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Sleep Disturbances and Attention Deficit Hyperactivity Disorder
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SLEEP MEDICINE CLINICS Sleep Med Clin 3 (2008) 469–478
Sleep Disturbances and Attention Deficit Hyperactivity Disorder Timothy F. Hoban, -
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Attention deficit hyperactivity disorder: clinical features, epidemiology, and comorbidities Disrupted sleep in children who have attention deficit hyperactivity disorder Disrupted sleep in adults who have attention deficit hyperactivity disorder Impact of attention deficit hyperactivity disorder treatments on sleep Treatment of sleep problems in patients who have attention deficit hyperactivity disorder
Particularly in the early years of the child’s development, parents may get different opinions from professionals who view the child in different settings. A pediatrician seeing the child in a busy office diagnoses ‘‘attention deficit disorder’’; a nursery school teacher who observes the child in an unruly classroom calls him ‘‘hyperactive’’.a psychologist or psychiatrist.decides he’s very active but not ‘‘hyper’’ and talks of emotional and family problems; while a neurologist, meeting with the child on a one-to-one basis,.says he is ‘‘normal.’’ —Stanley Turecki, child and family psychiatrist [1]
And a sleep specialist would say that the child may have an underlying sleep disorder. Recent research suggests that the relationship between attention deficit hyperactivity disorder (ADHD) and sleep disturbances is complex and bidirectional. Disrupted behavior related to ADHD may
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Sleep-disordered breathing associated with attention deficit hyperactivity disorder symptoms Other sleep disorders associated with attention deficit hyperactivity disorder symptoms Sleep and attention deficit hyperactivity disorder: potential pathophysiologic links Summary References
impact nighttime sleep by way of bedtime struggles, sleep-onset insomnia, or insufficient sleep duration. Conversely, primary sleep disorders, such as obstructive sleep apnea (OSA), restless legs syndrome (RLS), and periodic limb movement disorder (PLMD), cause daytime neurobehavioral symptoms which—especially in children—resemble those of ADHD. This article first examines how primary ADHD affects nighttime sleep. The effects of drug treatment on sleep in this population are reviewed, including the impact of stimulant medications and sleep-promoting agents. The article then examines the ways in which primary sleep disorders, such as OSA and RLS/PLMD, may cause daytime somnolence, inattention, and hyperactivity that mimic the features of ADHD. Discussion focuses on pediatric aspects of these conditions and briefly addresses available adult data.
Michael S. Aldrich Sleep Disorders Laboratory, Departments of Pediatrics and Neurology, University of Michigan, L3227 Women’s Hospital, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0203, USA E-mail address: [email protected] 1556-407X/08/$ – see front matter ª 2008 Elsevier Inc. All rights reserved.
sleep.theclinics.com
doi:10.1016/j.jsmc.2008.04.005
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Attention deficit hyperactivity disorder: clinical features, epidemiology, and comorbidities It has long been recognized that some children exhibit significant problems maintaining a level of attention and activity appropriate for age. Historically, terms such as ‘‘hyperkinetic syndrome,’’ ‘‘minimal brain dysfunction,’’ and ‘‘deficits in attention, motor control, and perception’’ have been used to describe this constellation of symptoms [2,3]. The American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) provides the most current and widely recognized definition of the syndrome [4]. DSM-IV defines ADHD as a condition characterized by persistent symptoms of inattention or hyperactivity-impulsivity sufficient to cause clinically significant impairment with age-appropriate academic, social, or occupational functioning. Although these diagnostic criteria specify that the symptoms cannot be the result of another underlying psychiatric disorder, the presence of underlying sleep disorders, such as OSA, does not preclude diagnosis of ADHD. ADHD is considered to be the most common psychiatric disorder of childhood, with estimated prevalence of 3% to 12% for school-aged children [5–8]. Although the condition often remits during childhood, it is estimated that between 1% and 2% of adults meet DSM-IV criteria for ADHD [9]. ADHD is often accompanied by other behavioral and developmental disorders that may additionally impact nighttime sleep. Epidemiologic and clinical studies of children who have ADHD have reported relatively high rates of comorbid mood, anxiety, and conduct disorders [10], conditions that have the potential to independently disrupt sleep duration or quality.
