtained from parents prior to the commencement of study procedures. The study protocol obtained ethical approval from the institutional review board at our university (approval code: 36049/11/22).

Statistical analysis of the collected data was performed using SPSS Prism version 20, 2013 (developed by IBM, Armonk, NY, USA). The Chi-square test was employed for categorical data, while the t test was utilized for numerical data. One-way analysis of variance (ANOVA) was conducted to compare the means across the four groups. Post hoc Tukey tests were subsequently applied for pairwise comparisons of group means. The F test was used to evaluate the regression model. A significance level of p < 0.05 was adopted as the threshold for interpreting the results of the tests of significance.

The present study employed a cross-sectional design and involved a cohort of 46 participants recently diagnosed with self-limited focal epilepsy, ranging in age from 6 to 12 years, encompassing both genders and 20 healthy children. As depicted in Tables 1 and 2, the distribution of age and sex did not exhibit statistically significant differences between the epilepsy patient group and the non-epileptic control group.

The polysomnogram parameters analyzed in the present study encompassed total sleep time, sleep latency, rapid eye movement (REM) latency, wake after sleep onset, sleep efficiency, sleep fragmentation, sleep stage transition index, arousal index, apnea–hypopnea index, periodic limb movement index, and the percentages of different sleep stages (N1, N2, N3, and REM) relative to total sleep time, as well as the REM sleep without atonia (RSWA) index. The F-test results revealed statistically significant differences among the groups for most of these measures, apart from the apnea–hypopnea index and the percentage of N1 sleep. Subsequent post hoc analyses were employed to delineate the specific group differences for each parameter, unveiling significant disparities between the epileptic children and their healthy counterparts across various domains, including total sleep time, sleep latency, REM latency, wake after sleep onset, sleep efficiency, sleep fragmentation, sleep stage transition index, arousal index, periodic limb movement index, and the percentages of N2, N3, and REM sleep relative to total sleep time, as well as the RSWA index. Notably, no significant differences were observed among the three epileptic groups (Table 3).

The mean epilepsy durations are similar across the three groups, ranging from 0.95 to 1.16 years without significant difference between them. The post hoc tests further confirm that there are no significant pairwise differences between the groups. The HASS score, which assesses the severity of epilepsy, shows a statistically significant difference among the groups, as indicated by the F-test p value of 0.03. The post hoc tests reveal that Group 1B has a significantly higher mean HASS score compared to Group 1A and 1C. The inter-ictal discharge load, which measures the frequency of epileptiform discharges between seizures, does not show a statistically significant difference among the three groups, as indicated by the F-test p value of 0.878. The post hoc tests further confirm that there are no significant pairwise differences in inter-ictal discharge load between the groups (Table 4).

Regarding the results of CBCL, there were significant differences in both internalizing problems including (anxious/depressed, withdrawn/depressed, somatic complaint) and externalizing problems including (rule breaking, aggressive behavior) between the epileptic groups and the control group where the epileptic groups were worse than the control group. Also, there were significant increases in the social problems, thought problems, and attention problem in the epileptic groups compared to control group. Regarding sluggish cognitive tempo, there were significant difference between the epileptic groups and the control group where the control group showed better results than the epileptic group. There was significant difference between the epileptic groups and the control group regarding the total competence in Favor to the control group. (Table 5).

There was no significant difference between the studied groups regarding IQ. Regarding the DF and the digit DB tests, there were significant differences between the epileptic groups and the control group where the control group showed better results than the epileptic groups. There were significant differences in both the TMTA (time and errors) and the TMTB (time and error) between the epileptic groups and the control group where the epileptic groups showed worse results than the control group.

There was a significant difference in the WCST correct response between the epileptic groups and the control group in favor to the control group. Regarding the COWAT, there were significant differences between the epileptic groups and the control group to the advantage of the control group (Table 6).

Regarding the ROCF test including copy, immediate recall, and late recall, there were significant differences between the epileptic groups and the control group where the control group showed better results than the epileptic groups. According to reading test, there were significant difference between the epileptic groups and the control group where the epileptic groups showed worse results than the control group.

According to the K-SADS assessment, a higher number of children in the epileptic groups experienced psychiatric disorders compared to the control group. In Group 1A, 11 children (50%) suffered from depression, while in Group 1B, 4 children (33.3%), and in Group 1C, 5 children (41.7%) experienced depression, in contrast to only 2 children (8%) in the control group. Furthermore, anxiety was reported in 11 children (50%) in Group 1A, 3 children (25%) in Group 1B, and 4 children (33.3%) in Group 1C, compared to 2 children (8%) in the control group. ADHD was more prevalent in the epileptic groups, with 13 children (59.1%) in Group 1A, 7 children (58.3%) in Group 1B, and 6 children (50%) in Group 1C suffering from ADHD, while only 2 children (8%) in the control group had ADHD. ODD was also more common in the epileptic groups, with 5 children (22.7%) in Group 1A, 3 children (25%) in Group 1B, and 1 child (8.3%) in Group 1C exhibiting ODD, compared to 1 child (4%) in the control group. Lastly, Conduct Disorder was observed in 3 children (13.6%) in Group 1A, 5 children (41.7%) in Group 1B, and 2 children (16.7%) in Group 1C, while only 1 child (4%) in the control group suffered from Conduct Disorder (Table 7).

