Curr Psychiatry Rep (2015) 17: 69 DOI 10.1007/s11920-015-0608-7
ATTENTION-DEFICIT DISORDER (A ROSTAIN, SECTION EDITOR)
Excessive Daytime Sleepiness in Patients With ADHD—Diagnostic and Management Strategies Stéphanie Bioulac 1,2 & Jean-Arthur Micoulaud-Franchi 2,3 & Pierre Philip 2,3
Published online: 1 July 2015 # Springer Science+Business Media New York 2015
Abstract The links between attention-deficit hyperactivity disorder (ADHD) and sleep disorders remain unclear. Specific sleep disorders are a frequent comorbid condition associated with ADHD according to a categorical approach. However, sleep disorders can also induce ADHD-like symptoms according to a dimensional approach and are thought to be the consequence of excessive daytime sleepiness. It may thus be difficult for clinicians to differentiate the diagnosis of ADHD comorbid with a sleep disorder from sleep disorders with ADHD-like symptoms. This distinction could be important for the appropriate management of patients with dual complaints of trouble maintaining attention and daytime sleepiness. This paper summarizes the main sleep disorders associated with ADHD: sleeprelated breathing disorders, sleep-related movement disorders, circadian rhythm sleep-wake disorders, and central disorders of hypersomnolence (aka hypersomnias). The history of presenting symptoms should be taken into account since ADHD is a neurodevelopmental disorder whereas ADHD symptoms comorbid with sleep disorder are not. Finally, we propose a model to clarify the links between ADHD, ADHD symptoms, and excessive daytime sleepiness induced by sleep disorders. Clinicians should therefore routinely assess, monitor, and manage This article is part of the Topical Collection on Attention-Deficit Disorder * Stéphanie Bioulac [email protected] 1
Centre Hospitalier Charles Perrens, Pôle de Pédopsychiatrie Universitaire, 121, rue de la Béchade, 33076 Bordeaux, Cedex, France
2
USR CNRS 3413 SANPSY “Sommeil, Attention et Neurospychiatrie”, Place Amélie Raba-Léon, 33076 Bordeaux, Cedex, France
3
Clinique du Sommeil, CHU Pellegrin, 33000 Bordeaux, France
the sleep problems of patients with ADHD who have both comorbidities and should search for the presence of ADHD symptoms in subjects with sleep disorders. Keywords Attention-deficit hyperactivity disorder . Sleep disorders . Sleep-related breathing disorder . Sleep-related movement disorders . Circadian rhythm sleep-wake disorders narcolepsy
Introduction Sleep disorders have been extensively investigated in individuals with attention-deficit hyperactivity disorder (ADHD), and their prevalence is reported to be in the range 25–55 % [1, 2••, 3•]. Sleep disturbances include difficulties in falling asleep, difficulties in awakening, and difficulties in maintaining adequate alertness for daily activities (excessive daytime sleepiness). Excessive daytime sleepiness affects 5 to 10 % of the general population [4] and is the primary complaint of many patients suffering from sleep disorders [5]. In sleep-related breathing disorders (SRBDs) and periodic limb movement disorder (PLMD), sleepiness occurs owing to chronically fragmented sleep. In circadian rhythm disorders, alteration of the sleep wake system regulation is responsible for the intrusion of sleepiness in daytime periods [6]. In narcolepsy, the mechanism involved is a central deficit in the waking systems. Even though specific sleep disorders are frequent comorbid disorders associated with ADHD, the biological links between ADHD and sleep disorders remain unclear. Moreover, sleep disorders can induce ADHD-like symptoms and are thought to be the consequence of excessive daytime sleepiness (EDS) according to a dimensional approach. Indeed, EDS can induce both alertness stabilization behavior similar to hyperactivity symptoms and a cognitive deficit, especially impaired
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sustained attention [7]. It may therefore be difficult for clinicians to differentiate the diagnosis of ADHD comorbid with a sleep disorder from sleep disorders with ADHD-like symptoms. However, this distinction could be important for the appropriate management of patients. The first aim of this paper is to summarize the main sleep disorders associated with ADHD. The second aim is to clarify the links between ADHD, ADHD symptoms, and EDS induced by sleep disorders in order to help clinicians to differentiate and manage patients with ADHD or ADHD symptoms and sleep disorders.
symptomatology after tonsillectomy in ADHD children with sleep-disordered breathing. These results were replicated by Li et al. [23], and in another study, 35 ADHD children with adenotonsillar hypertrophy showed significant improvement on inattention and hyperactivity scores after adenotonsillectomy [24]. Therefore, patients with ADHD should receive SRBD screening and treatment of comorbid SRBD should be considered for managing ADHD. In fact, in this setting of a comorbid condition, an improvement was found in ADHD symptoms following adenotonsillectomy in children with ADHD (in review, [16••]).