Disrupted sleep in children who have attention deficit hyperactivity disorder Sleep problems, such as bedtime resistance, night waking, and restlessness, are commonly reported by parents of children who have ADHD. Although sleep-related symptoms have not been included in DSM criteria for the condition since 1987 [11], the well-validated and widely used Conners’ Parent Rating Scale continues to include question items related to sleep [12]. Many early studies assessing the sleep of children who had ADHD used subjective assessment measures, such as parental questionnaires, structured interviews, or behavioral rating scales. Studies focusing primarily on parental report of sleep quality have consistently reported high rates of bedtime resistance, sleep-onset insomnia, night waking, and
restlessness [13–16]. Several case series have reported that poor sleep quality during infancy may be associated with increased risk for ADHD during later childhood [14,17]. Studies using questionnaires or sleep diaries to assess quantitative sleep parameters, such as sleep duration and sleep-onset latency, have reported less consistent findings for children who have ADHD. These include reports of sleep for children who have ADHD being shorter [18] or longer [19,20] than that of controls. Data provided by these and other studies relying primarily on parental assessment or data recording should be interpreted cautiously because of methodologic limitations, including significant variability of the diagnostic, exclusion, and control criteria used [21]. Research regarding sleep in children who have ADHD has increasingly used objective measures, such as polysomnography (PSG), actigraphy, and multiple sleep latency testing (MSLT), often supplemented by questionnaires, sleep logs, or validated rating scales. PSG measures of sleep duration and architecture in children who have ADHD have not revealed consistent abnormalities with respect to sleep-onset latency, sleep duration, or most aspects of sleep architecture [22]. Although several PSGbased studies have reported significant changes in rapid eye movement (REM) sleep for unmedicated children who have ADHD, the specific changes identified have been inconsistent, including reports of increased [23,24], decreased, or delayed [25,26] REM sleep. The most consistently reported PSG findings in children meeting DSM-IV criteria for ADHD are increased rates of movement and respiratory disturbances during sleep. Excessive periodic limb movements of sleep (PLMS) have been reported by several investigators. Huang and colleagues [27] assessed 88 school-aged children who had DSM-IV ADHD referred to a psychiatric clinic and compared PSG findings to those for 27 control subjects. Nine (10.2%) of the children who had ADHD demonstrated an elevated periodic limb movement index (PLMI) of more than five movements hourly, compared with only one of the controls. Golan and colleagues [28] reported that 5 of 34 children who have DSM-IV ADHD (15%) exhibited comparably excessive PLMS during PSG compared with none of 32 matched controls. These findings provide a degree of objective support for the premise that ADHD children are indeed more restless during nighttime sleep, in agreement with parental reports. High rates of sleep-disordered breathing (SDB) for children who had ADHD were also identified in these same series. Huang and colleagues [27] reported that 50 of 88 children who had ADHD (56.8%) had an apnea-hypopnea index (AHI) of
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greater than 1 and that 17 (19.3%) had AHIs exceeding 5. Golan and colleagues [28] found that 50% of children who had ADHD exhibited a respiratory disturbance index (RDI) exceeding 2, compared with only 22% of controls. In contrast to the high rates of SDB identified in these reports, studies using less stringent criteria for study entry or higher AHI cutoffs for the diagnosis of SDB have reported lower prevalence of OSA in children who have ADHD, ranging from 0% to 26% [29– 31]. These data tend to support the premise that childhood ADHD may be associated with SDB, although the strength and frequency of this association remain incompletely defined at present. Although relatively few studies have used MSLT in the assessment of children who have ADHD, most have reported objective evidence of sleepiness for this population. Golan and colleagues [28] used a modified MSLT protocol with 30-minute nap opportunities in their study of 34 children who had DSM-IV ADHD. They found that the children who had ADHD were significantly sleepier (mean sleep latency of 21.9 5.5 minutes) than controls (27.9 2.0 minutes). Although half the children in the cohort who had ADHD were found to have SDB (RDI>2), comparable levels of sleepiness were exhibited by the children who had ADHD without SDB. Lecendreux and colleagues [32] also identified significant daytime sleepiness for 30 boys who had DSM-IV ADHD compared with 22 matched controls. Although PSG findings did not differ between the two groups, mean sleep latency was significantly shorter for the ADHD children in three of the four MSLT naps. In addition, MSLT abnormalities correlated significantly with the standardized hyperactivity-impulsivity and inattentivepassivity indices of the Conners’ rating scale for the ADHD group. These MSLT data are in agreement with previous research reporting high rates of parentally reported sleepiness in ADHD children [15,18] and consistent with the premise that primary ADHD may represent a disorder of hypoarousal [33]. Studies of pediatric ADHD using actigraphy have yielded only limited additional information. Although older studies reported increased movements and diminished sleep efficiency in children who have ADHD compared with controls [34], recent studies using larger sample sizes have shown few significant differences in actigraphic parameters apart from increased night-to-night variability of sleep onset and sleep duration in one cohort of school-aged boys monitored for five consecutive nights [35]. Analysis of actigraphy and dim light melatonin onset in children who have DSM-IV ADHD and insomnia has suggested the presence
of delayed sleep phase compared with ADHD children who did not have insomnia [36].
Disrupted sleep in adults who have attention deficit hyperactivity disorder Data regarding sleep in adults meeting DSM-IV criteria for ADHD are presently scant and inconsistent. A small pilot study assessing 6 adults who had ADHD receiving pharmacologic treatment identified sleep-disordered breathing and sleep fragmentation in all subjects, with excessive periodic limb movements in 3 [37]. In contrast, a study of 20 unmedicated adults who had ADHD without SDB revealed increased sleep time and PLMS compared with controls without significant changes in other PSG or EEG parameters [38]. Actigraphy of adults who have unmedicated DSM-IV ADHD has documented delayed sleep onset and lower sleep efficiency compared with control subjects [39]. Larger, more rigorously controlled studies using objective outcomes are still required to better define the frequency and nature of sleep disruption associated with adult ADHD.
