Sleep Breath DOI 10.1007/s11325-014-1076-8

REVIEW

Sleep apneas and epilepsy comorbidity in childhood: a systematic review of the literature Maria Gogou & Katerina Haidopoulou & Maria Eboriadou & Evaggelos Pavlou

Received: 21 July 2014 / Revised: 24 September 2014 / Accepted: 5 November 2014 # Springer-Verlag Berlin Heidelberg 2014

Abstract Purpose Our aim is to review studies which assess the prevalence of sleep apneas in children with epilepsy and discuss possible mechanisms linking these two conditions, as well as the impact of sleep apneas on the prognosis of these children. Methods PubMed was used as the medical database source, and articles were selected and classified according to their originality, level of evidence, and relevance to the broad scope of the review. Results Children with epilepsy have a higher prevalence of sleep breathing disorders in comparison to healthy children, but this prevalence varies widely depending on the methodology of each study. Major risk factors for sleep apneas in childhood epilepsy include mainly poor seizure control and antiepileptic drug polytherapy. Indeed, epilepsy can trigger sleep apneas, as abnormal electrical discharge amplifies sleepinduced breathing instability, antiepileptic drugs disturb muscle tone, and vagus nerve stimulation modulates neurotransmission to airway muscles. On the other hand, sleep apneas enhance sleep fragmentation, thus reducing the threshold for the appearance of seizures. Moreover, they have a negative effect on the neurocognitive profile of these children, as they disturb neuroplasticity mechanisms and also have a probable association with sudden unexpected death in epilepsy. The M. Gogou : E. Pavlou 2nd Department of Pediatrics, School of Medicine, Aristotle University of Thessaloniki, University General Hospital of Thessaloniki AHEPA, Thessaloniki, Greece K. Haidopoulou : M. Eboriadou 4th Department of Pediatrics, School of Medicine, Aristotle University of Thessaloniki, General Hospital of Thessaloniki Papageorgiou, Thessaloniki, Greece M. Gogou (*) Dimitriou Nika 44, 60 100 Katerini, Greece e-mail: [email protected]

surgical treatment of sleep apneas has been found to reduce seizure frequency, and this can offer new therapeutic choices. Conclusions Between sleep apneas and childhood epilepsy, there is a complex relationship with reciprocal interactions. The presence of sleep apneas should be taken into account when designing the management of these children, as it creates therapeutic opportunities and limitations. Keywords Sleep . Apneas . Epilepsy . Children . Antiepileptic drugs . Cognitive function Abbreviations SA Sleep apneas OAHI Obstructive apnea-hypopnea index OSAS Obstructive sleep apnea (syndrome) OSAHS Obstructive sleep apnea-hypopnea syndrome SBD Sleep breathing disorder(s) AED Antiepileptic drug(s) VNS Vagus nerve stimulation SUDEP Sudden unexpected death in epilepsy

Introduction Epilepsy is one of the most common neurological disorders, affecting about 1 % of the general pediatric population [1]. The presence of comorbid disorders in epilepsy is associated with the poor quality of life and adverse prognostic implications [2]. Sleep disorders are increasingly recognized as a significant comorbid condition in children with epilepsy [3]. Sleep apneas (SA) consist a serious sleep disorder which can lead to many neurocognitive and cardiovascular complications; however, they have not been methodically studied in children with epilepsy. Our aim is to review studies which assess the prevalence of SA in children with epilepsy,

Sleep Breath

investigate putative mechanisms linking SA and childhood epilepsy, and discuss the impact of SA on the management of these children.

Search strategy and selection criteria PubMed was used as the medical database source. No language or year-of-publication restriction was placed on the literature searches, and all kinds of articles were included (original papers, reviews, case/series reports). The terms that were used were “epilepsy,” “sleep,” “children,” “seizures,” “sleep apneas,” “obstructive sleep apnea syndrome,” “antiepileptic drugs,” “vagus nerve stimulation,” “respiratory function,” “sleep disorders,” “sudep,” “cognitive problems,” and “pediatric sleep questionnaires”. Citations of relevant articles were also taken into account. Original papers and case/series reports including a mixed population but with a high proportion of children/young adults were also considered. The final list of articles was generated on the basis of originality and included 61 original papers, 15 reviews, 7 case reports, 2 guideline manuals, 1 series report, 1 comment, and 1 letter to editor. The articles were classified according to their relevance to the scope of this review and their level of evidence [4]. (Table 1; Fig. 1) Table 1

Levels of evidence

Level Description 1

2

3

4

Evidence provided by a prospective study in a broad spectrum of persons with the suspected condition, using a reference (gold) standard for case definition, where test is applied in a blinded fashion, and enabling the assessment of appropriate test of diagnostic accuracy. All persons undergoing the diagnostic test have the presence or absence of the disease determined. Level I studies are judged to have a low risk of bias Evidence provided by a prospective study of a narrow spectrum of persons with the suspected condition or a well-designed retrospective study of a broad spectrum of persons with an established condition (by “gold standard”) compared to a broad spectrum of controls, where test is applied in a blinded evaluation, and enabling the assessment of appropriate tests of diagnostic accuracy. Level II studies are judged to have a moderate risk of bias Evidence provided by a retrospective study where either person with the established condition or controls are of a narrow spectrum and where the reference standard, if not objective, is applied by someone other than the person that performed (interpreted) the test. Level III studies are judged to have a moderate to high risk of bias Any study design where test is not applied in an independent evaluation or evidence is provided by expert opinion alone or in descriptive case series without controls. There is no blinding or there may be inadequate blinding. The spectrum of persons tested may be broad or narrow. Level IV studies are judged to have a very high risk of bias

Definitions of respiratory events during sleep in children According to the criteria of the American Academy of Sleep Medicine (2007), SA are divided into obstructive, central, and mixed. An obstructive sleep apnea (OSA) is characterized by a >90 % drop in the signal amplitude of airflow for >90 % of the entire event, compared with the baseline amplitude, and the event lasts for at least two breaths with continued respiratory effort. A central apnea is associated with the absence of inspiratory effort throughout the duration of the event and one of the following: 1) the event lasts for ≥20 s or 2) the event lasts for at least two missed breaths and is associated with an arousal, an awakening, or a >3 % desaturation. In mixed apneas, the event is associated with an absent inspiratory effort in the initial phase of the effort, followed by respiratory effort before the end of the event. A hypopnea is defined as a >50 % drop in airflow signal amplitude, compared with the baseline amplitude, for ≥90 % of the duration of the event. In addition, the event must last for at least two missed breaths and should be associated with an arousal, awakening, or a >3 % desaturation. Sleep-related hypoventilation is scored when ≥25 % of the total sleep time is spent with CO2 ≥ 50 mmHg, as measured by nasal sensors of end-tidal CO2. The number of (obstructive and mixed) apneas (and hypopneas) per hour of sleep is defined as obstructive apnea(-hypopnea) index (OA(H)I). When OAHI ≥2, obstructive sleep apnea-hypopnea syndrome (OSAHS) is present, while obstructive sleep apnea syndrome (OSAS) is diagnosed when OAI ≥1 [5, 6].