Sleep Disorders Associated With ADHD
ADHD and SRMD
ADHD and SRBDs
There are two common sleep-related movement disorders (SRMD): the restless legs syndrome (RLS) and periodic limb movement disorder (PLMD). RLS is a neurological disorder characterized by an irresistible urge to move the legs with an uncomfortable sensation that is relieved by movement and is worse at rest and most severe at night [25]. Since Picchietti et al. reported the association between ADHD and RLS in 1998, several studies have investigated this relationship [26–29]. Cortese et al. [30] emphasized the importance of identifying RLS during clinical evaluation of children with ADHD. In fact, the comorbid condition increases the risk of both disorders. While 2 % of typically developing children (aged 8–17 years) are reported to meet the diagnostic criteria for RLS [31], up to 44 % of children with ADHD have symptoms of RLS and 26 % of children with RLS have symptoms of ADHD [1, 11, 28]. This association has also been reported in adults [32, 33]. A recent German study [34] suggested a strong link between RLS and adult ADHD symptoms. Nevertheless, meticulous attention is required in the assessment of ADHD patients because RLS patients can be mistaken as ADHD patients and ADHD can also be accompanied by RLS. PLMD is a clinical syndrome characterized by periodic limb movements of sleep (PLMS). PLMS is a polysomnographic measure obtained with anterior tibialis EMG monitoring and is characterized by ≥4 series of pseudo-rhythmic spontaneous movements lasting 0.5 to 10 s and recurring every 5 to 90 s [35]. PLMDs are present in 80 % of patients with RLS. Typical movements consist of simultaneous flexion of the hips, knees, and ankles. Most patients including both adults and children are actually not aware of the involuntary limb movements. The limb jerks are more often reported by bed partners or by parents. Patients experience frequent awakenings from sleep, non-restorative sleep, daytime fatigue, and/or daytime sleepiness. The bed partner’s sleep quality tends to be affected more often than that of the patient. In addition, Chervin et al. recently found that PLMD with and without arousals became more common after adenotonsillectomy in a population of 144 children, of whom 58 were diagnosed as
SRBD is a disorder varying from primary snoring to upper airway resistance syndrome, obstructive ventilation, and obstructive sleep apnea (OSA). OSA, the most common SRBD, is characterized by the occurrence during sleep of abnormally frequent episodes (apnea/hypopnea index >5/h for the American Academy of Sleep Medicine; >10/h in France, threshold for treatment eligibility in France) of complete or partial obstruction of the upper airways responsible for hypopneas and apneas when ventilation is interrupted for ≥10 s. Grading of the sleep apnea syndrome in children differs from adults: it is generally agreed that an apnea-hypopnea index (AHI) ≥1/h is abnormal [8]. SRBD has been regularly associated with neurobehavioral and neurocognitive deficit including inattentive or hyperactive symptoms [1, 9–11]. The relationship between SRBD and ADHD (as a categorical diagnosis according to Diagnostic and Statistical Manual (DSM) criteria) or ADHD symptoms (as a dimensional approach based on a scale) is still controversial [12]. Several studies suggest an increased incidence of SRBD ranging from 25 to 57 % among children and adolescents diagnosed with ADHD (using diagnostic criteria) [13–16••]. Nevertheless, other studies question this relationship, as they find no such increased incidence of patients with ADHD associated with SRBD [17–19]. Heterogeneous selection criteria (for example, variability between studies on AHI cutoffs used to diagnose SRBD; some use a cutoff of >5 per hour while others use >1 per hour) and variability in whether a clinical diagnosis of ADHD or an ADHD rating scale is used to assess ADHD symptoms might explain some of the inconsistency in these results [16••, 20, 21]. A recent meta-analysis [16••] suggests that pediatric populations suffering from SRBD are at increased risk of presenting with symptoms of ADHD, including inattention and hyperactivity. Moreover, beneficial effects of SRBD therapy on ADHD symptoms have been reported. In a comparative controlled study, Huang et al. [22] found a significant improvement in ADHD
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having ADHD [26]. This finding raises questions about the links between this PLMD and OSA. ADHD and Circadian Rhythm Sleep-Wake Disorders The major feature of circadian rhythm sleep-wake disorders is the misalignment of sleep pattern timing with the terrestrial cycle, leading to disrupted sleep and impaired functioning. Delayed sleep-phase syndrome, which occurs primarily in adolescence, is characterized by sleep onset insomnia, evening diurnal preference, and difficulty waking. Dim-light melatonin onset (DLMO) is a reliable marker of circadian function [36]. Van der Heijden [37, 38] demonstrated that DLMO is delayed in children with ADHD compared with controls. Van der Heijden [39] and Weiss MD [40] described a significant improvement in sleep onset delay after supplementation of exogenous melatonin. In the same line, Van Veen [41] showed that ADHD adults comorbid with sleep onset insomnia exhibited a delayed melatonin onset compared to ADHD adults without sleep onset insomnia and compared to healthy control subjects. Moreover, Rybak showed that the severity of the disorder in ADHD adults was correlated with later circadian preference (evening type) [42]. Some findings suggest that Beveningness^ (characteristic of being most active and alert during the evening, i.e., Ba night owl^, may be strongly associated with ADHD, especially with the inattention subtype [43, 44]. Similarly, Caci suggested that eveningness may constitute an endophenotype of the inattentive subtype of ADHD [45]. At the molecular level, the circadian system consists of a series of transcriptional feedback loops of clock genes, which in turn produce endocrine, physiological, and behavioral outputs with a near 24-h periodicity. Circadian rhythms may be measured by self-sampling of oral mucosa to assess the rhythmic expression of the clock genes BMAL1 and PER2. In a comparative study between ADHD adults and controls, Baird et al. [46] found that the clock genes BMAL1 and PER2 showed a circadian rhythmicity in controls that was absent in the ADHD group. ADHD and Central Disorders of Hypersomnolence (aka Hypersomnias) The main central disorders of hypersomnolence include narcolepsy and idiopathic hypersomnia and are characterized by EDS. Narcolepsy is defined by periods of irresistible sleepiness and sleep attacks of brief duration, frequently accompanied by one or more of the auxiliary symptoms: cataplexy, sleep paralysis, and hypnagogic hallucinations. In idiopathic hypersomnia, sleepiness and sleep attacks are generally of longer duration and are more resistible than in narcolepsy. The auxiliary symptoms are also absent. Narcolepsy with cataplexy is associated in 85 to 95 % of cases with a deficiency in the hypothalamic neuropeptide hypocretin/orexin (Hcrt), as
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evidenced by low or undetectable levels of Hcrt in the cerebrospinal fluid (CSF) [47–49]. A few studies have examined the comorbidity between the diagnoses of ADHD and narcolepsy [50–52]. In the study by Ohayon of a population of 320 narcoleptic subjects compared to 1464 controls, the rate of ADHD in childhood was 5.4 versus 2.5 %, respectively. ADHD and Behavioral Sleep Deprivation Reduced sleep efficiency and decreased sleep quality perceived both by the child and his parents are complaints often described in ADHD subjects [53]. Problematic behaviors at bedtime, upon awakening, and during the night are frequently reported by parents of ADHD children [54]. Problems getting to sleep have been described in various studies as a higher frequency of bedtime resistance [55, 56], increased sleeponset difficulties [54], and interruptions during bedtime routines [55, 57]. Problems in maintaining sleep are also frequent, and higher levels of nocturnal activity have commonly been described in ADHD children [53]. Moreover, increased nightto-night sleep duration variability in ADHD children may occur [58–60]. For example, in a recent study, Spruyt et al. [61] showed that children (mean age 9.4 years) slept, on average, 6 h and 58 min with a variability of 1 h 3 min. Their sleepiness scores were also highly variable from day to day. These findings underline the difficulties of transitioning from wake to sleep and from sleep to wake in ADHD patients. Last but not least, the issue of staying up too late to engage in recreational activities such as videogames and internet surfing should be thoroughly evaluated. To summarize, sleep problems in ADHD subjects are likely to be multidirectional and multifactorial in origin [53]. .