Impact of attention deficit hyperactivity disorder treatments on sleep Stimulants represent the most frequently prescribed class of medication administered for the treatment of ADHD, used by approximately 2% of schoolaged children in the United States [40]. Although insomnia is generally considered to be a frequent side effect of stimulant treatment, studies of stimulant use in patients who have ADHD have in fact reported variable impact on nighttime sleep, most often in the mild-to-moderate range. Methylphenidate (MPH) is the stimulant for which the most sleep-related data exist. Use of standard-release preparations at doses of 0.3 to 0.5 mg/ kg/d in school-aged children who have ADHD was associated with modestly reduced total sleep time [41] and increased sleep onset latency [42] in several placebo-controlled trials that used once- or twice-daily dosing. Placebo-controlled crossover trials comparing twice a day dosing of standard MPH to three times a day dosing reported that a third, late-afternoon dose had minimal impact on quantitative sleep parameters or subjectively rated sleep quality in children [43,44]. Sustained-release preparations of methylphenidate less often require late-afternoon dosing; however, the longer duration of action for these agents still results in the potential for pharmacologic impact on nighttime sleep. Several large, double-blind pediatric trials comparing extended-release MPH administered once daily, standard-release MPH
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administered three times a day, and placebo reported no significant differences in subjectively rated sleep quality among any of the treatment arms [45,46]. A long-term, open-label study following 407 children who had ADHD and good response to extended-release MPH in previous controlled trials reported a 14.7% prevalence of insomnia and good or excellent sleep quality for 74% of subjects on interim analysis after 12 months [47]. Limited data exist regarding the impact of amphetamine agents on sleep in patients who have ADHD. Although a 15-month double-blind, placebo-controlled trial of dextroamphetamine treatment in ADHD children using individually titrated doses reported no adverse sleep effects compared with baseline and placebo [40], a blinded crossover trial comparing dextroamphetamine at 0.3 mg/kg/d to MPH 0.6 mg/kg/d (twice a day dosing) reported more frequent insomnia during amphetamine treatment (70%) compared with MPH (64%) and baseline (54%) [48]. A 4-week placebo-controlled trial of extended-release mixed amphetamine salts using forced-dose titration in adolescents who had ADHD identified insomnia for 12% of patients receiving active treatment and 3.7% of patients receiving placebo [49]. A preapproval study of lisdexamfetamine dimesylate at doses of 30 to 70 mg/d in 176 children who had DSM-IV ADHD reported insomnia for 19% of treatment subjects compared with 3% for a placebo group [50]. Several studies suggest that the risk for sleep disruption in patients who had ADHD treated with stimulants is to some extent dose-related [49,51,52]. Less well studied but frequently observed in practice is a phenomenon wherein the sleep of a patient who has ADHD improves with stimulant treatment. It is uncertain whether this clinical improvement represents a direct pharmacologic effect of medication or a secondary effect resulting from improved behavior leading up to bedtime [53]. Atomoxetine is a nonstimulant, long-acting ADHD treatment for which limited sleep data have been reported. A recent meta-analysis assessing long-term (>2 year) treatment data in 6- and 7-year old children who had DSM-IV ADHD reported low rates of sleep-related side effects, with sleep-onset insomnia for 5.1% of subjects and somnolence for 8.5% [54]. A comparable meta-analysis assessing long-term treatment in adolescents did not report sleep problems among adverse events affecting at least 10% of subjects, although fatigue was reported in 14.8% [55]. In a crossover trial comparing twice a day atomoxetine to three times a day MPH in 85 children who had
DSM-IV ADHD, insomnia was seen less frequently during treatment with atomoxetine (6.3%) than for MPH (26.6%) [56]. Among 218 adults who had DSM-IV ADHD receiving atomoxetine as either 80 mg once daily or 40 mg twice daily, split dosing was associated with more frequent insomnia (25.5% of subjects) than once-daily dosing (16.7%) [57].
Treatment of sleep problems in patients who have attention deficit hyperactivity disorder Despite the high frequency of subjectively reported sleep problems in patients who have ADHD, pharmacologic treatment of ADHD-related insomnia has received limited study, consisting of a few clinical studies and case series assessing children. Because no medications have been labeled by the United States Food and Drug Administration (FDA) for treatment of any sleep disorder in children, these studies address off-label treatment exclusively. Several recent trials and case series suggest that low-dose melatonin may be effective in alleviating ADHD-related insomnia. A randomized, doubleblind, placebo-controlled trial assessing 105 unmedicated children meeting DSM-IV criteria for ADHD assessed the effects of melatonin administered at 7:00 PM compared with placebo for 4 weeks [58]. Children treated with melatonin 3 to 6 mg (based on body weight) reduced their latency to sleep onset by 26.9 47.8 minutes compared with an increase of 10.5 37.4 minutes for controls (P<.0001) and increased their total sleep time. Although no significant side effects were reported, there was no change in behavior, cognition, or quality of life for treated patients in this study. Significant improvements in sleep-onset latency have also been reported for children who have stimulant-treated ADHD following treatment with melatonin at doses of 3 mg at bedtime [59] and at doses of 5 mg (coupled with sleep hygiene interventions) [60]. Use of clonidine for treatment of ADHD-associated insomnia has been reported to be effective in uncontrolled case series [61,62]. Prince and colleagues [63] reported that clonidine at a median nighttime dose of 157 14 mg was associated with significant subjective improvements in ADHD-associated sleep disturbances for 53 of 62 patients (85%) in a retrospective pediatric study. Although two thirds of children in this study were also using stimulants, effectiveness of clonidine therapy did not vary with age, gender, or concurrent treatment. This study also reported mild side effects for 31% of subjects, including morning sedation for
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24% and fatigue for 11%. Other reports have raised concern that concurrent use of clonidine and methylphenidate in children may be associated with increased risk for sudden death [64], and the safety of this medication combination has been the subject of vigorous subsequent debate [65–67]. Other drugs reported to be effective for treatment of ADHD-associated insomnia on the basis of anecdotal or case reports include diphenhydramine, cyproheptadine, trazodone, mirtazapine, guanfacine, and tricyclic antidepressants [68–70]. Several reports suggest that structured behavioral interventions may be effective as primary [71,72] or adjunctive [60] treatment of insomnia in some children who have ADHD.