Assessment of sleep apneas in children All night polysomnography is the gold standard for the diagnosis of sleep apneas in children, as it consists of an objective measure of respiratory function, quantifies respiratory events (duration, severity) during sleep, and permits their analysis [7]. However, due to its technical difficulties and expense, questionnaires have been developed to assist in screening pediatric population for the symptoms of sleep disturbances. Most of these questionnaires consist of parent report tools and are applicable mainly in children of (pre)school age as well as in early adolescents. Questionnaires for preschool children tend to focus on sleep environment, whereas in children of school age sleep-wake patterns, diversity of sleep behaviors and sleep breathing disorders (SBD) are mostly assessed [8]. As regards SBD, according to Marcus et al. [9], the most diagnostic screening tests had low sensitivity and specificity and cannot be used for clinical purposes. Goodwin et al. [10] have found that snoring, excessive daytime sleepiness, and learning problems are each highly specific but not sensitive enough for SBD in 6- to 11-year-old children. Moreover, the

Sleep Breath

Fig. 1 Results of literature search about sleep apneas in childhood epilepsy

pediatric sleep questionnaire published by Chervin et al. [11] predicted polysomnographic results to an extent useful for research but not reliable enough for most individual patients. In the study of van Someren et al. [12], in which history and clinical examination by a pediatrician or otolaryngologist were compared with abbreviated polysomnography (PSG) (video recording, oximetry, measurement of snoring), both the sensitivity and specificity of the clinician’s impression of OSAS were low. Villa et al. [13] developed a sleep clinical record, a tool consisting of three items (physical examination,

subjective symptoms, history of neurobehavioral problems), which was found to be sensitive enough for OSAS in children. In general, the increase of the number of children participating in the above studies, the amelioration of their methodology, and a better understanding of pathophysiology of SBD could permit the development of better screening tools as alternatives to full PSG. Moreover, according to Spruyt et al. [8], adherence to psychometric tool development requirements is necessary for the generalization of the results of studies based on these tools. The validation and

Sleep Breath

standardization of sleep questionnaires to specific pediatric populations, such as children with epilepsy, are also an area for future research.

Epidemiology of SA in childhood epilepsy We were able to identify 11 studies reporting data on the prevalence of sleep breathing disorders (SBD) in children with epilepsy. Among them are included studies where the diagnosis was based on pediatric Sleep Habits Questionnaires/Sleep Disturbance Scales as well as polysomnographic studies, with all of them having an evidence level of 3 or 4. The prevalence of SBD in studies based on questionnaires varies widely from 6 to 65 % [14–19]. Results are also conflicting, as Chan et al. [14] and Maganti et al. [15] report significantly higher SBD prevalence and SBD scores in children with epilepsy in comparison to healthy children, while Samaitienė et al. [16], Tang et al. [17], and Ong et al. [18] have not detected any significant difference among the groups (Table 2). Studies based on polysomnography focus mainly on the presence of OSA and report a rate of OSAS between 20 and 80 % in children with epilepsy [20–23]. With regard to other SBD, Jain et al. [20] report a rate of central apneas at 6 % and of sleep-related hypoventilation at 6 %, while Kaleyias et al. [21] have identified a frequency of hypoventilation at 12.5 % in children with epilepsy. Only Maganti et al. [24] found no significant difference in polysomnographic respiratory sleep parameters between children with idiopathic epilepsy and healthy children, but it should be mentioned that their sample was very small (11 patients, 8 controls), and all patients had good seizure control and normal encephalogram (EEG) (Table 2). Table 2

Although the above studies suggest the increased prevalence of SA in children with epilepsy compared to that in the general pediatric population, their limitations should not be ignored. Most of these studies have included children with epilepsy associated with comorbidities, such as genetic syndromes, cerebral palsy, and neurodevelopmental disorders, which may affect the prevalence of SA. Furthermore, as regards questionnaire-based studies, they rely on the parental reports of SBD, which may not be accurate and do not consist a robust measure. According to Blunden et al. [25], parents very often do not discuss the sleep-related issues of their children, if the pediatrician does not bring them up. Apart from that, according to Vitelli et al. [26], the signs of nocturnal seizures often overlap with sleep respiratory events, thus leading to a parents’ difficulty in distinguishing abnormal events related to primary sleep disorders from epileptic seizures. On the other hand, the limitations of polysomnographic studies usually are the small number of participants, the lack of a control group, and the fact that most of them are not based on the random populations of children with epilepsy but on the samples of children, who have been referred to sleep centers due to various sleep complaints (Fig. 2). In general, current data about the prevalence of SA in childhood epilepsy comes from the analysis of diverse populations, is limited to populations not large enough to indicate the true extent of the overlap seizures and SA, and there are also significant differences in methodology to be considered. These can lead to an underestimation or an overestimation of the real prevalence, depending on the exact type of each study, and the wide variability of the results is indicative of this fact. Another limitation of these studies is that the presence of other risk factors for SA (increased body mass index (BMI), hypertrophic tonsils/adenoids) has rarely been taken into account. Although data of the above surveys may represent only a rough approximation of the true co-occurrence of epilepsy and

Studies about prevalence of sleep breathing disorders among children with epilepsy based on questionnaires (Q) or polysomnography (PSG)

Study

Method Evidence Population level

DA Becker et al. [22] R Maganti et al. [15] LC Ong et al. [18]