Links Between ADHD, ADHD Symptoms, and EDS EDS, which is a very frequent symptom, is evaluated both by a clinical scale and electrophysiological measures. The most widely used clinical scale is the Epworth Sleepiness Scale (ESS) [62]. The ESS is a self-administered questionnaire that asks the subject to rate his or her probability of falling asleep. Subjects fill in a scale of increasing probability from 0 to 3 for eight different situations that most people engage in during their daily lives. A score in the 0–8 range is considered to be normal while a score above 11 indicates moderate-to-severe sleepiness, suggesting that expert medical advice should be sought. With regard to electrophysiological measures, the multiple sleep latency test (MSLT) and the maintenance of wakefulness test (MWT) are currently used in sleep medicine for the evaluation of EDS. On the day following standard nocturnal recording, the MSLT is administered 2 h after waking up [63]. Five
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20-min naps are recorded every 2 h. Subjects are prone and are allowed 20 min to fall asleep for each recording session. The MWT consists in four 40-min MWT trials, as recommended by the American Academy of Sleep Medicine [5]. Subjects are not allowed to use any artificial strategy to stay awake such as moving continuously or singing, and they are in a semi-recumbent position. They are asked to fight against any sleepiness that they feel in a soporific condition. From EDS to ADHD Symptoms Sleep specialists have studied symptoms of ADHD in populations of narcoleptic adults [52, 64–68]. Oosterloo et al. [52] found that symptoms of ADHD were present in 18.9 % of patients with narcolepsy. In the study of Modestino [64], childhood ADHD symptoms were significantly more frequent in the narcoleptic group than in the control group. The other studies detail cognitive deficits in narcoleptic adult patients such as attention deficits [65, 66] and executive function deficits [67, 69, 70]. Thus, it has been suggested that being sleepy might explain not only inattention but also hyperactivity and impulsivity as a strategy to stay awake. This finding has generated a model for ADHD involving a deficit in alertness [71, 72]. In this model, motor hyperactivity, at least in some ADHD children, may be a counter-behavior for staying awake [73]. The use of stimulant medication to treat ADHD and the improvement of ADHD symptoms with modafinil, which is commonly used to treat narcolepsy [74–77], strengthen the idea of a deficit in alertness in ADHD. Moreover, some of the therapeutic effects of stimulant medication in ADHD could be due to their effect on EDS, which interrupts the autoregulatory hyperactivity behavior [7]. From ADHD to EDS ADHD subjects often complain of sleepiness in unstimulating conditions even when they are sufficiently rested. Daytime sleepiness evaluated with the clinical scale has been linked to ADHD in children primarily and adults in many [52, 78•, 79, 80] but not all studies [81–83]. In the same line, using an objective tool (the MSLT), four studies demonstrated that ADHD children exhibited EDS in comparison with healthy subjects, although some of them had no organic sleep disorders documented by polysomnography [26, 84–86]. Another study by Prihodova [87] found no difference between ADHD children and controls on the MSLT but did find significant alertness variability during MSLT in ADHD children, which could be a sign of dysregulated arousal. Similarly, the metaanalysis by Cortese et al. [30, 54] showed that children with ADHD exhibited significantly pathological results on the MSLT compared to controls. The contrary result was found by the team of Wiebe [88••] who did not find any significant difference on the MSLT between ADHD and control children.
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Unlike in the pediatric field, research studies in sleep medicine in ADHD adult patients are relatively scarce. Oosterloo et al. found that 37 % of ADHD adult patients met the criteria for subjective EDS [52], and Yoon [78•] demonstrated that subjective sleepiness was associated with fatigue in ADHD with combined subtype but not in ADHD with inattentive subtype. A recent study using the MSLT showed that ADHD patients’ reports of EDS were verified by shorter sleep latency on the MSLT [16••]. ADHD patients with subjective higher daytime tiredness fell asleep faster during MSLT, but they did not differ from controls in mean MSLT. Likewise, in the pediatric field, contrary results were found with objective measures of sleepiness. A low level of arousal can also be related to EEG measurements. The most classical is EEG spectral analysis. Indeed, many EEG studies have found an increase in slow EEG activity in the theta and delta range and a reduced beta EEG activity in patients with ADHD [89]. Less widespread is the use of EEG alertness stages [7]. Using EEG, different alertness stages can be discerned during both sleep and wakefulness. Using an EEG-based algorithm (Vigilance Algorithm Leipzid, VIGALL), different alertness stages can be described from high alertness to relaxed wakefulness to drowsiness and sleep onset [90]. Sander et al. [91] using this algorithm found that children with ADHD exhibited a low and unstable level of EEG alertness. This is in line with the result of Prihodova [87] who found significant variability in alertness during MSLT in ADHD children. Measurements on EEG spectral analysis and EEG alertness stages are very consistent in children but not in adolescents or adults. This fact could explain the negative results of Sobanski et al. [92] in adults with ADHD. However, abnormal EEG activity is not found in all children with ADHD [89]. Low and dysregulated arousal should be considered more as a physiological feature of a substantial subgroup of ADHD children, which could represent a prognostic marker rather than a diagnostic marker [89]. Indeed, stimulant medication was found to be more efficient in children with high slow EEG activity [93] or unstable EEG alertness [91]. Moreover, sleep disorders that reduce the level of arousal and destabilize alertness are known to worse symptomatology in children with ADHD [94], whereas interventions that improve sleep quality improve it [95]. Children with low and unstable levels of arousal could be those who would benefit the most from these behavioral interventions. Thus, it is worthwhile defining specific subgroups of patients with ADHD who could benefit from specific therapeutic approaches. In children with ADHD, these subgroups could be defined with EEG measurements (EEG spectral power [89] and EEG alertness stages [7] and MSLT [26, 84–86]. In adults with ADHD, a subgroup of patients with impaired alertness could also be defined. Therefore, one could assume that within a context of EDS, some ADHD adults would display pathological maintenance wakefulness test (MWT) scores, which would also be an
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objective marker of cognitive impairment. To confirm this hypothesis, our team designed a study whose objectives were to explore objective daytime sleepiness with a MWT in a population of ADHD adult patients and to relate MWT scores to simulated driving performance [96]. We administered the MWT and not the MSLT because the MWT may be used to assess an individual’s ability to remain awake when his or her inability to remain awake constitutes a public or personal safety issue [5]. It also appears that patients suffering from sleep disorders with EDS may exhibit pathological scores on the MWT compared to healthy subjects [97–100]. Our study demonstrates for the first time that a significant proportion of ADHD adults exhibit objective EDS. One of the main results is that 35 % of ADHD patients were severely sleepy on the MWT with a mean sleep latency of 14.2 min (pathological score ≤19 min). Even though we did not aim to relate EDS to a specific sleep disorder, another interesting result is that within this subgroup of sleepy ADHD adults (n=14), 11 of them were free of sleep-disordered breathing and/or periodic leg movements at a pathological level. Therefore, one question is whether this subgroup of sleepy ADHD patients represents a particular subgroup. This result corroborates the hypothesis of the central origin of the EDS: a Bhypo-arousal state^ such as in narcolepsy has been suggested by a few authors [101•]. Beyond this physiopathological issue, our study may have clinical implications. In fact, the use of wakefulness-promoting medication (i.e., modafinil treatment currently used in narcolepsy) rather than stimulant medication (methylphenidate) in this subgroup of subjects might be indicated. This new therapeutic strategy should be assessed in the future.