Sleep-disordered breathing associated with attention deficit hyperactivity disorder symptoms The first modern descriptions of childhood OSA reported hyperactivity, inattention, and learning problems as frequently associated symptoms [73]. An early series of 50 pediatric cases identified hyperactivity in 42% of affected children and poor academic performance for 16% [74]. Although these early reports described children who had relatively severe OSA, subsequent reports have suggested that even isolated snoring may be associated with increased risk for daytime inattention and hyperactivity during childhood [75]. Several large community-based, cross-sectional studies have reported that habitual snoring is associated with increased risk for parentally reported hyperactivity [76,77]. In addition, snoring was found to be three times as prevalent in a cohort of children who had clinically diagnosed ADHD (33%) compared with children who did not have ADHD drawn from child psychiatry (11%) and general pediatrics (9%) clinics [78]. Contemporary studies assessing children undergoing surgery for clinically diagnosed SDB also report high rates of inattention and hyperactivity compared with controls [79] or compared with postoperative assessment [79,80]. Among 78 children in the Washtenaw County adenotonsillectomy cohort studied before and after clinically indicated adenotonsillectomy, 22 children (28%) met DSM-IV criteria for ADHD preoperatively, compared with 7% of controls. On postoperative follow-up 1 year later, 11 of the 22 children who had ADHD (50%) no longer qualified for that diagnosis. Surprisingly, standardized PSG measures, such as AHI, did not predict baseline neurobehavioral morbidity or postoperative improvement in any areas apart from sleepiness, whereas a validated
questionnaire better predicted initial hyperactivity and its subsequent improvement for this cohort [81]. Other studies have also suggested that the relationship between SDB and ADHD is complex and cannot be predicted based solely on the frequency of respiratory disturbances detected by standard PSG. Some investigators have identified higher sleepiness and hyperactivity scores for children who had suspected SDB compared with controls, but found that these scores did not differ between subjects who had OSA and those who had primary snoring [82]. In a cohort of 5- to 7-year-old children who had parentally reported ADHD symptoms, children who had mild ADHD symptoms were most likely to have PSG-confirmed OSA (26%) compared with children who had significant ADHD symptoms (5%) or controls (5%) [29]. This poor correlation between AHI and neurocognitive consequences in patients who have OSA suggests that the causative mechanism is not reliably demonstrated by standard PSG techniques. It is hoped that new technologies designed to increase sensitivity of PSG for subtle airway obstruction and microarousals may provide improved predictive value in this area [83]. It remains uncertain what proportion of patients who have ADHD have clinically significant SDB as a sole or contributing underlying cause. In recent pediatric series assessing children meeting DSM-IV criteria for ADHD, the prevalence of associated OSA varied substantially depending on the AHI criteria used for the diagnosis of OSA. Studies using low AHI cutoffs identified high rates of OSA: 56.8% for Huang and colleagues (OSA defined as AHI>1) and 50% for Golan and colleagues (RDI>2) [27,28]. Sangal and colleagues [26,84] reported that none of 40 children who had DSM-IV ADHD had OSA defined as AHI>5; however, 57.5% of these subjects demonstrated AHI>1. Although these and other studies suggest that a large proportion of children who have ADHD have associated SDB, further large-scale studies using standard, contemporary criteria for the diagnosis of ADHD and OSA will be required to better define the strength and frequency of this association.
Other sleep disorders associated with attention deficit hyperactivity disorder symptoms Data regarding the association of RLS and PLMD with ADHD have been derived primarily from pediatric studies. Although the prevalence of RLS/PLMD in children has not been precisely defined, leg restlessness was reported for 17% of children in a large cross-sectional survey and up to 45% of adult RLS
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patients reported onset of symptoms before age 20 [85,86]. Several lines of investigation support the premise that childhood RLS/PLMD may be associated with ADHD symptoms. First, there is compelling evidence that ADHD is overrepresented among children who have PSG-confirmed PLMD. In a retrospective review of 129 children and adolescents who had PLMD (PLMI>5 on PSG), 117 (91%) met DSM-IIIR or DSM-IV criteria for ADHD [87]. The association was particularly strong for the children whose PLMI exceeded 25, 15 of whom (94%) had ADHD. Second, children who have restless legs symptoms are more likely to be rated as hyperactive than children who do not have leg restlessness. In a cohort of 866 children recruited from community-based pediatrics clinics, 18% of children who had restless legs symptoms were found to have high hyperactivity index scores compared with 11% of children who did not have leg restlessness (P<.05) [86]. In a separate account describing 32 children who had clinically diagnosed RLS, inattentiveness was reported for 8 (25%) [88]. Finally, multiple studies suggest that children meeting DSM-IV criteria for ADHD are more likely to have excessive periodic limb movements than other children. In an early report, Picchietti and colleagues [89] compared 14 consecutive children who had newly diagnosed ADHD to 10 control subjects. Nine of 14 (64%) children who had ADHD demonstrated PLMI greater than 5 during PSG compared with none of the controls (P<.0015). All 9 of the children who had ADHD with excessive PLMS had a longstanding history of sleep problems and met ICSD criteria for PLMD. Excessive PLMS during PSG of children who had DSM-IV ADHD compared with controls were also reported by Huang and colleagues (10% versus 0%) and by Golan and colleagues (15% versus 0%) [27,28]. Data regarding the association between RLS/ PLMD and adult ADHD are scant. Wagner and colleagues [90] prospectively evaluated 62 adults who had RLS and found that 26% met DSM-IV criteria for ADHD compared with 6% of patients who had insomnia and 5% of control subjects. Among the patients who had RLS, the RLS symptom severity score was greater for patients who had ADHD compared with those who did not (P<.04). Data regarding the impact of RLS/PLMD treatment on ADHD symptoms are even more limited. In an uncontrolled, seven-patient series assessing children who had RLS/PLMD and DSM-IV ADHD, dopaminergic therapy was associated with significant improvements of ADHD symptoms as measured by the Conners’ Parent Rating Scale
(P<.04), with three children no longer meeting criteria for ADHD following treatment [91]. Detailed examination of the impact of other sleep disorders on waking neurocognitive function is beyond the scope of this article; however, daytime inattention and hyperactivity have also been reported in children who have narcolepsy [92,93], delayed sleep phase syndrome [72], and insufficient nighttime sleep [94,95].