PSG Q Q

4 3 3

J Kaleyias et al. [21] SS Tang et al. [17]

PSG Q

4 3

S Miano et al. [23]

PSG

4

B Chan et al. [14] Q SV Jain et al. [19] Q R Samaitienė et al. [16] Q

3 4 3

SV Jain et al. [20, 29]

4

PSG

Outcomes

AHI ≥1.5 in 80 % of children SBD in 65 % of epileptic children (vs 3.9 % in controls) High scores of SBD in 11 % of epileptic children (vs 3 % in controls) 40 epileptic children with sleep complaints SBD in 42.5 % of children; OSAS in 20 % 43 children with rolandic epilepsy vs 494 SBD scores higher in epileptic children but not controls significantly different from controls 11 children with epilepsy and mental retardation AHI >5 in 3 of 11 children 30 epileptic children with sleep complaints 26 epileptic children vs controls 92 epileptic children vs their healthy siblings

63 epileptic children vs 169 controls 80 epileptic children 61 children with rolandic epilepsy vs 25 controls 108 epileptic children with sleep complaints

SBD scores significantly higher in the epilepsy group OSA in 65 % of children SBD in 6.6 % of epileptic children, but SBD scores not significantly different from controls OSA in 41.6 % and CA in 6 % of children

Sleep Breath Fig. 2 Studies about the prevalence of sleep apneas among children with epilepsy

SA, it is most likely that the observed coexistence of OSAS and epilepsy in these studies is much higher than a simple cooccurrence of both diseases expected by chance. Assuming a lifetime prevalence of 1 % for epilepsy and 3 % for OSAS in the general pediatric population, the two diseases should cooccur by chance in approximately only 0.3 % [1, 27, 28].

Risk factors We have identified only five studies investigating possible risk factors for SA in children with epilepsy, which refer mainly to OSA and have an evidence level of 3 or 4. Most of them have identified seizure control and number of antiepileptic drugs (AED) as significant risk factors for OSA. Jain et al. [19] have found that the prevalence of OSAS was significantly higher in the group of children with severe epilepsy compared to the group with mild disease. Moreover, children on >1 AED had a significantly higher prevalence of OSAS than that of children on ≤1 AED [19]. In a more recent study, Jain et al. [29] have also identified uncontrolled epilepsy as a risk factor for OSA as compared with primary snoring. The severity of OSA also increased with AED polytherapy [29]. Furthermore, Becker et al. [22] observed a significant correlation between the length of apnea and seizure frequency, indicating that children with a higher frequency of seizures experienced longer respiratory events. On the contrary, there was no statistically

significant association between OSA and BMI z scores, age, type of epilepsy (idiopathic generalized-localization related), and specific AED [8, 14, 22]. Only Kaleyias et al. [21] found a trend toward obesity in children with poor control of seizures, compared with children who were seizure free or with good seizure control. In contrast to adult patients with epilepsy, whose major risk factors for OSA are anatomical (high BMI, large neck circumference), it seems that typical risk factors for OSA in the general pediatric population (increased BMI, small age) do not consist significant risk factors for OSA in children with epilepsy [30]. It could be assumed that the existence of OSA in childhood epilepsy is mostly influenced by epilepsy itself and AED, but more studies on this topic are needed to establish this assumption. On this basis, it would also be interesting to investigate the phenotypical features of SA in epileptic children (e.g., their prevalence in various sleep stages) in comparison to SA of other origin, as well as the risk for SA in sleep-related epilepsies (e.g., rolandic, frontal lobe) in comparison to wakefulness epilepsies. Moreover, it should be mentioned that, as children with uncontrolled epilepsy are more likely to be on multiple AED, it is difficult to differentiate the effect of medications from the effect of the disease itself on the prevalence of OSA. In general, all the above studies about prevalence and risk factors for SA in children with epilepsy have an evidence level of 3 or 4. For that reason, according to Aurora NL et al. [31],

Sleep Breath

they do not meet the AASM levels of recommendation for a standard or a guideline. Therefore, pediatricians are urged to use clinical judgment to determine the need for polysomnography in children with epilepsy in order to diagnose a comorbid SBD [31].

Epilepsy as a triggering factor for SA The effect of epileptic activity The increased frequency of OSA in children with epilepsy raises the question if epilepsy can facilitate the appearance of SA. In general, apneas have a strong relationship with epilepsy, as they may be an ictal or a postictal manifestation and are associated not only with generalized epileptic seizures but also with focal seizures without generalization [32–35]. Sleep onset is associated with a series of changes that combine to produce the so-called breathing instability. The most important of these changes is the reduction in the “wakefulness drive to breathe,” which describes the influence of cerebral activity (primary and sensory cortices, basal ganglia, thalamic nuclei) on the volitional and behavioral regulation of breathing. The activation of the above centers is presumably decreased during sleep and leads to reduction in ventilation [36]. Moreover, the decreased central drive to the upper airway dilator muscles (genioglossus) and to the respiratory pump muscles (diaphragm), especially in REM stage, reduces upper airway dilator muscle tonicity and predisposes to airway collapse and appearance of obstructive apneas [37]. Apart from these, a shift from central to metabolic control of respiration takes place during sleep, which results in the appearance of central apneas. Central apneas also consist a normal phenomenon during transition from wake to sleep as well as a compensatory mechanism after ventilatory overshoots, which follow obstructive apneic events [38, 39]. Epilepsy predisposes to SA by amplifying the sleepinduced breathing instability. Seizures can cause sleep instability, thereby increasing the number of arousals and consequently the number of transitions from wake to sleep, leading to an increased number of sleep-onset central apneas [40]. Furthermore, it has been reported that the intraoperative stimulation of various targets in the frontal and temporal lobes during epilepsy surgeries can generate brief apneic episodes [41, 42]. Similarly, in experimental animal models, seizures and interictal epileptiform discharges (IED) stimulate cerebral structures, provoking respiratory arrest (perhaps via the descending projections from regions of the brain to the brainstem respiratory centers). The simultaneous recordings of phrenic and laryngeal motor nerve during these experiments have shown that the induced epileptic discharges are associated with irregular ictal nerve activity, leading to either a peripheral obstructive (poor coordination of laryngeal dilators

with diaphragmatic function) or a central (inhibited phrenic nerve activity) mechanism of respiratory dysfunction [43, 44]. In conclusion, the ability to maintain stable breathing during sleep onset is a function of how the respiratory control system responds to ventilatory perturbations that occur at this time. In children with epilepsy, breathing instability induced by sleep is associated with disturbed respiratory patterns and sleep disorganization caused by the abnormal electrical discharge, thus giving genesis to SA, either as an ictal or a postictal phenomenon (Fig. 3). It is worth-mentioning that SA can continue for up to 1.000 s after the onset of seizure activity [43]. The effect of antiepileptic treatment i)

ii)