Fig. 1 Integrative model for ADHD, ADHD symptoms, EDS, and sleep disorder comorbidities. Psychiatrists and sleep specialists should consider whether ADHD is worsening by a comorbid sleep disorder or if a sleep disorder has induced EDS and ADHD-like symptoms without ADHD
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Proposition of a Model From these observations, an integrative model can be proposed for ADHD, ADHD symptoms, EDS, and sleep disorder comorbidities (Fig. 1). Indeed, ADHD can be associated with EDS in a subgroup of patients. In this subgroup, EDS can be a core pathogenic factor. It can induce both alertness stabilization behavior similar to hyperactivity symptoms and a cognitive deficit, especially impaired sustained attention. Furthermore, ADHD is frequently associated with sleep disorders that can induce EDS and worsen the prognosis of the disorder. Psychiatrists should carefully evaluate and treat sleep disorders in patients with ADHD (as a categorical diagnosis according to DSM criteria) in order to improve ADHD. Sleep treatment should form part of the multimodal approach to ADHD based on stimulant medication, behavioral, and cognitive strategies, etc. However, sleep disorders can also induce ADHD symptoms (as a dimensional approach) that should not be confused with ADHD. In this case, treatment of only the sleep disorder should be associated with the disappearance of ADHD symptoms.
Behavioral Management of Sleep Problems ADHD induced by sleep disorders and ADHD-related sleep disorders pose a difficult clinical problem, so the clinician should gather a developmental and family history (of ADHD and sleep problems) and get the patient to maintain a sleep diary in order to determine the extent of the sleep problems.
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Management of sleep problems in ADHD is crucial, as they may aggravate ADHD symptoms. First of all, a baseline sleep evaluation during the initial assessment of ADHD is recommended [3•]. The initial screening should include questionnaires such as the B: bedtime issues, E: excessive daytime sleepiness, A: night awakenings, R: regularity and duration of sleep, and S: snoring (BEARS) [102] and the Children’s Sleep Habits Questionnaire [103]. If some sleep problems are identified, children and/or parents should maintain a sleep diary for 15 days. Some sleep disorders can be assessed with a clinical interview while others require specific polysomnographic recording associated or/not with other objective tools such as the MSLT or MWT. Moreover, given the impact of psychiatric comorbidities on sleep, any associated psychopathologies should be evaluated systematically in ADHD patients [3•]. For example, bedtime resistance might be induced by anxious comorbidity in some subjects, while it might be related to a sleep-onset delay due to a delayed sleep-phase syndrome or to psychostimulant treatment in others. Therefore, the underlying cause of bedtime resistance in any given patient needs to be elucidated. Behavioral management primarily involves sleep hygiene. Healthy sleep practices comprise a regular sleep/wake schedule, adequate opportunity for sleep, calming and structured bedtime routines, the avoidance of caffeine, large amounts of liquids, naps, exercise, avoidance of alerting activities such as the use of electronic devices just before bedtime, sleeping only in bed, using one’s bed only for sleeping, and attention to environmental factors such as light, noise, and temperature [1, 2••, 3•, 11]. When assessing children’s sleep needs, it is crucial to educate parents about signals that suggest that a child is not getting sufficient sleep, such as difficulty waking up in the morning and sleeping longer at weekends. Nutrition may also play a role in sleep hygiene, although there is insufficient evidence to recommend any specific diet [3•]. The efficacy of behavioral sleep interventions has been demonstrated for insomnia in typically developing children, including parent education, graduated extinction, and bedtime fading [104, 105]. Clinical studies of behavioral strategies to improve sleep in ADHD children are limited. A recent randomized clinical trial including 27 families with parents and children showed that delivering a behavioral sleep intervention is feasible in ADHD children and that children’s sleep assessed by parent reports was improved [106]. Finally, clinicians should keep in mind that if sleep disorders are suspected as being due to ADHD medications, alternative dosing formulations or treatments may be required.
Conclusion The distinction between ADHD comorbid with sleep disorder and sleep disorders with ADHD symptoms can be difficult.
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However, the history of the symptoms is important to take into account especially since ADHD is a neurodevelopmental disorder (as now clearly underlined in the DSM-5), whereas ADHD symptoms associated with a sleep disorder comorbidity are not. Clinicians should therefore routinely assess, monitor, and manage sleep problems in the presence of both comorbidities in children and adults with ADHD and vice versa, as recommended by ADHD guidelines [107, 108]. As an initial step, a careful history and obtaining a sleep log can help in clarifying the nature and origins of EDS. In more complex cases, a structured comorbidity assessment may be required with multidisciplinary teams working together to treat the comorbidities. Future work and longitudinal research should clarify the direction of the relationship between ADHD, ADHD symptoms, and sleep disorders. Exploration of wakefulness and sleep is a gateway to better understanding of the physiopathology of ADHD.