Sleep and attention deficit hyperactivity disorder: potential pathophysiologic links Clinical and experimental evidence support the notion that deficient levels of arousal may underlie some of the neurocognitive impairments common to ADHD and sleep disorders. MSLT studies of children who have rigorously diagnosed ADHD have reported high rates of sleepiness compared with controls [28,32], consistent with cross-sectional studies showing strong associations between sleepiness and ADHD behaviors [76]. Although the concept that hyperactive and inattentive children are actually sleepy seems counterintuitive, it is highly consistent with findings from studies of pediatric sleep restriction that have reported inattention, hyperactivity, and impaired reaction times as prominent waking symptoms in sleep-deprived children [94–96]. The current theoretic framework regarding central nervous system mechanisms linking OSA and ADHD primarily focuses on the prefrontal cortex, which subserves many aspects of executive function, including attention and working memory [33]. The hypothesis that the behaviors associated with ADHD result from aberrant executive regulation by the prefrontal cortex is supported by positron emission tomography studies of patients who had ADHD demonstrating abnormal dopaminergic metabolism in this area [97]. Data indicating that the cognitive and emotional deficits that result from sleep disruption also localize to the prefrontal cortex [98,99] lend further support to this theory. It remains uncertain whether the effects of OSA on the prefrontal cortex are mediated by disruption of sleep quality, sleepiness, intermittent hypoxia, or alternative mechanisms [100]. Models linking RLS/PLMD with ADHD are presently less well developed than those for OSA. One hypothesis is that daytime inattention and hyperactivity resulting from RLS/PLMD may represent nonspecific manifestations of disturbed sleep quality and daytime sleepiness similar to those exhibited by sleep-deprived children. Another is that RLS/PLMD and ADHD may both result from underlying central nervous system disturbances of dopamine metabolism [90]. An intriguing
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possibility suggested by Cortese and colleagues [22] is that diurnal restlessness and motor activity secondary to RLS might mimic the symptoms of ADHD to the point that the waking symptoms are misclassified.
Summary Existing research suggests that a close but complex relationship exists between the daytime behaviors that define ADHD and disturbances of nighttime sleep. Present data suggest that substantial, but not precisely defined, numbers of children presenting with symptoms of ADHD may in fact have sleep disorders as a primary underlying cause or treatable comorbid condition. Further work is required to better elucidate the common pathophysiologic mechanisms underlying these conditions and more clearly define their impact as important and treatable public health problems.
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[39] Boonstra AM, Kooij JJ, Oosterlaan J, Sergeant JA, Buitelaar JK, Van Someren EJ. Hyperactive night and day? Actigraphy studies in adult ADHD: a baseline comparison and the effect of methylphenidate. Sleep 2007;30(4): 433–42. [40] Gillberg C, Melander H, von Knorring AL, et al. Long-term stimulant treatment of children with attention-deficit hyperactivity disorder symptoms. A randomized, double-blind, placebocontrolled trial. [see comment]. Arch Gen Psychiatry 1997;54(9):857–64. [41] Tirosh E, Sadeh A, Munvez R, Lavie P. Effects of methylphenidate on sleep in children with attention-deficient hyperactivity disorder. An activity monitor study. Am J Dis Child 1993; 147(12):1313–5. [42] Schwartz G, Amor LB, Grizenko N, et al. Actigraphic monitoring during sleep of children with ADHD on methylphenidate and placebo. J Am Acad Child Adolesc Psychiatry 2004; 43(10):1276–82. [43] Kent JD, Blader JC, Koplewicz HS, Abikoff H, Foley CA. Effects of late-afternoon methylphenidate administration on behavior and sleep in attention-deficit hyperactivity disorder. [see comment]. Pediatrics 1995;96(2 Pt 1):320–5. [44] Stein MA, Blondis TA, Schnitzler ER, et al. Methylphenidate dosing: twice daily versus three times daily. Pediatrics 1996;98(4 Pt 1): 748–56. [45] Pelham WE, Gnagy EM, Burrows-Maclean L, et al. Once-a-day Concerta methylphenidate versus three-times-daily methylphenidate in laboratory and natural settings. [see comment]. Pediatrics 2001;107(6):E105. [46] Wolraich ML, Greenhill LL, Pelham W, et al. Randomized, controlled trial of oros methylphenidate once a day in children with attention-deficit/hyperactivity disorder. Pediatrics 2001;108(4):883–92. [47] Wilens T, Pelham W, Stein M, et al. ADHD treatment with once-daily OROS methylphenidate: interim 12-month results from a long-term open-label study. J Am Acad Child dolesc Psychiatry 2003;42(4):424–33. [48] Efron D, Jarman F, Barker M. Side effects of methylphenidate and dexamphetamine in children with attention deficit hyperactivity disorder: a double-blind, crossover trial. Pediatrics 1997;100(4):662–6. [49] Spencer TJ, Wilens TE, Biederman J, Weisler RH, Read SC, Pratt R. Efficacy and safety of mixed amphetamine salts extended release (Adderall XR) in the management of attention-deficit/hyperactivity disorder in adolescent patients: a 4-week, randomized, double-blind, placebocontrolled, parallel-group study. Clin Ther 2006;28(2):266–79. [50] Biederman J, Krishnan S, Zhang Y, McGough JJ, Findling RL. Efficacy and tolerability of
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SLEEP MEDICINE CLINICS Sleep Med Clin 3 (2008) 469–478
Sleep Disturbances and Attention Deficit Hyperactivity Disorder Timothy F. Hoban, -
