EJIHPE | Free Full-Text | The Influence of Sleep Disorders on Neurobiological Structures and Cognitive Processes in Pediatric Population with ASD and Epilepsy: A Systematic Review

EJIHPE | Free Full-Text | The Influence of Sleep Disorders on Neurobiological Structures and Cognitive Processes in Pediatric Population with ASD and Epilepsy: A Systematic Review

1. Introduction

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder that typically begins in the first 30 months of life and affects the normal development of the brain in terms of social and communication skills [1]. Common characteristics of ASD encompass a wide and heterogeneous range of symptoms, including impaired social relationships [2], difficulties in verbal and non-verbal communication [3], problems processing sensory information [4], as well as restricted and repetitive patterns of behavior [5].
Between 5–40% of children with ASD develop epilepsy during their developmental course [6]. This high incidence appears to follow a bimodal distribution, with an initial peak between 1–5 years of age and a second peak during prepuberty and adolescence [7]. There is a significant difference in the rates of epilepsy in children with ASD without comorbid conditions compared to those who exhibit neurological disorders, such as intellectual disability, hypotonic syndrome, or cerebral palsy, which exhibit epilepsy. In this second group, epilepsy rates are higher, affecting more than 60% of patients [8].
Among the comorbid disorders in the pediatric population with ASD, sleep disorders (SD) stand out, primarily manifesting as difficulties in sleep onset, maintenance, nighttime awakenings, and sleep apnea [9]. Generally, individuals with ASD have a multifactorial etiology, tend to be chronic, and have negative consequences on the patient and/or the family environment, both in their progression and quality of life [10]. Sleep disorders (SD) are reported in 6–25% of the pediatric population, but this figure rises to between 50–95% in children with ASD and epilepsy [11]. SD in the population with ASD and epilepsy can be similar to those seen in the general pediatric population, with the most prevalent being onset insomnia, nighttime awakenings, and reduced total sleep time [12].
SD should hold a prominent place in the diagnostic and therapeutic stage for individuals with ASD and epilepsy. The pediatric population with ASD and epilepsy has proven effects on cognition and behavior, which become even more evident in patients with this comorbidity. These effects can be specific to certain genetic conditions and may, therefore, require a specific clinical approach and intervention [13]. The pathophysiology of SD in children with ASD and epilepsy is multifactorial, with some patients having a direct relationship with their specific genetic diagnosis or phenotype. SD in this population is often associated with common causes of sleep problems in the general pediatric population [14]. These factors are related to neurobiochemistry, seizures and epileptic syndromes, and specific cognitive impairments seen in this population. Regarding the neurobiochemistry of SD, various neurobiological anomalies have been described in ASD and epilepsy, highlighting alterations in neurotransmitters and hormones involved in sleep regulation [15]. On one hand, serotonin, through its modulation of cholinergic neurons in the brainstem, plays a critical role in suppressing REM sleep and promoting wakefulness [16]. However, a decrease in serotonin synthesis has been observed in children with ASD compared to those who do not have it [17]. On the other hand, melatonin, produced by the pineal gland, is a key regulator of circadian rhythms, and a decrease in melatonin during sleep has been reported in children [18] and young adults [19] with ASD and epilepsy. Therefore, due to the neurobiological alterations in children with ASD, sleep can be affected by this disorder. Additionally, it is observed that individuals with ASD who have epilepsy have a direct relationship with sleep disorders.
Epileptic syndromes, particularly those affecting the frontal lobe, are characterized by seizures that occur exclusively or predominantly during non-rapid eye movement sleep (NREM) [20]. Interictal epileptiform discharges (IEDs) are sharp waves or spikes that occur on an electroencephalogram (EEG) between seizures. IEDs refer to abnormal electrical brain activity between seizures in individuals with epilepsy. Chronic sleep deprivation can lower the seizure threshold, making it more likely for IEDs to trigger actual seizures. This connection underscores the importance of maintaining good sleep habits and managing sleep disorders in epilepsy patients to reduce the risk of seizures. Like seizures, IEDs are activated during NREM sleep and suppressed during REM sleep [21]. Chronic sleep deprivation can be caused by sleep disorders that disrupt and interfere with sleep, such as obstructive sleep apnea (OSA). In OSA, breathing pauses awaken the patient from sleep due to a protective response, resulting in fragmented sleep. A study on the treatment of OSA in children with ASD and epilepsy has shown an improvement in seizure control [22]. Other sleep disorders, such as insomnia, can also lead to sleep deprivation and worsen seizure control [23]. Therefore, paying attention to sleep in children with ASD and seizures and implementing appropriate treatment strategies can result in better seizure control.
Epileptic seizures themselves can impact sleep, and this influence is not limited to the moment of seizure onset. Complex partial seizures of the temporal lobe decrease REM sleep, especially when they occur during sleep but also when they happen the day before sleep onset [24]. These changes may result from disruption in circadian rhythms or hormonal influences resulting from seizures.
Regarding the cognitive impairments that seizures related to sleep and IEDs produce in learning, memory, and daytime behavior, these are still largely unknown and represent a rapidly expanding area of research [25]. Sleep-related problems have been shown to disrupt daytime behavior and academic performance [26]. Sleep-related problems are significantly more common in children with ASD and epilepsy. Researchers have attempted to establish a correlation between behavioral problems identified in epilepsy patients and various sleep indices. In Zwaigenbaum et al.’s study [27], it was found that rapid eye movement latency, apnea duration, and periodic leg movements in children with epilepsy correlated with depression, inattention, hyperactivity, and/or oppositional defiant disorder. Therefore, sleep disorders in the pediatric population with ASD and epilepsy constitute a comorbidity that negatively influences overall developmental progress, impairing the acquisition of skills such as communication, attention, emotional control, and the quality of life of this group.