Compliance with Ethics Guidelines Conflict of Interest Stéphanie Bioulac, Jean-Arthur MicoulaudFranchi, and Pierre Philip declare that they have no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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ATTENTION-DEFICIT DISORDER (A ROSTAIN, SECTION EDITOR)
Excessive Daytime Sleepiness in Patients With ADHD—Diagnostic and Management Strategies Stéphanie Bioulac 1,2 & Jean-Arthur Micoulaud-Franchi 2,3 & Pierre Philip 2,3
Published online: 1 July 2015 # Springer Science+Business Media New York 2015
Abstract The links between attention-deficit hyperactivity disorder (ADHD) and sleep disorders remain unclear. Specific sleep disorders are a frequent comorbid condition associated with ADHD according to a categorical approach. However, sleep disorders can also induce ADHD-like symptoms according to a dimensional approach and are thought to be the consequence of excessive daytime sleepiness. It may thus be difficult for clinicians to differentiate the diagnosis of ADHD comorbid with a sleep disorder from sleep disorders with ADHD-like symptoms. This distinction could be important for the appropriate management of patients with dual complaints of trouble maintaining attention and daytime sleepiness. This paper summarizes the main sleep disorders associated with ADHD: sleeprelated breathing disorders, sleep-related movement disorders, circadian rhythm sleep-wake disorders, and central disorders of hypersomnolence (aka hypersomnias). The history of presenting symptoms should be taken into account since ADHD is a neurodevelopmental disorder whereas ADHD symptoms comorbid with sleep disorder are not. Finally, we propose a model to clarify the links between ADHD, ADHD symptoms, and excessive daytime sleepiness induced by sleep disorders. Clinicians should therefore routinely assess, monitor, and manage This article is part of the Topical Collection on Attention-Deficit Disorder * Stéphanie Bioulac [email protected] 1
Centre Hospitalier Charles Perrens, Pôle de Pédopsychiatrie Universitaire, 121, rue de la Béchade, 33076 Bordeaux, Cedex, France
2
USR CNRS 3413 SANPSY “Sommeil, Attention et Neurospychiatrie”, Place Amélie Raba-Léon, 33076 Bordeaux, Cedex, France
3
Clinique du Sommeil, CHU Pellegrin, 33000 Bordeaux, France
the sleep problems of patients with ADHD who have both comorbidities and should search for the presence of ADHD symptoms in subjects with sleep disorders. Keywords Attention-deficit hyperactivity disorder . Sleep disorders . Sleep-related breathing disorder . Sleep-related movement disorders . Circadian rhythm sleep-wake disorders narcolepsy
Introduction Sleep disorders have been extensively investigated in individuals with attention-deficit hyperactivity disorder (ADHD), and their prevalence is reported to be in the range 25–55 % [1, 2••, 3•]. Sleep disturbances include difficulties in falling asleep, difficulties in awakening, and difficulties in maintaining adequate alertness for daily activities (excessive daytime sleepiness). Excessive daytime sleepiness affects 5 to 10 % of the general population [4] and is the primary complaint of many patients suffering from sleep disorders [5]. In sleep-related breathing disorders (SRBDs) and periodic limb movement disorder (PLMD), sleepiness occurs owing to chronically fragmented sleep. In circadian rhythm disorders, alteration of the sleep wake system regulation is responsible for the intrusion of sleepiness in daytime periods [6]. In narcolepsy, the mechanism involved is a central deficit in the waking systems. Even though specific sleep disorders are frequent comorbid disorders associated with ADHD, the biological links between ADHD and sleep disorders remain unclear. Moreover, sleep disorders can induce ADHD-like symptoms and are thought to be the consequence of excessive daytime sleepiness (EDS) according to a dimensional approach. Indeed, EDS can induce both alertness stabilization behavior similar to hyperactivity symptoms and a cognitive deficit, especially impaired
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sustained attention [7]. It may therefore be difficult for clinicians to differentiate the diagnosis of ADHD comorbid with a sleep disorder from sleep disorders with ADHD-like symptoms. However, this distinction could be important for the appropriate management of patients. The first aim of this paper is to summarize the main sleep disorders associated with ADHD. The second aim is to clarify the links between ADHD, ADHD symptoms, and EDS induced by sleep disorders in order to help clinicians to differentiate and manage patients with ADHD or ADHD symptoms and sleep disorders.
symptomatology after tonsillectomy in ADHD children with sleep-disordered breathing. These results were replicated by Li et al. [23], and in another study, 35 ADHD children with adenotonsillar hypertrophy showed significant improvement on inattention and hyperactivity scores after adenotonsillectomy [24]. Therefore, patients with ADHD should receive SRBD screening and treatment of comorbid SRBD should be considered for managing ADHD. In fact, in this setting of a comorbid condition, an improvement was found in ADHD symptoms following adenotonsillectomy in children with ADHD (in review, [16••]).