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Attention deficit hyperactivity disorder: clinical features, epidemiology, and comorbidities Disrupted sleep in children who have attention deficit hyperactivity disorder Disrupted sleep in adults who have attention deficit hyperactivity disorder Impact of attention deficit hyperactivity disorder treatments on sleep Treatment of sleep problems in patients who have attention deficit hyperactivity disorder
Particularly in the early years of the child’s development, parents may get different opinions from professionals who view the child in different settings. A pediatrician seeing the child in a busy office diagnoses ‘‘attention deficit disorder’’; a nursery school teacher who observes the child in an unruly classroom calls him ‘‘hyperactive’’.a psychologist or psychiatrist.decides he’s very active but not ‘‘hyper’’ and talks of emotional and family problems; while a neurologist, meeting with the child on a one-to-one basis,.says he is ‘‘normal.’’ —Stanley Turecki, child and family psychiatrist [1]
And a sleep specialist would say that the child may have an underlying sleep disorder. Recent research suggests that the relationship between attention deficit hyperactivity disorder (ADHD) and sleep disturbances is complex and bidirectional. Disrupted behavior related to ADHD may
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Sleep-disordered breathing associated with attention deficit hyperactivity disorder symptoms Other sleep disorders associated with attention deficit hyperactivity disorder symptoms Sleep and attention deficit hyperactivity disorder: potential pathophysiologic links Summary References
impact nighttime sleep by way of bedtime struggles, sleep-onset insomnia, or insufficient sleep duration. Conversely, primary sleep disorders, such as obstructive sleep apnea (OSA), restless legs syndrome (RLS), and periodic limb movement disorder (PLMD), cause daytime neurobehavioral symptoms which—especially in children—resemble those of ADHD. This article first examines how primary ADHD affects nighttime sleep. The effects of drug treatment on sleep in this population are reviewed, including the impact of stimulant medications and sleep-promoting agents. The article then examines the ways in which primary sleep disorders, such as OSA and RLS/PLMD, may cause daytime somnolence, inattention, and hyperactivity that mimic the features of ADHD. Discussion focuses on pediatric aspects of these conditions and briefly addresses available adult data.
Michael S. Aldrich Sleep Disorders Laboratory, Departments of Pediatrics and Neurology, University of Michigan, L3227 Women’s Hospital, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0203, USA E-mail address: [email protected] 1556-407X/08/$ – see front matter ª 2008 Elsevier Inc. All rights reserved.
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Attention deficit hyperactivity disorder: clinical features, epidemiology, and comorbidities It has long been recognized that some children exhibit significant problems maintaining a level of attention and activity appropriate for age. Historically, terms such as ‘‘hyperkinetic syndrome,’’ ‘‘minimal brain dysfunction,’’ and ‘‘deficits in attention, motor control, and perception’’ have been used to describe this constellation of symptoms [2,3]. The American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) provides the most current and widely recognized definition of the syndrome [4]. DSM-IV defines ADHD as a condition characterized by persistent symptoms of inattention or hyperactivity-impulsivity sufficient to cause clinically significant impairment with age-appropriate academic, social, or occupational functioning. Although these diagnostic criteria specify that the symptoms cannot be the result of another underlying psychiatric disorder, the presence of underlying sleep disorders, such as OSA, does not preclude diagnosis of ADHD. ADHD is considered to be the most common psychiatric disorder of childhood, with estimated prevalence of 3% to 12% for school-aged children [5–8]. Although the condition often remits during childhood, it is estimated that between 1% and 2% of adults meet DSM-IV criteria for ADHD [9]. ADHD is often accompanied by other behavioral and developmental disorders that may additionally impact nighttime sleep. Epidemiologic and clinical studies of children who have ADHD have reported relatively high rates of comorbid mood, anxiety, and conduct disorders [10], conditions that have the potential to independently disrupt sleep duration or quality.
Disrupted sleep in children who have attention deficit hyperactivity disorder Sleep problems, such as bedtime resistance, night waking, and restlessness, are commonly reported by parents of children who have ADHD. Although sleep-related symptoms have not been included in DSM criteria for the condition since 1987 [11], the well-validated and widely used Conners’ Parent Rating Scale continues to include question items related to sleep [12]. Many early studies assessing the sleep of children who had ADHD used subjective assessment measures, such as parental questionnaires, structured interviews, or behavioral rating scales. Studies focusing primarily on parental report of sleep quality have consistently reported high rates of bedtime resistance, sleep-onset insomnia, night waking, and