Antiepileptic drugs Apart from epilepsy itself, antiepileptic treatment (both pharmacological and non-pharmacological) can also predispose to SA. Several AED like valproate, gabapentin, and carbamazepine have been associated with side effects, which consist of known risk factors for OSA in childhood. These side effects mainly include weight gain and endocrine disorders (hypothyroidism) [45, 46]. Furthermore, AED have multiple mechanisms of action, targeting ion channels, receptors and transporters of neurotransmitters, as well as enzymes involved in the metabolism of neurotransmitters, leading to various neuromodulatory effects [47–49]. These effects could interfere with neural mechanisms involved in the control of breathing and muscle tone and disturb them, thus facilitating the appearance of SA [50]. All the above mechanisms, which involve epileptic discharges and effects of AED in the genesis of SA, are in accordance with the findings of previously reported studies, which have identified uncontrolled epilepsy and drug polytherapy as significant risk factors for OSA in children with epilepsy [19, 29]. More specifically, it is anticipated that a higher density of discharges leads to more sleep fragmentation, and more AED used result in more complex modifications of neuronal circuits, thus increasing the risk for SA, and on this basis, a dose-dependent relationship could be speculated. Vagus nerve stimulation In general, according to a systematic review of Parhizgar et al. [51], vagus nerve stimulation (VNS) can cause adverse effects on respiration, including voice alteration, dyspnea, coughing, sore throat, and pharyngitis, most of which are due to left vocal cord adduction caused by the stimulation of the left recurrent laryngeal nerve. However, changes in respiratory patterns during sleep have also been reported in children with VNS use, especially in high stimulation

Sleep Breath

Fig. 3 Between sleep and epilepsy, there are complex and reciprocal interactions. (arrow up increases, arrow down decreases, plus sign amplifying)

frequencies. Khurana et al. [52] have observed OSA in 15 % of children after placement of VNS; Nagarajan et al. [53] have found respiratory breathing abnormalities in sleep during the PSG of seven of eight epileptic children on VNS, while SBD were present in eight of nine children after VNS implantation in a retrospective study of Hsieh et al. [54]. Zaaimi et al. [55] have also shown that VNS decreased respiratory amplitude and disturbed the coupling between the heart and

respiratory rate during sleep in children with pharmacoresistant epilepsy. Moreover, Malow et al. [56] have reported a clinically significant deterioration of respiratory function during sleep after the placement of VNS in children with pre-existing OSA and proposed that lowering stimulus frequency could prevent exacerbation of OSA. Both central and peripheral mechanisms can explain this effect of VNS, and they are based on the fact that vagus nerve is connected to

Sleep Breath

the brainstem respiratory control center and relays information from baroreceptors and chemoreceptors [51]. In this way, the stimulation of peripheral vagal afferents activates motor efferents of neurons in respiratory control centers of the brainstem, thus altering neuromuscular transmission to the upper airway muscles. Furthermore, VNS can modulate central projections to the brainstem reticular formation, altering breathing frequency and depth of respiration [57]. Therefore, polysomnography before VNS implantation should be considered to identify children with pre-existing OSA.

The impact of sleep apneas on children with epilepsy The impact on course of epilepsy The coexistence of epilepsy and SA is of great importance, as SA can worsen epilepsy in many ways. Apneas lead to arousals (cortical or subcortical), which cause children to spend more time in sleep stages N1 and N2, thus decreasing the total duration of REM stage. REM sleep is characterized by asynchronous neuronal discharge patterns, which exert a protective effect against epileptic activity, whereas synchronous neuronal activity in non-REM sleep facilitates the appearance of seizures [58, 59]. Besides, sleep fragmentation and sleep deprivation due to frequent arousals increase neuronal excitability and reduce the threshold for the appearance of seizures. Hypoxia caused by apneic events can also trigger seizures in susceptible individuals [60, 61] (Fig. 3). In accordance are the results of Miano et al. [87] who have observed paroxysmal epileptiform activity in 14.2 % of children with OSAS in polysomnographic recordings, whereas in the group of children with primary snoring, the frequency was 0 %. The observed prevalence was also higher than that observed in healthy children in previous studies [62]. A second prospective study of Miano S et al. [63] confirmed the high prevalence of epileptic activity in children with SBD, as it revealed a rate of interictal epileptiform discharges at 16.1 % among 298 children with SBD who underwent video-polysomnography. In the same study, totally 7 of these children with SBD were finally found to have nocturnal seizures (rolandic epilepsy, frontal lobe epilepsy) [63]. These findings enhance the hypothesis for a potential role of SA as a triggering factor for epileptic activity. The impact on cognitive functions Cognitive impairments and neurobehavioral problems are frequent in children with epilepsy, even in so-called benign epilepsies (e.g., rolandic epilepsy). These impairments include