Sleep Disorders Associated With ADHD
ADHD and SRMD
ADHD and SRBDs
There are two common sleep-related movement disorders (SRMD): the restless legs syndrome (RLS) and periodic limb movement disorder (PLMD). RLS is a neurological disorder characterized by an irresistible urge to move the legs with an uncomfortable sensation that is relieved by movement and is worse at rest and most severe at night [25]. Since Picchietti et al. reported the association between ADHD and RLS in 1998, several studies have investigated this relationship [26–29]. Cortese et al. [30] emphasized the importance of identifying RLS during clinical evaluation of children with ADHD. In fact, the comorbid condition increases the risk of both disorders. While 2 % of typically developing children (aged 8–17 years) are reported to meet the diagnostic criteria for RLS [31], up to 44 % of children with ADHD have symptoms of RLS and 26 % of children with RLS have symptoms of ADHD [1, 11, 28]. This association has also been reported in adults [32, 33]. A recent German study [34] suggested a strong link between RLS and adult ADHD symptoms. Nevertheless, meticulous attention is required in the assessment of ADHD patients because RLS patients can be mistaken as ADHD patients and ADHD can also be accompanied by RLS. PLMD is a clinical syndrome characterized by periodic limb movements of sleep (PLMS). PLMS is a polysomnographic measure obtained with anterior tibialis EMG monitoring and is characterized by ≥4 series of pseudo-rhythmic spontaneous movements lasting 0.5 to 10 s and recurring every 5 to 90 s [35]. PLMDs are present in 80 % of patients with RLS. Typical movements consist of simultaneous flexion of the hips, knees, and ankles. Most patients including both adults and children are actually not aware of the involuntary limb movements. The limb jerks are more often reported by bed partners or by parents. Patients experience frequent awakenings from sleep, non-restorative sleep, daytime fatigue, and/or daytime sleepiness. The bed partner’s sleep quality tends to be affected more often than that of the patient. In addition, Chervin et al. recently found that PLMD with and without arousals became more common after adenotonsillectomy in a population of 144 children, of whom 58 were diagnosed as
SRBD is a disorder varying from primary snoring to upper airway resistance syndrome, obstructive ventilation, and obstructive sleep apnea (OSA). OSA, the most common SRBD, is characterized by the occurrence during sleep of abnormally frequent episodes (apnea/hypopnea index >5/h for the American Academy of Sleep Medicine; >10/h in France, threshold for treatment eligibility in France) of complete or partial obstruction of the upper airways responsible for hypopneas and apneas when ventilation is interrupted for ≥10 s. Grading of the sleep apnea syndrome in children differs from adults: it is generally agreed that an apnea-hypopnea index (AHI) ≥1/h is abnormal [8]. SRBD has been regularly associated with neurobehavioral and neurocognitive deficit including inattentive or hyperactive symptoms [1, 9–11]. The relationship between SRBD and ADHD (as a categorical diagnosis according to Diagnostic and Statistical Manual (DSM) criteria) or ADHD symptoms (as a dimensional approach based on a scale) is still controversial [12]. Several studies suggest an increased incidence of SRBD ranging from 25 to 57 % among children and adolescents diagnosed with ADHD (using diagnostic criteria) [13–16••]. Nevertheless, other studies question this relationship, as they find no such increased incidence of patients with ADHD associated with SRBD [17–19]. Heterogeneous selection criteria (for example, variability between studies on AHI cutoffs used to diagnose SRBD; some use a cutoff of >5 per hour while others use >1 per hour) and variability in whether a clinical diagnosis of ADHD or an ADHD rating scale is used to assess ADHD symptoms might explain some of the inconsistency in these results [16••, 20, 21]. A recent meta-analysis [16••] suggests that pediatric populations suffering from SRBD are at increased risk of presenting with symptoms of ADHD, including inattention and hyperactivity. Moreover, beneficial effects of SRBD therapy on ADHD symptoms have been reported. In a comparative controlled study, Huang et al. [22] found a significant improvement in ADHD
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having ADHD [26]. This finding raises questions about the links between this PLMD and OSA. ADHD and Circadian Rhythm Sleep-Wake Disorders The major feature of circadian rhythm sleep-wake disorders is the misalignment of sleep pattern timing with the terrestrial cycle, leading to disrupted sleep and impaired functioning. Delayed sleep-phase syndrome, which occurs primarily in adolescence, is characterized by sleep onset insomnia, evening diurnal preference, and difficulty waking. Dim-light melatonin onset (DLMO) is a reliable marker of circadian function [36]. Van der Heijden [37, 38] demonstrated that DLMO is delayed in children with ADHD compared with controls. Van der Heijden [39] and Weiss MD [40] described a significant improvement in sleep onset delay after supplementation of exogenous melatonin. In the same line, Van Veen [41] showed that ADHD adults comorbid with sleep onset insomnia exhibited a delayed melatonin onset compared to ADHD adults without sleep onset insomnia and compared to healthy control subjects. Moreover, Rybak showed that the severity of the disorder in ADHD adults was correlated with later circadian preference (evening type) [42]. Some findings suggest that Beveningness^ (characteristic of being most active and alert during the evening, i.e., Ba night owl^, may be strongly associated with ADHD, especially with the inattention subtype [43, 44]. Similarly, Caci suggested that eveningness may constitute an endophenotype of the inattentive subtype of ADHD [45]. At the molecular level, the circadian system consists of a series of transcriptional feedback loops of clock genes, which in turn produce endocrine, physiological, and behavioral outputs with a near 24-h periodicity. Circadian rhythms may be measured by self-sampling of oral mucosa to assess the rhythmic expression of the clock genes BMAL1 and PER2. In a comparative study between ADHD adults and controls, Baird et al. [46] found that the clock genes BMAL1 and PER2 showed a circadian rhythmicity in controls that was absent in the ADHD group. ADHD and Central Disorders of Hypersomnolence (aka Hypersomnias) The main central disorders of hypersomnolence include narcolepsy and idiopathic hypersomnia and are characterized by EDS. Narcolepsy is defined by periods of irresistible sleepiness and sleep attacks of brief duration, frequently accompanied by one or more of the auxiliary symptoms: cataplexy, sleep paralysis, and hypnagogic hallucinations. In idiopathic hypersomnia, sleepiness and sleep attacks are generally of longer duration and are more resistible than in narcolepsy. The auxiliary symptoms are also absent. Narcolepsy with cataplexy is associated in 85 to 95 % of cases with a deficiency in the hypothalamic neuropeptide hypocretin/orexin (Hcrt), as
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evidenced by low or undetectable levels of Hcrt in the cerebrospinal fluid (CSF) [47–49]. A few studies have examined the comorbidity between the diagnoses of ADHD and narcolepsy [50–52]. In the study by Ohayon of a population of 320 narcoleptic subjects compared to 1464 controls, the rate of ADHD in childhood was 5.4 versus 2.5 %, respectively. ADHD and Behavioral Sleep Deprivation Reduced sleep efficiency and decreased sleep quality perceived both by the child and his parents are complaints often described in ADHD subjects [53]. Problematic behaviors at bedtime, upon awakening, and during the night are frequently reported by parents of ADHD children [54]. Problems getting to sleep have been described in various studies as a higher frequency of bedtime resistance [55, 56], increased sleeponset difficulties [54], and interruptions during bedtime routines [55, 57]. Problems in maintaining sleep are also frequent, and higher levels of nocturnal activity have commonly been described in ADHD children [53]. Moreover, increased nightto-night sleep duration variability in ADHD children may occur [58–60]. For example, in a recent study, Spruyt et al. [61] showed that children (mean age 9.4 years) slept, on average, 6 h and 58 min with a variability of 1 h 3 min. Their sleepiness scores were also highly variable from day to day. These findings underline the difficulties of transitioning from wake to sleep and from sleep to wake in ADHD patients. Last but not least, the issue of staying up too late to engage in recreational activities such as videogames and internet surfing should be thoroughly evaluated. To summarize, sleep problems in ADHD subjects are likely to be multidirectional and multifactorial in origin [53]. .