restlessness [13–16]. Several case series have reported that poor sleep quality during infancy may be associated with increased risk for ADHD during later childhood [14,17]. Studies using questionnaires or sleep diaries to assess quantitative sleep parameters, such as sleep duration and sleep-onset latency, have reported less consistent findings for children who have ADHD. These include reports of sleep for children who have ADHD being shorter [18] or longer [19,20] than that of controls. Data provided by these and other studies relying primarily on parental assessment or data recording should be interpreted cautiously because of methodologic limitations, including significant variability of the diagnostic, exclusion, and control criteria used [21]. Research regarding sleep in children who have ADHD has increasingly used objective measures, such as polysomnography (PSG), actigraphy, and multiple sleep latency testing (MSLT), often supplemented by questionnaires, sleep logs, or validated rating scales. PSG measures of sleep duration and architecture in children who have ADHD have not revealed consistent abnormalities with respect to sleep-onset latency, sleep duration, or most aspects of sleep architecture [22]. Although several PSGbased studies have reported significant changes in rapid eye movement (REM) sleep for unmedicated children who have ADHD, the specific changes identified have been inconsistent, including reports of increased [23,24], decreased, or delayed [25,26] REM sleep. The most consistently reported PSG findings in children meeting DSM-IV criteria for ADHD are increased rates of movement and respiratory disturbances during sleep. Excessive periodic limb movements of sleep (PLMS) have been reported by several investigators. Huang and colleagues [27] assessed 88 school-aged children who had DSM-IV ADHD referred to a psychiatric clinic and compared PSG findings to those for 27 control subjects. Nine (10.2%) of the children who had ADHD demonstrated an elevated periodic limb movement index (PLMI) of more than five movements hourly, compared with only one of the controls. Golan and colleagues [28] reported that 5 of 34 children who have DSM-IV ADHD (15%) exhibited comparably excessive PLMS during PSG compared with none of 32 matched controls. These findings provide a degree of objective support for the premise that ADHD children are indeed more restless during nighttime sleep, in agreement with parental reports. High rates of sleep-disordered breathing (SDB) for children who had ADHD were also identified in these same series. Huang and colleagues [27] reported that 50 of 88 children who had ADHD (56.8%) had an apnea-hypopnea index (AHI) of
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greater than 1 and that 17 (19.3%) had AHIs exceeding 5. Golan and colleagues [28] found that 50% of children who had ADHD exhibited a respiratory disturbance index (RDI) exceeding 2, compared with only 22% of controls. In contrast to the high rates of SDB identified in these reports, studies using less stringent criteria for study entry or higher AHI cutoffs for the diagnosis of SDB have reported lower prevalence of OSA in children who have ADHD, ranging from 0% to 26% [29– 31]. These data tend to support the premise that childhood ADHD may be associated with SDB, although the strength and frequency of this association remain incompletely defined at present. Although relatively few studies have used MSLT in the assessment of children who have ADHD, most have reported objective evidence of sleepiness for this population. Golan and colleagues [28] used a modified MSLT protocol with 30-minute nap opportunities in their study of 34 children who had DSM-IV ADHD. They found that the children who had ADHD were significantly sleepier (mean sleep latency of 21.9 5.5 minutes) than controls (27.9 2.0 minutes). Although half the children in the cohort who had ADHD were found to have SDB (RDI>2), comparable levels of sleepiness were exhibited by the children who had ADHD without SDB. Lecendreux and colleagues [32] also identified significant daytime sleepiness for 30 boys who had DSM-IV ADHD compared with 22 matched controls. Although PSG findings did not differ between the two groups, mean sleep latency was significantly shorter for the ADHD children in three of the four MSLT naps. In addition, MSLT abnormalities correlated significantly with the standardized hyperactivity-impulsivity and inattentivepassivity indices of the Conners’ rating scale for the ADHD group. These MSLT data are in agreement with previous research reporting high rates of parentally reported sleepiness in ADHD children [15,18] and consistent with the premise that primary ADHD may represent a disorder of hypoarousal [33]. Studies of pediatric ADHD using actigraphy have yielded only limited additional information. Although older studies reported increased movements and diminished sleep efficiency in children who have ADHD compared with controls [34], recent studies using larger sample sizes have shown few significant differences in actigraphic parameters apart from increased night-to-night variability of sleep onset and sleep duration in one cohort of school-aged boys monitored for five consecutive nights [35]. Analysis of actigraphy and dim light melatonin onset in children who have DSM-IV ADHD and insomnia has suggested the presence
of delayed sleep phase compared with ADHD children who did not have insomnia [36].
Disrupted sleep in adults who have attention deficit hyperactivity disorder Data regarding sleep in adults meeting DSM-IV criteria for ADHD are presently scant and inconsistent. A small pilot study assessing 6 adults who had ADHD receiving pharmacologic treatment identified sleep-disordered breathing and sleep fragmentation in all subjects, with excessive periodic limb movements in 3 [37]. In contrast, a study of 20 unmedicated adults who had ADHD without SDB revealed increased sleep time and PLMS compared with controls without significant changes in other PSG or EEG parameters [38]. Actigraphy of adults who have unmedicated DSM-IV ADHD has documented delayed sleep onset and lower sleep efficiency compared with control subjects [39]. Larger, more rigorously controlled studies using objective outcomes are still required to better define the frequency and nature of sleep disruption associated with adult ADHD.