deficits in reading or writing, worse IQ scores, problems in visual-spatial coordination, and memory and verbal fluency, and they can be present even at the onset of the disease [64, 65]. As it is known that specific sleep stages and sleep patterns are involved in learning and memory consolidation, it can be hypothesized that epileptiform activity during sleep may interfere with these processes, thus leading to cognitive dysfunction [66, 67]. On the other hand, the neurocognitive profile of children with OSAS shows many similarities with that found in children with epilepsy. More specifically, O’Brien LM et al. [68] have found that children with polysomnographically confirmed SBD score significantly lower than control groups on attention/executive tests as well as on tests concerning phonological processing, a skill critical for learning to read. Bourke R et al. [69] have identified a lower general intellectual ability and academic functioning in children with SBD regardless of severity, and Hamasaki Uema SF et al. [70] have shown that children with obstructive SBD have a significantly worse performance on tests of learning and memory. Although, Honaker SM et al. [71] have identified overall cognitive performances in normative range in school-aged children with SBD, their verbal skills were also problematic. On the contrary, Jackman AR et al. [72] have found that in preschool children, SBD of any severity was not associated with lower cognitive performance but only with poorer behavior. During the developmental period of brain, all possible comorbid conditions associated with epilepsy have a huge and accumulative potential impact on cognitive and sociobehavioral skills, thus worsening the prognosis of the disease. Moreover, respiratory events during sleep can enhance sleep fragmentation and instability and result in disturbance of neuroplasticity mechanisms [73]. In this way, it may be assumed that cognitive and behavioral complications in pediatric epilepsy could be the consequences not only of the primary fundamental characteristics of the disease but also of sleep disorders and mainly of SA. Sudden unexpected death The high prevalence of SA in epileptic children is also of clinical interest due to its possible relationship with sudden unexpected death in epilepsy (SUDEP). Although SUDEP is generally rare in childhood, it represents a frequent epilepsyrelated category of death among these children [74, 75]. Most cases occur in bed and at night, presumably during sleep. The causes are still unknown, but autonomic dysfunction and cardiopulmonary abnormalities during and between seizures have been proposed as possible mechanisms [76–78]. A systematic review of (near-) SUDEP cases has revealed a frequent presence of seizure-related apneas and postictal respiratory arrest [79]. Furthermore, many studies have recorded an increased mortality due to SUDEP in children with chronic

Sleep Breath

uncontrolled epilepsy, thus identifying seizure control as a very important risk factor [80, 81]. In the light of the fact that sleep is a possible trigger for the occurrence of SUDEP, SA lead to a higher frequency of seizures, and the most important risk factor for SUDEP is an increased seizure frequency; it is reasonable to hypothesize that SA may be a facilitator for SUDEP [82]. In conclusion, owing to the detrimental effects of SA on seizure control and on neurocognitive function and also to their probable association with SUDEP, children with epilepsy should be screened for SA. Although other factors may also account for poor seizure control, identifying the presence of SA is important, as therapeutic options are offered.

Treatment of sleep apneas The impact of SA on epilepsy and of epilepsy on SA can also be proven by the fact that the treatment of SA may alter the course of the disease. Totally, five articles on this topic were found with an evidence level of 4. Segal et al. [83] studied 27 children with OSAS and epilepsy, who underwent tonsillectomy or adenoidectomy for the treatment of OSAS and found that 3 months after surgery, 70.3 % of children exhibited a reduction in seizure frequency (37 % of children had become seizure free). There was a strong trend toward seizure remission with each percentile increase in BMI and younger age at time of surgery [83]. Similarly, Malow et al. [84] assessed an at least 45 % reduction in seizure frequency in 3 adults and 1 child during the CPAP treatment of OSAS. Koh et al. [85] studied 9 children with neurodevelopmental disorders who had welldocumented sleep apneic episodes and were treated surgically for OSA. In the first 12 months after surgery, seizure frequency was reduced in 5 patients (56 %) [85]. This leads to the hypothesis that SA treatment may be considered as an attempt to decrease seizure frequency, especially in children with poor seizure control. More studies with larger samples are needed to establish this, and another interesting parameter that could be studied is the effect of non-invasive therapies of SA on seizure control. However, an adverse event that was observed in an 18year-old girl with OSAS and epilepsy after the introduction of CPAP should be mentioned. More specifically, there was a transient increase in epileptiform discharges upon the introduction of CPAP. This increase was attributed to the increased number of arousals and decreased total sleep time in the first days of the therapy (due to difficulty in compliance with CPAP). Four months later, the epileptic discharges had been normalized [86]. This case highlights the importance of good compliance with CPAP, which may not be always easy, especially in populations of children. Furthermore, Miano et al.

[87] have reported the case of a 5-year-old obese child with severe OSAS, in whom nocturnal frontal lobe seizures developed within a week after therapy when CPAP was started. This was attributed to NREM sleep instability (increased cyclic alternating pattern rate and A1 index during slowwave sleep), which was observed during microstructure sleep analysis [87]. Although in literature, there are, to our knowledge, no other references of adverse effects on epilepsy due to SA treatment, these two cases underlie the complexity of interactions between sleep respiratory variables and epilepsy. They also suggest that implementation of treatment for SA in children with epilepsy (especially CPAP therapy) should be accompanied by close monitoring, as it may paradoxically act as a triggering factor of paroxysmal events. As regards the effect of epilepsy surgical treatment on SA, Zanzmera et al. [88] studied patients (adults and children) who underwent epilepsy surgery. A reduction of AHI was observed in patients with good surgical outcome 3 months after surgery. Although the difference was not significant, it is also indicative of a possible association [88].

Conclusions In conclusion, the prevalence of SA among epileptic children exceeds that of the general pediatric population. However, more studies based on larger samples and including control groups are needed to assess the exact frequency. Between SA and childhood epilepsy, there is a complex relationship with reciprocal interactions. This relationship could be characterized as causal, as SA have been proven to facilitate the appearance of epileptiform activity and also trigger seizures, thus resulting in the poorer control of epilepsy and enhancing the neurobehavioral complications of the disease. On the other hand, the above relationship could also be resultant, as epilepsy has been found to predispose to SA either by amplifying the sleep-induced breathing instability or as a consequence of antiepileptic treatment. Moreover, according to Gaitatzis et al. [2], as SA occur more often in the presence of epilepsy and vice versa, this may suggest an underlying brain state or even a specific genetic background (e.g., mutations in genes coding for ion channels or neurotrophic factors) that predate the onset of epilepsy and also favor the appearance of apneas. Further investigation of the relationship between SA and epilepsy is of interest, as it can improve the differential diagnosis of epilepsy, provide new epidemiological clues to the linking mechanisms, and influence the choices of treatment, creating both therapeutic limitations and opportunities. Choosing AED without significant effect on sleep or lowering the stimulation frequency in VNS are options that could prevent the appearance or exacerbation of SA, and on the

Sleep Breath

other hand, the treatment of SA (surgical or not) could improve seizure control in children with uncontrolled epilepsy. Pediatricians should therefore routinely screen children with epilepsy (especially those with poor seizure control) for signs and symptoms of SA and refer those of high risk to sleep centers, as polysomnography is the standard clinical practice for diagnosis of SA. On the other hand, the existence of SA should be taken into consideration when deciding a treatment strategy in children with epilepsy.