Links Between ADHD, ADHD Symptoms, and EDS EDS, which is a very frequent symptom, is evaluated both by a clinical scale and electrophysiological measures. The most widely used clinical scale is the Epworth Sleepiness Scale (ESS) [62]. The ESS is a self-administered questionnaire that asks the subject to rate his or her probability of falling asleep. Subjects fill in a scale of increasing probability from 0 to 3 for eight different situations that most people engage in during their daily lives. A score in the 0–8 range is considered to be normal while a score above 11 indicates moderate-to-severe sleepiness, suggesting that expert medical advice should be sought. With regard to electrophysiological measures, the multiple sleep latency test (MSLT) and the maintenance of wakefulness test (MWT) are currently used in sleep medicine for the evaluation of EDS. On the day following standard nocturnal recording, the MSLT is administered 2 h after waking up [63]. Five
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20-min naps are recorded every 2 h. Subjects are prone and are allowed 20 min to fall asleep for each recording session. The MWT consists in four 40-min MWT trials, as recommended by the American Academy of Sleep Medicine [5]. Subjects are not allowed to use any artificial strategy to stay awake such as moving continuously or singing, and they are in a semi-recumbent position. They are asked to fight against any sleepiness that they feel in a soporific condition. From EDS to ADHD Symptoms Sleep specialists have studied symptoms of ADHD in populations of narcoleptic adults [52, 64–68]. Oosterloo et al. [52] found that symptoms of ADHD were present in 18.9 % of patients with narcolepsy. In the study of Modestino [64], childhood ADHD symptoms were significantly more frequent in the narcoleptic group than in the control group. The other studies detail cognitive deficits in narcoleptic adult patients such as attention deficits [65, 66] and executive function deficits [67, 69, 70]. Thus, it has been suggested that being sleepy might explain not only inattention but also hyperactivity and impulsivity as a strategy to stay awake. This finding has generated a model for ADHD involving a deficit in alertness [71, 72]. In this model, motor hyperactivity, at least in some ADHD children, may be a counter-behavior for staying awake [73]. The use of stimulant medication to treat ADHD and the improvement of ADHD symptoms with modafinil, which is commonly used to treat narcolepsy [74–77], strengthen the idea of a deficit in alertness in ADHD. Moreover, some of the therapeutic effects of stimulant medication in ADHD could be due to their effect on EDS, which interrupts the autoregulatory hyperactivity behavior [7]. From ADHD to EDS ADHD subjects often complain of sleepiness in unstimulating conditions even when they are sufficiently rested. Daytime sleepiness evaluated with the clinical scale has been linked to ADHD in children primarily and adults in many [52, 78•, 79, 80] but not all studies [81–83]. In the same line, using an objective tool (the MSLT), four studies demonstrated that ADHD children exhibited EDS in comparison with healthy subjects, although some of them had no organic sleep disorders documented by polysomnography [26, 84–86]. Another study by Prihodova [87] found no difference between ADHD children and controls on the MSLT but did find significant alertness variability during MSLT in ADHD children, which could be a sign of dysregulated arousal. Similarly, the metaanalysis by Cortese et al. [30, 54] showed that children with ADHD exhibited significantly pathological results on the MSLT compared to controls. The contrary result was found by the team of Wiebe [88••] who did not find any significant difference on the MSLT between ADHD and control children.
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Unlike in the pediatric field, research studies in sleep medicine in ADHD adult patients are relatively scarce. Oosterloo et al. found that 37 % of ADHD adult patients met the criteria for subjective EDS [52], and Yoon [78•] demonstrated that subjective sleepiness was associated with fatigue in ADHD with combined subtype but not in ADHD with inattentive subtype. A recent study using the MSLT showed that ADHD patients’ reports of EDS were verified by shorter sleep latency on the MSLT [16••]. ADHD patients with subjective higher daytime tiredness fell asleep faster during MSLT, but they did not differ from controls in mean MSLT. Likewise, in the pediatric field, contrary results were found with objective measures of sleepiness. A low level of arousal can also be related to EEG measurements. The most classical is EEG spectral analysis. Indeed, many EEG studies have found an increase in slow EEG activity in the theta and delta range and a reduced beta EEG activity in patients with ADHD [89]. Less widespread is the use of EEG alertness stages [7]. Using EEG, different alertness stages can be discerned during both sleep and wakefulness. Using an EEG-based algorithm (Vigilance Algorithm Leipzid, VIGALL), different alertness stages can be described from high alertness to relaxed wakefulness to drowsiness and sleep onset [90]. Sander et al. [91] using this algorithm found that children with ADHD exhibited a low and unstable level of EEG alertness. This is in line with the result of Prihodova [87] who found significant variability in alertness during MSLT in ADHD children. Measurements on EEG spectral analysis and EEG alertness stages are very consistent in children but not in adolescents or adults. This fact could explain the negative results of Sobanski et al. [92] in adults with ADHD. However, abnormal EEG activity is not found in all children with ADHD [89]. Low and dysregulated arousal should be considered more as a physiological feature of a substantial subgroup of ADHD children, which could represent a prognostic marker rather than a diagnostic marker [89]. Indeed, stimulant medication was found to be more efficient in children with high slow EEG activity [93] or unstable EEG alertness [91]. Moreover, sleep disorders that reduce the level of arousal and destabilize alertness are known to worse symptomatology in children with ADHD [94], whereas interventions that improve sleep quality improve it [95]. Children with low and unstable levels of arousal could be those who would benefit the most from these behavioral interventions. Thus, it is worthwhile defining specific subgroups of patients with ADHD who could benefit from specific therapeutic approaches. In children with ADHD, these subgroups could be defined with EEG measurements (EEG spectral power [89] and EEG alertness stages [7] and MSLT [26, 84–86]. In adults with ADHD, a subgroup of patients with impaired alertness could also be defined. Therefore, one could assume that within a context of EDS, some ADHD adults would display pathological maintenance wakefulness test (MWT) scores, which would also be an
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objective marker of cognitive impairment. To confirm this hypothesis, our team designed a study whose objectives were to explore objective daytime sleepiness with a MWT in a population of ADHD adult patients and to relate MWT scores to simulated driving performance [96]. We administered the MWT and not the MSLT because the MWT may be used to assess an individual’s ability to remain awake when his or her inability to remain awake constitutes a public or personal safety issue [5]. It also appears that patients suffering from sleep disorders with EDS may exhibit pathological scores on the MWT compared to healthy subjects [97–100]. Our study demonstrates for the first time that a significant proportion of ADHD adults exhibit objective EDS. One of the main results is that 35 % of ADHD patients were severely sleepy on the MWT with a mean sleep latency of 14.2 min (pathological score ≤19 min). Even though we did not aim to relate EDS to a specific sleep disorder, another interesting result is that within this subgroup of sleepy ADHD adults (n=14), 11 of them were free of sleep-disordered breathing and/or periodic leg movements at a pathological level. Therefore, one question is whether this subgroup of sleepy ADHD patients represents a particular subgroup. This result corroborates the hypothesis of the central origin of the EDS: a Bhypo-arousal state^ such as in narcolepsy has been suggested by a few authors [101•]. Beyond this physiopathological issue, our study may have clinical implications. In fact, the use of wakefulness-promoting medication (i.e., modafinil treatment currently used in narcolepsy) rather than stimulant medication (methylphenidate) in this subgroup of subjects might be indicated. This new therapeutic strategy should be assessed in the future.