Based on this, the aim of this systematic literature review was to compile relevant data from research on the relationship between sleep disorders and the pediatric population with ASD and epilepsy. Furthermore, the specific objectives were to analyze the neurobiological alterations related to sleep disorders and describe the cognitive performance related to the pediatric population diagnosed with ASD and epilepsy. The hypotheses of this systematic review were as follows: (I) It is expected that the neurobiological and neurochemical alterations described in children with ASD and epilepsy will disrupt brain activity and give rise to various sleep disorders, and (II) it is expected that sleep disorders in this population will limit cognitive competencies and alterations in basic and higher-order cognitive processes will be observed.

2. Materials and Methods

This work presents a systematic literature review on ASD and epilepsy and how sleep disorders are affected in this population. The question to be addressed is the relationship between sleep disorders, cognitive impairments, and emotional disturbances in family members in the pediatric population with ASD and epilepsy, following the criteria of the following PICO (Patient, Intervention, Comparison, Outcomes) model: (P) Individuals diagnosed with ASD and epilepsy. (I) Not applicable. (C) Not applicable. (O) Sleep disorders. To ensure the precision of the research question, criteria related to individuals with ASD and epilepsy were specified, comparing their symptoms and the results of their respective diagnostic assessments [28]. Furthermore, this literature review adhered to the guidelines and recommendations established in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [29].

2.1. Search Strategy

An electronic search was conducted between March 2023 and July 2023 in the following databases: Medline, PubMed, PsycINFO, Web of Science, and Google Scholar. The search was limited to peer-reviewed articles published in journals and/or available online and written in Spanish or English. To ensure that the included articles were current, the search was limited to the last 20 years. The following terms in the article title, abstract, and keywords were considered in the study’s search: epilepsy, ASD, and sleep disorders.

Regarding the search strategy, the following terms were used, combined with Boolean operators: “(epilepsy) AND (ASD) AND (sleep disorders)”, “(epilepsy comorbidity) AND (ASD) AND (cognitive impairments)”, “(causes of sleep disorders) AND (ASD and epilepsy)”.

2.2. Study Selection Process

To obtain highly relevant published studies based on the study’s objectives and PRISMA guidelines [30], inclusion and exclusion criteria were established before the systematic review. To improve the search’s quality, a peer review was conducted using the standardized Peer Review of Electronic Search Strategies (PRESS) tool [31]. In this way, in the initial stage of study pre-selection, based on the information provided in the title and abstract, the following inclusion criteria were considered for the selection of relevant articles: (I) study samples reflect the comorbidities of the two conditions under study (epilepsy-ASD and sleep disorders); (II) these conditions have been specifically evaluated; and (III) evaluations have been conducted by professionals in psychology or medicine. As for exclusion criteria, the following were considered: (I) individual case reports without a methodological design; (II) studies of epilepsy unrelated to ASD or vice versa; and (III) reviews, editorials, or abstracts of studies presented at conferences.

In the second stage of study selection, a comprehensive analysis of articles meeting the specified inclusion criteria was carried out. In this process, the following inclusion criteria were considered: (I) study participants had an official diagnosis of ASD; (II) the article accurately described the parameters of the evaluation conducted on the participants; and (III) individual characteristics of sleep disorders in study participants were specified.

The process of selecting studies included in this systematic review was conducted by two researchers and consisted of four phases. In the first phase, scientific literature in the fields of psychology and medicine was reviewed in major databases. In the second phase, each researcher reviewed the title and abstract of each eligible article in accordance with the pre-established inclusion and exclusion criteria. In the third phase, articles meeting the inclusion and exclusion criteria underwent a detailed analysis using a thorough reading of the full text. Finally, in the fourth phase, the examination and exclusion of articles that did not address the topic of interest in this systematic review were completed, evaluating the main information from the selected articles.

2.3. Final Study Selection

During the initial search for studies, a total of 632 potentially eligible articles were found, distributed as follows: 175 from Medline, 183 from PubMed, 167 from PsycINFO, 93 from Google Scholar (via manual bibliographic search), and 32 from Web of Science. Figure 1 presents a flowchart illustrating the study selection process, following the PRISMA statement [32]. Out of this total, 322 duplicate references were discarded. Finally, a total of 22 articles have been selected and included in this systematic review (Table 1).