Conflict of interest None.

References 1. Wirrell E, Blackman M, Barlow K, Mah J, Hamiwka L (2005) Sleep disturbances in children with epilepsy compared with their nearestaged siblings. Dev Med Child Neurol 47:754–759 2. Gaitatzis A, Sisodiya SM, Sander JW (2012) The somatic comorbidity of epilepsy: a weighty but often unrecognized burden. Epilepsia 53:1282–1293 3. Larson AM, Ryther RC, Jennesson M, Geffrey AL, Bruno PL, Anagnos CJ et al (2012) Impact of pediatric epilepsy on sleep patterns and behaviors in children and parents. Epilepsia 53:1162– 1169 4. Edlund W, Gronseth G, Yuen S, Franklin G (2004) Clinical practice guideline process manual. American Academy of Neurology, St. Paul 5. Chang SJ, Chae KY (2010) Obstructive sleep apnea syndrome in children: epidemiology, pathophysiology, diagnosis and sequelae. Korean J Pediatr 53:863–871 6. Iber C, Ancoli-Israel S, Chesson AL Jr, Quan SF (2007) The AASM manual for the scoring of sleep and associated events: rules, terminology and technical specifications. Am Acad Sleep Med 47–48 7. Spruyt K, Gozal D (2011) Pediatric sleep questionnaires as diagnostic or epidemiological tools: a review of currently available instruments. Sleep Med Rev 15:19–32 8. Spruyt K, Gozal D (2011) Development of pediatric sleep questionnaires as diagnostic or epidemiological tools: a brief review of dos and don'ts. Sleep Med Rev 15:7–17 9. Marcus CL, Brooks LJ, Draper KA, Gozal D, Halbower AC, Jones J et al (2012) Diagnosis and management of childhood obstructive sleep apnea syndrome. Pediatrics 130:714–755 10. Goodwin JL, Kaemingk KL, Mulvaney SA, Morgan WJ, Quan SF (2005) Clinical screening of school children for polysomnography to detect sleep-disordered breathing—the Tucson Children's Assessment of Sleep Apnea study (TuCASA). J Clin Sleep Med 1: 247–254 11. Chervin RD, Weatherly RA, Garetz SL, Ruzicka DL, Giordani BJ, Hodges EK et al (2007) Pediatric sleep questionnaire: prediction of sleep apnea and outcomes. Arch Otolaryngol Head Neck Surg 133: 216–222 12. van Someren V, Burmester M, Alusi G, Lane R (2000) Are sleep studies worth doing? Arch Dis Child 83:76–81 13. Villa MP, Paolino MC, Castaldo R, Vanacore N, Rizzoli A, Miano S et al (2013) Sleep clinical record: an aid to rapid and accurate diagnosis of paediatric sleep disordered breathing. Eur Respir J 41: 1355–1361 14. Chan B, Cheong EY, Grace Ng SF, Chan YC, Lee QU, Chan KY (2011) Evaluation of sleep disturbances in children with epilepsy: a questionnaire-based case–control study. Epilepsy Behav 21:437–440

15. Maganti R, Hausman N, Koehn M, Sandok E, Glurich I, Mukesh BN (2006) Excessive daytime sleepiness and sleep complaints among children with epilepsy. Epilepsy Behav 8:272–277 16. Samaitienė R, Norkūnienė J, Tumienė B, Grikinienė J (2013) Sleep and behavioral problems in rolandic epilepsy. Pediatr Neurol 48:115– 122 17. Tang SS, Clarke T, Owens J, Pal DK (2010) Sleep behavior disturbances in rolandic epilepsy. J Child Neurol 26:239–243 18. Ong LC, Yang WW, Wong SW, alSiddiq F, Khu YS (2010) Sleep habits and disturbances in Malaysian children with epilepsy. J Ped Child Health 46:80–84 19. Jain SV, Simakajornboon S, Shapiro SM, Morton LD, Leszczyszyn DJ, Simakajornboon N (2012) Obstructive sleep apnea in children with epilepsy: prospective pilot trial. Acta Neurol Scand 125:3–6 20. Jain SV, Simakajornboon N, Glauser TA (2013) Provider practices impact adequate diagnosis of sleep disorders in children with epilepsy. J Child Neurol 28:589–595 21. Kaleyias J, Cruz M, Goraya JS, Valencia I, Khurana DS, Legido A et al (2008) Spectrum of polysomnographic abnormalities in children with epilepsy. Pediatr Neurol 39:170–176 22. Becker DA, Fennell EB, Carney PR (2004) Daytime behavior and sleep disturbance in childhood epilepsy. Epilepsy Behav 5:708–715 23. Miano S, Bruni O, Aricò D, Elia M, Ferri R (2010) Polysomnographic assessment of sleep disturbances in children with developmental disabilities and seizures. Neurol Sci 3:575–583 24. Maganti R, Sheth RD, Hermann BP, Weber S, Gidal BE, Fine J (2005) Sleep architecture in children with idiopathic generalized epilepsy. Epilepsia 46:104–109 25. Blunden S, Lushington K, Lorenzen B, Ooi T, Fung F, Kennedy D (2004) Are sleep problems under-recognised in general practice? Arch Dis Child 89:708–712 26. Vitelli O, Miano S, Tabarrini A, Mazzotta AR, Supino MC, Forlani M, Villa MP (2014) Epilepsy and sleep-disordered breathing as false friends: a case report. J Child Neurol 29:114–117 27. Lumeng JC, Chervin RD (2008) Epidemiology of pediatric obstructive sleep apnea. Proc Am Thorac Soc 5:242–252 28. Hoellinger P, Khatami R, Gugger M, Hess CW, Bassetti CL (2006) Epilepsy and obstructive sleep apnea. Eur Neurol 55:74–79 29. Jain SV, Horn PS, Simakajornboon N, Glauser TA (2013) Obstructive sleep apnea and primary snoring in children with epilepsy. J Child Neurol 28:77–82 30. Venturi M, Neves GS, Pontes IM, Valois A, Gomes Mda M (2011) Risk and determinant factors for obstructive sleep apnea in patients with epilepsy. Arq Neuropsiquiatr 69:924–927 31. Aurora RN, Lamm CI, Zak RS, Kristo DA, Bista SR, Rowley JA, Casey KR (2012) Practice parameters for the non-respiratory indications for polysomnography and multiple sleep latency testing for children. Sleep 35:1467–1473 32. Miyagawa T, Sotero M, Avellino AM, Kuratani J, Saneto RP, Ellenbogen RG et al (2007) Apnea caused by mesial temporal lobe mass lesions in infants: report of 3 cases. J Child Neurol 22:1079–1083 33. Ramelli GP, Donati F, Bianchetti M, Vassella F (1998) Apnoeic attacks as an isolated manifestation of epileptic seizures in infants. Eur J Paediatr Neurol 2:187–191 34. Sharma VK, Teoh HL, Chan BP (2010) Cerebral vasomotor reactivity in epilepsy patients. J Neurol 257:1565 35. O’Regan ME, Brown JK (2005) Abnormalities in cardiac and respiratory function observed during seizures in childhood. Dev Med Child Neurol 47:4–9 36. McKay LC, Atalla A, Morrell MJ (2010) Physiology and neural control of breathing during sleep. Eur Respir Monogr 50:1–16 37. Gutierrez MJ, Zhu J, Rodriguez-Martinez CE, Nino CL, Nino G (2013) Nocturnal phenotypical features of obstructive sleep apnea (OSA) in asthmatic children. Pediatr Pulmonol 48:592–600 38. Dempsey JA, Smith CA, Blain GM, Xie A, Gong Y, Teodorescu M (2012) Role of central/peripheral chemoreceptors and their