The present study explored the complex relationship between self-limited focal epilepsies of childhood and their potential impact on sleep architecture, cognitive functions, behavioral patterns, and emotional well-being. The findings revealed significant differences in polysomnographic parameters between children with benign focal epilepsies and their healthy counterparts.

Children with epilepsy had a shorter total sleep time, prolonged sleep latency, increased wake after sleep onset, decreased sleep efficiency, increased sleep fragmentation, and an increased sleep stage transition index. These disturbances in sleep architecture underscore the profound influence of epileptic discharges on the natural sleep patterns in these children.

Epilepsy is a complex, multidimensional condition that extends beyond the occurrence of seizures alone. It is associated with alterations in both the macrostructure and microstructure of sleep. These changes are multifactorial, arising from the underlying pathology, comorbid neuropsychiatric and sleep disorders, as well as the effects of pharmacological and non-pharmacological treatments. Accumulating evidence suggests that epileptic activity exerts a direct impact on sleep architecture, sleep continuity, and sleep oscillations [20].

The study conducted by Bruni and colleagues [21] included SeLECTS drug naïve children and healthy control. They reported that compared to controls, children with SeLECTS epilepsy showed shorter total sleep time, longer REM sleep latency, lower sleep efficiency, and lower percentage of REM sleep. Additionally, Clemens and colleagues [22] evaluated 11 children with SeLECTS and healthy control. These children were free from medication or taking a single low-dose drug. The epileptic children had an average sleep duration that was 34 min shorter compared to the control group, although this difference was not statistically significant the epileptic children experienced a longer wake after sleep onset duration.

The previous study results by Gogou and colleagues [23] indicated that epilepsy affects sleep quality, as almost all parameters of sleep architecture were worse in the epilepsy group. The observed abnormalities in sleep architecture included an increase in the percentage of N1 and N2 sleep stages, an increase in the arousal index, an increase in the periodic limb movement index, an increase in sleep onset latency, as well as a reduction in the percentage of REM sleep and sleep efficiency. A meta-analysis revealed that a longer sleep latency and greater latency of REM were the most significant finding among patients with SeLECTS [24]. The underlying mechanisms behind sleep disturbances in children with SeLECTS are not fully understood, but several hypotheses have been proposed. One theory suggests that the epileptic discharges themselves, particularly those occurring during sleep, may contribute to sleep fragmentation and alterations in sleep architecture. Additionally, the presence of subclinical seizures or interictal epileptiform discharges during sleep may disrupt normal sleep patterns [20].

The present study uncovered significant deficits in cognitive domains among children with benign focal epilepsies. Impairments were observed in verbal fluency, visuospatial abilities, non-verbal memory, executive functions, and reading proficiency. These findings challenge the traditional notion of these epilepsies being truly "benign," as they appear to have a detrimental effect on various cognitive processes. The observed deficits in executive functions, such as cognitive flexibility, set shifting, and inhibition, align with previous research linking epileptiform discharges during NREM sleep to impairments in these domains [17].

In the stud by Li and colleagues [7], the researchers aimed to explore the relationship between neural network changes and cognitive impairment in newly diagnosed children with SeLECTS. The results showed that SeLECTS patients had significantly lower WISC scores compared to controls, and their functional connectivity network patterns were significantly altered particularly in the functional connections between the posterior cingulate cortex and frontal lobe. Quantified by graph theory analysis revealed increased connection strength, decreased path length, and decreased clustering coefficient in SeLECTS patients across various frequency bands. Correlation analysis demonstrated positive associations between full-scale IQ, verbal comprehension index, perceptual reasoning index, and specific network measures, suggesting that the trend of cognitive impairment in early SeLECTS children may be related to changes in their functional connectivity network patterns [7].

Zhang and colleagues [25] found that SeLECTS patients who experienced a higher frequency of epileptic discharges during the first cycle of NREM sleep performed significantly worse on tests measuring arithmetic skills, executive functioning, attention, and memory compared to those with a lower discharge frequency. Patients who exhibited high-frequency oscillations demonstrated poorer performance across various cognitive domains, including arithmetic, executive function, vocabulary, visual perception, auditory perception, spatial memory, and response ability. Their findings suggest that a higher burden of epileptic discharges during NREM sleep can have a detrimental impact on various cognitive functions, including arithmetic, executive functioning, attention, memory, perception, and processing speed. Also, Currie and colleagues [26] reported that children with SeLECTS exhibited significantly poorer performance compared to typically developing children on measures of word reading, reading comprehension, and non-verbal IQ.