Lastly, regarding the methodological design of the selected studies, quasi-experimental studies with assessments at one or multiple points in time, both cross-sectional and intra-group and inter-group longitudinal assessments to evaluate differences, were conducted.

4. Discussion

The primary objective of this systematic review was to analyze the available evidence regarding the relationship between sleep disorders and neurobiological and cognitive alterations in the pediatric population with ASD. Additionally, the specific objectives were to examine the neurobiological alterations that occur due to sleep disorders and to describe the dysfunctions in cognitive processes in children diagnosed with ASD and epilepsy.

Regarding the neurobiological alterations present in individuals with these comorbid disorders, scientific literature has demonstrated that, in pediatric neurological conditions, the impact of sleep disorders involves dysregulation of a significant portion of the nervous system. This, in turn, signifies dysfunction in the GABAergic and serotonergic systems, implying a disruption of the hormonal system, specifically the one responsible for melatonin regulation [55,56,57]. However, research in this field is very limited due, in part, to the scarcity of studies, the small number of homogeneous samples, and the variability in the manifestations of neurological alterations in clinical variables and their etiology, making the studies inconclusive [58,59]. Nevertheless, this dysregulation of different neurological systems negatively impacts the developmental maturation of individuals with ASD and epilepsy, as it affects the learning processes [60], causing the symptoms of ASD itself to be more pronounced with greater disruptions in communication and language or in social behavior [61].
Regarding the cognitive changes due to sleep disorders (SD), it is noteworthy that they are part of the current definition of this comorbidity and have a significant impact on children with ASD and epilepsy adaptation to their environment, their relationships with peers, and cognitive development. In the past decade, the negative impact of early epilepsy on cognitive capacity has been confirmed, establishing it as a predictor of difficulties in the development of these functions in children with ASD and epilepsy [62]. All of this results in cognitive processes such as attention or memory showing reduced performance compared to the ASD population without epilepsy. This may be because, in childhood, neuronal plasticity mechanisms are at their peak, trying to consolidate attention and memory mechanisms via the assimilation of environmental stimuli [63]. However, the existence of an SD will have a negative effect and reduce the ability to integrate knowledge from acquired context stimuli, as it will reduce cognitive alertness, preventing proper attentional focus, limiting the information captured by the child’s sensory system from being recorded and stored in memory [64].

The strengths and limitations of this study should be considered. A limitation of this study is that it relied on a review of existing literature, so the availability and quality of the included studies may have influenced the results. Since no original research was conducted and no new data were collected, there is a possibility that some relevant studies were omitted or that the results are influenced by publication bias. Additionally, the quality and methodology of the studies included in the review may vary, which can affect the reliability of the findings. Therefore, the results should be interpreted with caution and take into account the inherent limitations of the literature review. However, a strength of this study is that it considered recent and relevant research, providing an updated insight into the neurobiological causes of sleep disorders, cognitive impairments, and emotional disturbances in families with children with ASD and epilepsy. By including previous high-quality studies, a solid foundation was established for understanding the phenomena studied, and a broader coverage of the existing literature was achieved. Furthermore, by reviewing both international and national studies, a global perspective of research in the field was obtained, increasing the generalizability of the results. Another strength of this study is that it addressed multiple aspects related to sleep disorders, cognitive impairments, and emotional disturbances in the studied population. By examining the neurobiological causes and potential relationships between these phenomena, a more comprehensive and holistic understanding of the issue was achieved. This allows for the identification of key areas for intervention and the development of more effective therapeutic strategies.

The results of this study have important implications both in the clinical and research domains. In the clinical realm, it highlights the importance of assessing and addressing sleep disorders and neurological and cognitive impairments in individuals with ASD and epilepsy. Healthcare professionals should consider these areas and adopt a comprehensive approach to improve the quality of life for affected individuals and their families. Regarding future research, there is a suggestion to delve deeper into the understanding of the underlying neurobiological causes of sleep disorders in this population. It is necessary to review the action of neurotransmitters such as serotonin, GABA, and other substances like dopamine, which play a crucial role in sleep behavior disorders. In addition, studies exploring specific therapeutic interventions aimed at improving the quality of sleep patterns in individuals with ASD and epilepsy are needed. Furthermore, protocols for assessing cognitive processes affected by sleep disorders, such as memory, attention, or executive functions, should be established. Longitudinal studies can also be conducted to better comprehend the evolution of sleep disorders and cognitive impairments over time in individuals with ASD and epilepsy, comparing cognitive impairments and neurobiological activity based on types of sleep disorders. These investigations might allow for the assessment of the long-term effectiveness of different intervention approaches and provide insights into how these phenomena develop and change over time.

In conclusion, this review underscores the importance of understanding the neurobiological causes of sleep disorders and neurobiological and cognitive impairments in individuals with ASD and epilepsy. The results support the existence of relationships between these phenomena and emphasize the need for a comprehensive approach to the assessment and treatment of these conditions. Further research is required to deepen our understanding and develop more effective interventions that comprehensively address sleep disorders and neurobiological and cognitive impairments in individuals with ASD and epilepsy.

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