Sleep Breath

39. 40.

41.

42.

43.

44.

45.

46.

47. 48.

49. 50. 51.

52.

53.

54.

55.

56.

57.

58.

59.

interdependence in the pathophysiology of sleep apnea. Adv Exp Med Biol 758:343–349 Foresman BH (2000) Sleep and breathing disorders: the genesis of obstructive sleep apnea. J Am Osteopath Assoc 100:1–8 Terzano MG, Parrino L, Anelli S, Boselli M, Clemens B (1992) Effects of generalized interictal EEG discharges on sleep stability: assessment by means of cyclic alternating pattern. Epilepsia 33:317– 326 Kaada BR, Jasper H (1952) Respiratory responses to stimulation of temporal pole, insula, and hippocampal and limbic gyri in man. AMA Arch Neurol Psychiatry 68:609–619 Bonvallet M, Bobo EG (1972) Changes in phrenic activity and heart rate elicited by localized stimulation of amygdala and adjacent structures. Electroencephalogr Clin Neurophysiol 32:1–16 St-John WM, Rudkin AH, Homes GL, Leiter JC (2006) Changes in respiratory-modulated neural activities, consistent with obstructive and central apnea, during fictive seizures in an in situ anaesthetized rat preparation. Epilepsy Res 70:218–228 Terndrup TE, Darnall R, Knuth SL, Bartlett D Jr (1999) Effects of experimental cortical seizures on respiratory motor nerve activities in piglets. J Appl Physiol 86:2052–2058 Kanemura H, Sano F, Maeda Y, Sugita K, Aihara M (2012) Valproate sodium enhances body weight gain in patients with childhood epilepsy: a pathogenic mechanisms and open-label clinical trial of behavior therapy. Seizure 21:496–500 Verrotti A, Laus M, Scardapane A, Franzoni E, Chiarelli F (2009) Thyroid hormones in children with epilepsy during long-term administration of carbamazepine and valproate. Eur J Endocrinol 160:81– 86 Legros B, Bazil CW (2003) Effects of antiepileptic drugs on sleep architecture: a pilot study. Sleep Med 4:51–55 Bertorelli R, Ferri N, Adami M, Ongini E (1996) Effects of four antiepileptic drugs on sleep and waking in the rat under both light and dark phases. Pharmacol Biochem Behav 53:559–565 Bazil CW (2003) Effects of antiepileptic drugs on sleep structure: are all drugs equal? CNS Drugs 17:719–728 Manni R, Terzaghi M (2010) Comorbidity between epilepsy and sleep disorders. Epilepsy Res 90:171–177 Parhizgar F, Nugent K, Raj R (2011) Obstructive sleep apnea and respiratory complications associated with vagus nerve stimulators. J Clin Sleep Med 7:401–407 Khurana DS, Reumann M, Hobdell EF, Neff S, Valencia I, Legido A et al (2007) Vagus nerve stimulation in children with refractory epilepsy: unusual complications and relationship to sleepdisordered breathing. Childs Nerv Syst 23:1309–1312 Nagarajan L, Walsh P, Gregory P, Stick S, Maul J, Ghosh S (2003) Respiratory pattern changes in sleep in children on vagal nerve stimulation for refractory epilepsy. Can J Neurol Sci 30:224–227 Hsieh T, Chen M, McAfee A, Kifle Y (2008) Sleep-related breathing disorder in children with vagal nerve stimulators. Pediatr Neurol 38: 99–103 Zaaimi B, Grebe R, Berquin P, Wallois F (2009) Vagus nerve stimulation induces changes in respiratory sinus arrhythmia of epileptic children during sleep. Epilepsia 50:2473–2480 Malow BA, Edwards J, Marzec M, Sagher O, Fromes G (2000) Effects of vagus nerve stimulation on respiration during sleep: a pilot study. Neurology 55:1450–1454 Ebben MR, Sethi NK, Conte M, Pollak CP, Labar D (2008) Vagus nerve stimulation, sleep apnea, and CPAP titration. J Clin Sleep Med 4:471–473 Liu DB, Zhou LF, Zhong JW, Wang J (2004) Changes of sleep architecture in children with obstructive sleep apnea syndrome. Zhonghua Er Ke Za Zhi 42:284–286 Aneja S, Gupta M (2005) Sleep and childhood epilepsy. Indian J Pediatr 72:687–690