Fig. 1 Integrative model for ADHD, ADHD symptoms, EDS, and sleep disorder comorbidities. Psychiatrists and sleep specialists should consider whether ADHD is worsening by a comorbid sleep disorder or if a sleep disorder has induced EDS and ADHD-like symptoms without ADHD
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Proposition of a Model From these observations, an integrative model can be proposed for ADHD, ADHD symptoms, EDS, and sleep disorder comorbidities (Fig. 1). Indeed, ADHD can be associated with EDS in a subgroup of patients. In this subgroup, EDS can be a core pathogenic factor. It can induce both alertness stabilization behavior similar to hyperactivity symptoms and a cognitive deficit, especially impaired sustained attention. Furthermore, ADHD is frequently associated with sleep disorders that can induce EDS and worsen the prognosis of the disorder. Psychiatrists should carefully evaluate and treat sleep disorders in patients with ADHD (as a categorical diagnosis according to DSM criteria) in order to improve ADHD. Sleep treatment should form part of the multimodal approach to ADHD based on stimulant medication, behavioral, and cognitive strategies, etc. However, sleep disorders can also induce ADHD symptoms (as a dimensional approach) that should not be confused with ADHD. In this case, treatment of only the sleep disorder should be associated with the disappearance of ADHD symptoms.
Behavioral Management of Sleep Problems ADHD induced by sleep disorders and ADHD-related sleep disorders pose a difficult clinical problem, so the clinician should gather a developmental and family history (of ADHD and sleep problems) and get the patient to maintain a sleep diary in order to determine the extent of the sleep problems.
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Management of sleep problems in ADHD is crucial, as they may aggravate ADHD symptoms. First of all, a baseline sleep evaluation during the initial assessment of ADHD is recommended [3•]. The initial screening should include questionnaires such as the B: bedtime issues, E: excessive daytime sleepiness, A: night awakenings, R: regularity and duration of sleep, and S: snoring (BEARS) [102] and the Children’s Sleep Habits Questionnaire [103]. If some sleep problems are identified, children and/or parents should maintain a sleep diary for 15 days. Some sleep disorders can be assessed with a clinical interview while others require specific polysomnographic recording associated or/not with other objective tools such as the MSLT or MWT. Moreover, given the impact of psychiatric comorbidities on sleep, any associated psychopathologies should be evaluated systematically in ADHD patients [3•]. For example, bedtime resistance might be induced by anxious comorbidity in some subjects, while it might be related to a sleep-onset delay due to a delayed sleep-phase syndrome or to psychostimulant treatment in others. Therefore, the underlying cause of bedtime resistance in any given patient needs to be elucidated. Behavioral management primarily involves sleep hygiene. Healthy sleep practices comprise a regular sleep/wake schedule, adequate opportunity for sleep, calming and structured bedtime routines, the avoidance of caffeine, large amounts of liquids, naps, exercise, avoidance of alerting activities such as the use of electronic devices just before bedtime, sleeping only in bed, using one’s bed only for sleeping, and attention to environmental factors such as light, noise, and temperature [1, 2••, 3•, 11]. When assessing children’s sleep needs, it is crucial to educate parents about signals that suggest that a child is not getting sufficient sleep, such as difficulty waking up in the morning and sleeping longer at weekends. Nutrition may also play a role in sleep hygiene, although there is insufficient evidence to recommend any specific diet [3•]. The efficacy of behavioral sleep interventions has been demonstrated for insomnia in typically developing children, including parent education, graduated extinction, and bedtime fading [104, 105]. Clinical studies of behavioral strategies to improve sleep in ADHD children are limited. A recent randomized clinical trial including 27 families with parents and children showed that delivering a behavioral sleep intervention is feasible in ADHD children and that children’s sleep assessed by parent reports was improved [106]. Finally, clinicians should keep in mind that if sleep disorders are suspected as being due to ADHD medications, alternative dosing formulations or treatments may be required.
Conclusion The distinction between ADHD comorbid with sleep disorder and sleep disorders with ADHD symptoms can be difficult.
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However, the history of the symptoms is important to take into account especially since ADHD is a neurodevelopmental disorder (as now clearly underlined in the DSM-5), whereas ADHD symptoms associated with a sleep disorder comorbidity are not. Clinicians should therefore routinely assess, monitor, and manage sleep problems in the presence of both comorbidities in children and adults with ADHD and vice versa, as recommended by ADHD guidelines [107, 108]. As an initial step, a careful history and obtaining a sleep log can help in clarifying the nature and origins of EDS. In more complex cases, a structured comorbidity assessment may be required with multidisciplinary teams working together to treat the comorbidities. Future work and longitudinal research should clarify the direction of the relationship between ADHD, ADHD symptoms, and sleep disorders. Exploration of wakefulness and sleep is a gateway to better understanding of the physiopathology of ADHD.
Compliance with Ethics Guidelines Conflict of Interest Stéphanie Bioulac, Jean-Arthur MicoulaudFranchi, and Pierre Philip declare that they have no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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