A previous study conducted on 93 children with SeLEAS reported that on neuropsychological testing, their IQ and subtest scores on the WISC-R were within normal limits. However, some minor statistically significant differences were found compared to controls in the arithmetic, comprehension, and picture arrangement subtests^. [27] Another study found that children with SeLEAS exhibited a mean full-scale IQ score within the normal range but significantly lower than the normative mean. Their verbal IQ and processing speed did not differ significantly from the normative data. However, these children demonstrated significant deficits compared to norms in areas such as simple auditory/visual reaction times, visual attention, visual-motor integration, and verbal memory. While their overall IQ fell in the normal range, specific cognitive domains involving speed, attention, visual-motor abilities, and memory were impacted in this syndrome [28].

A study investigated language deficits in SeLECTS and ICOE-G. Surprisingly, both patient groups exhibited significant language deficits compared to controls. ICOE-G patients performed worse than SeLECTS patients on tests of semantic functions. However, no associations were found between the severity of language impairment and clinical parameters of the epilepsies. The findings suggest that language dysfunction can occur across different self-limited focal epilepsy types, reflecting the distributed representation of language networks in the brain. Furthermore, recent epileptic activity did not impact the degree of language deficits in these patients [29].

Another study examined cognitive and behavioral profiles across patient groups with ICOE-G and SeLEAS compared to healthy controls. Patients with SeLEAS exhibited lower scores across all intelligence domains, with performance IQ significantly lower than both the ICOE-G group and controls. Both patient groups demonstrated verbal memory impairments and psychomotor slowing. However, only the SeLEAS group showed deficits in visual memory and reading abilities. Writing and arithmetic skills were compromised in both groups [30].

Previous studies showed that children with SeLECTS suffer heterogeneous cognitive deficits correlated to NREM epileptiform discharges. It was found that centrotemporal spikes may be associated with widespread adverse effects on attentional networks. Also, other studies had shown that a high frequency of IEDs could be correlated with lower executive functions [31].

The current study shed light on the elevated prevalence of behavioral and emotional disturbances among children with benign focal epilepsies. Increased rates of internalizing problems (anxiety, depression, and somatic complaints), externalizing problems (rule-breaking, aggressive behavior), social problems, thought problems, and attention deficits were observed in these children compared to their healthy counterparts. Moreover, the study revealed a higher incidence of psychiatric comorbidities, including depression, anxiety, ADHD, ODD, and conduct disorder, among children with benign focal epilepsies.

Our result is going with the study of Samaitienė and colleagues [32] who found that treated patients with SeLECTS exhibited significantly higher scores across multiple behavioral domains compared to patients with peripheral nervous system disorders. Specifically, they had more issues with social problems, anxiety/depression, aggressive behavior, and attentional problems. Earlier age of first seizure was linked to more delinquent behavior, and longer epilepsy duration was positively related to withdrawn behavior and delinquency.

Previous work of Sousa and colleagues [33] revealed that most patients with SeLECTS had mild-to-severe impairments in executive functioning areas. A significant percentage of cases had emotional and behavioral dysregulation scores that fell into the abnormal category. The significance of thorough screening processes covering cognitive, behavioral, and affective domains for all patients diagnosed with SeLECTS is highlighted by these findings.

There is increasing evidence suggesting a bidirectional relationship between epilepsy and certain psychiatric comorbidities, especially depression and ADHD. Depression may precede the onset of seizures. Likewise, ADHD occurs more frequently in children with epilepsy compared to controls, while epilepsy is also more common in children with ADHD. The brain regions implicated in temporal lobe and frontal lobe epilepsy have been linked to the neurobiology of depression and anxiety disorders. While further research is needed to firmly establish this bidirectionality [34].

The findings of this study emphasize the need for a more comprehensive understanding and management approach for self-limited focal epilepsies of childhood. These conditions were traditionally considered relatively benign, the observed impact on sleep, cognitive functioning, behavior, and emotional well-being challenges in this perception. Early identification and interventions targeting these associated impairments could potentially mitigate the long-term consequences and improve overall outcomes for children with benign focal epilepsies [35].

It is important to note that the study did not find significant differences among the three subtypes of benign focal epilepsies in terms of polysomnographic parameters, cognitive deficits, or behavioral/emotional disturbances. This suggests that the impact of these epilepsies may share common underlying mechanisms, irrespective of their specific clinical presentations.

While the study provides useful insights, it is essential to acknowledge its limitations. The cross-sectional design limits the ability to establish causal connections between epilepsy and the observed impairments. Longitudinal studies are warranted to elucidate the temporal dynamics and potential bidirectional interactions between epileptic discharges, sleep disturbances, cognitive deficits, and behavioral/emotional problems. Additionally, the study focused on drug-naive children, and the potential consequences of antiepileptic medications on these domains remain unexplored.

The findings of this study challenge the traditional perception of benign focal epilepsies of childhood as truly benign conditions. The observed disturbances in sleep architecture, cognitive impairments, and elevated rates of behavioral and emotional problems highlight the need for a more comprehensive and multidisciplinary approach to the management of these epilepsies. Early identification and targeted interventions addressing sleep, cognitive, and psychosocial aspects could potentially improve overall outcomes and quality of life for children with benign focal epilepsies.