60. Scholle S, Zwacka G (2001) Arousals and obstructive sleep apnea syndrome in children. Clin Neurophysiol 112:984–991 61. Gu XQ, Haddad GG (2003) Maturation of neuronal excitability in hippocampal neurons of mice chronically exposed to cyclic hypoxia. Am J Physiol Cell Physiol 284:1156–1163 62. Miano S, Paolino MC, Peraita-Adrados R, Montesano M, Barberi S, Villa MP (2009) Prevalence of EEG paroxysmal activity in a population of children with obstructive sleep apnea syndrome. Sleep 32: 522–529 63. Miano S, Tabarrini A, Vitelli O, Mazzotta A, Del Pozzo M, Rabasco J et al (2013) The cooccurrence of interictal discharges and seizures in pediatric sleep-disordered breathing. Epilepsy Behav 29:508–512 64. Verrotti A, Filippini M, Matricardi S, Agostinelli MF, Gobbi G (2014) Memory impairment and Benign Epilepsy with centrotemporal spike (BECTS): a growing suspicion. Brain Cogn 84:123–131 65. Lopes R, Simões MR, Leal AJ (2014) Neuropsychological abnormalities in children with the Panayiotopoulos syndrome point to parietal lobe dysfunction. Epilepsy Behav 31:50–55 66. Kwon S, Seo HE, Hwang SK (2012) Cognitive and other neuropsychological profiles in children with newly diagnosed benign rolandic epilepsy. Korean J Pediatr 55:383–387 67. Braakman HM, Ijff DM, Vaessen MJ, Debeij-van Hall MH, Hofman PA, Backes WH et al (2012) Cognitive and behavioural findings in children with frontal lobe epilepsy. Eur J Paediatr Neurol 16:707–715 68. O'Brien LM, Mervis CB, Holbrook CR, Bruner JL, Smith NH, McNally N et al (2004) Neurobehavioral correlates of sleepdisordered breathing in children. J Sleep Res 13:165–172 69. Bourke R, Anderson V, Yang JS, Jackman AR, Killedar A, Nixon GM et al (2011) Cognitive and academic functions are impaired in children with all severities of sleep-disordered breathing. Sleep Med 12:489–496 70. Hamasaki Uema SF, Nagata Pignatari SS, Fujita RR, Moreira GA, Pradella-Hallinan M, Weckx L (2007) Assessment of cognitive learning function in children with obstructive sleep breathing disorders. Braz J Otorhinolaryngol 73:315–320 71. Honaker SM, Gozal D, Bennett J, Capdevila OS, Spruyt K (2009) Sleep-disordered breathing and verbal skills in school-aged community children. Dev Neuropsychol 34:588–600 72. Jackman AR, Biggs SN, Walter LM, Embuldeniya US, Davey MJ, Nixon GM et al (2012) Sleep-disordered breathing in preschool children is associated with behavioral, but not cognitive, impairments. Sleep Med 13:621–631 73. Parisi P, Bruni O, Pia Villa M, Verrotti A, Miano S, Luchetti A et al (2010) The relationship between sleep and epilepsy: the effect on cognitive functioning in children. Dev Med Child Neurol 52:805– 810 74. Morentin B, Alcaraz R (2002) Sudden unexpected death in epilepsy in children and adolescents. Rev Neurol 34:462–465 75. Terra VC, Scorza FA, Arida RM, Fernandes RM, Wichert-Ana L, Machado HR et al (2011) Mortality in children with severe epilepsy: 10 years of follow-up. Arq Neuropsiquiatr 69:766–769 76. Singh K, Katz ES, Zarowski M, Loddenkemper T, Llewellyn N, Manganaro S et al (2013) Cardiopulmonary complications during pediatric seizures: a prelude to understanding SUDEP. Epilepsia 54: 1083–1091 77. Meyer S, Shamdeen MG, Gottschling S, Strittmatter M, Gortner L (2011) Sudden unexpected death in epilepsy in children. J Paediatr Child Health 47:326–331 78. Camfield P, Camfield C (2005) Sudden unexpected death in people with epilepsy: a pediatric perspective. Semin Pediatr Neurol 12:10– 14 79. Langan Y, Nashef L, Sander JW (2000) Sudden unexpected death in epilepsy: a series of witnessed deaths. J Neurol Neurosurg Psychiatry 68:211–213

Sleep Breath 80. Weber P, Bubl R, Blauenstein U, Tillmann BU, Lütschg J (2005) Sudden unexplained death in children with epilepsy: a cohort study with an eighteen-year follow-up. Acta Paediatrm 94:564–567 81. Terra VC, Scorza FA, Sakamoto AC, Pinto KG, Fernandes RM, Arida RM et al (2009) Does sudden unexpected death in children with epilepsy occur more frequently in those with high seizure frequency? Arq Neuropsiquiatr 67:1001–1002 82. Andersen ML, Tufik S, Cavalheiro EA, Arida RM, de Albuquerque M, Matos G et al (2012) Lights out! It is time for bed. Warning: obstructive sleep apnea increases risk of sudden death in people with epilepsy. Epilepsy Behav 23:510–511 83. Segal E, Vendrame M, Gregas M, Loddenkemper T, Kothare SV (2012) Effect of treatment of obstructive sleep apnea on seizure outcomes in children with epilepsy. Pediatr Neurol 46:359–362 84. Malow BA, Weatherwax KJ, Chervin RD, Hoban TF, Marzec ML, Martin C et al (2003) Identification and treatment of obstructive sleep

85.

86.

87.

88.

apnea in adults and children with epilepsy: a prospective pilot study. Sleep Med 4:509–515 Koh S, Ward SL, Lin M, Chen LS (2000) Sleep apnea treatment improves seizure control in children with neurodevelopmental disorders. Pediatr Neurol 22:36–39 Hitomi T, Oga T, Tsuboi T, Yoshimura C, Kato T, Ikeda A et al (2012) Transient increase in epileptiform discharges after the introduction of nasal continuous positive airway pressure in a patient with obstructive sleep apnea and epilepsy. Intern Med 51:2453–2456 Miano S, Pelliccia A, Evangelisti M, Pagani J, Villa MP (2008) Role of continuous positive airway pressure therapy on the pathogenesis of sleep-related frontal lobe epilepsy in a child with obstructive sleep apnea syndrome. J Child Neurol 23:124–128 Zanzmera P, Shukla G, Gupta A, Goyal V, Srivastava A, Garg A et al (2013) Effect of successful epilepsy surgery on subjective and objective sleep parameters—a prospective study. Sleep Med 14:333–338