Impact of attention deficit hyperactivity disorder treatments on sleep Stimulants represent the most frequently prescribed class of medication administered for the treatment of ADHD, used by approximately 2% of schoolaged children in the United States [40]. Although insomnia is generally considered to be a frequent side effect of stimulant treatment, studies of stimulant use in patients who have ADHD have in fact reported variable impact on nighttime sleep, most often in the mild-to-moderate range. Methylphenidate (MPH) is the stimulant for which the most sleep-related data exist. Use of standard-release preparations at doses of 0.3 to 0.5 mg/ kg/d in school-aged children who have ADHD was associated with modestly reduced total sleep time [41] and increased sleep onset latency [42] in several placebo-controlled trials that used once- or twice-daily dosing. Placebo-controlled crossover trials comparing twice a day dosing of standard MPH to three times a day dosing reported that a third, late-afternoon dose had minimal impact on quantitative sleep parameters or subjectively rated sleep quality in children [43,44]. Sustained-release preparations of methylphenidate less often require late-afternoon dosing; however, the longer duration of action for these agents still results in the potential for pharmacologic impact on nighttime sleep. Several large, double-blind pediatric trials comparing extended-release MPH administered once daily, standard-release MPH
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administered three times a day, and placebo reported no significant differences in subjectively rated sleep quality among any of the treatment arms [45,46]. A long-term, open-label study following 407 children who had ADHD and good response to extended-release MPH in previous controlled trials reported a 14.7% prevalence of insomnia and good or excellent sleep quality for 74% of subjects on interim analysis after 12 months [47]. Limited data exist regarding the impact of amphetamine agents on sleep in patients who have ADHD. Although a 15-month double-blind, placebo-controlled trial of dextroamphetamine treatment in ADHD children using individually titrated doses reported no adverse sleep effects compared with baseline and placebo [40], a blinded crossover trial comparing dextroamphetamine at 0.3 mg/kg/d to MPH 0.6 mg/kg/d (twice a day dosing) reported more frequent insomnia during amphetamine treatment (70%) compared with MPH (64%) and baseline (54%) [48]. A 4-week placebo-controlled trial of extended-release mixed amphetamine salts using forced-dose titration in adolescents who had ADHD identified insomnia for 12% of patients receiving active treatment and 3.7% of patients receiving placebo [49]. A preapproval study of lisdexamfetamine dimesylate at doses of 30 to 70 mg/d in 176 children who had DSM-IV ADHD reported insomnia for 19% of treatment subjects compared with 3% for a placebo group [50]. Several studies suggest that the risk for sleep disruption in patients who had ADHD treated with stimulants is to some extent dose-related [49,51,52]. Less well studied but frequently observed in practice is a phenomenon wherein the sleep of a patient who has ADHD improves with stimulant treatment. It is uncertain whether this clinical improvement represents a direct pharmacologic effect of medication or a secondary effect resulting from improved behavior leading up to bedtime [53]. Atomoxetine is a nonstimulant, long-acting ADHD treatment for which limited sleep data have been reported. A recent meta-analysis assessing long-term (>2 year) treatment data in 6- and 7-year old children who had DSM-IV ADHD reported low rates of sleep-related side effects, with sleep-onset insomnia for 5.1% of subjects and somnolence for 8.5% [54]. A comparable meta-analysis assessing long-term treatment in adolescents did not report sleep problems among adverse events affecting at least 10% of subjects, although fatigue was reported in 14.8% [55]. In a crossover trial comparing twice a day atomoxetine to three times a day MPH in 85 children who had
DSM-IV ADHD, insomnia was seen less frequently during treatment with atomoxetine (6.3%) than for MPH (26.6%) [56]. Among 218 adults who had DSM-IV ADHD receiving atomoxetine as either 80 mg once daily or 40 mg twice daily, split dosing was associated with more frequent insomnia (25.5% of subjects) than once-daily dosing (16.7%) [57].
Treatment of sleep problems in patients who have attention deficit hyperactivity disorder Despite the high frequency of subjectively reported sleep problems in patients who have ADHD, pharmacologic treatment of ADHD-related insomnia has received limited study, consisting of a few clinical studies and case series assessing children. Because no medications have been labeled by the United States Food and Drug Administration (FDA) for treatment of any sleep disorder in children, these studies address off-label treatment exclusively. Several recent trials and case series suggest that low-dose melatonin may be effective in alleviating ADHD-related insomnia. A randomized, doubleblind, placebo-controlled trial assessing 105 unmedicated children meeting DSM-IV criteria for ADHD assessed the effects of melatonin administered at 7:00 PM compared with placebo for 4 weeks [58]. Children treated with melatonin 3 to 6 mg (based on body weight) reduced their latency to sleep onset by 26.9 47.8 minutes compared with an increase of 10.5 37.4 minutes for controls (P<.0001) and increased their total sleep time. Although no significant side effects were reported, there was no change in behavior, cognition, or quality of life for treated patients in this study. Significant improvements in sleep-onset latency have also been reported for children who have stimulant-treated ADHD following treatment with melatonin at doses of 3 mg at bedtime [59] and at doses of 5 mg (coupled with sleep hygiene interventions) [60]. Use of clonidine for treatment of ADHD-associated insomnia has been reported to be effective in uncontrolled case series [61,62]. Prince and colleagues [63] reported that clonidine at a median nighttime dose of 157 14 mg was associated with significant subjective improvements in ADHD-associated sleep disturbances for 53 of 62 patients (85%) in a retrospective pediatric study. Although two thirds of children in this study were also using stimulants, effectiveness of clonidine therapy did not vary with age, gender, or concurrent treatment. This study also reported mild side effects for 31% of subjects, including morning sedation for
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24% and fatigue for 11%. Other reports have raised concern that concurrent use of clonidine and methylphenidate in children may be associated with increased risk for sudden death [64], and the safety of this medication combination has been the subject of vigorous subsequent debate [65–67]. Other drugs reported to be effective for treatment of ADHD-associated insomnia on the basis of anecdotal or case reports include diphenhydramine, cyproheptadine, trazodone, mirtazapine, guanfacine, and tricyclic antidepressants [68–70]. Several reports suggest that structured behavioral interventions may be effective as primary [71,72] or adjunctive [60] treatment of insomnia in some children who have ADHD.
Sleep-disordered breathing associated with attention deficit hyperactivity disorder symptoms The first modern descriptions of childhood OSA reported hyperactivity, inattention, and learning problems as frequently associated symptoms [73]. An early series of 50 pediatric cases identified hyperactivity in 42% of affected children and poor academic performance for 16% [74]. Although these early reports described children who had relatively severe OSA, subsequent reports have suggested that even isolated snoring may be associated with increased risk for daytime inattention and hyperactivity during childhood [75]. Several large community-based, cross-sectional studies have reported that habitual snoring is associated with increased risk for parentally reported hyperactivity [76,77]. In addition, snoring was found to be three times as prevalent in a cohort of children who had clinically diagnosed ADHD (33%) compared with children who did not have ADHD drawn from child psychiatry (11%) and general pediatrics (9%) clinics [78]. Contemporary studies assessing children undergoing surgery for clinically diagnosed SDB also report high rates of inattention and hyperactivity compared with controls [79] or compared with postoperative assessment [79,80]. Among 78 children in the Washtenaw County adenotonsillectomy cohort studied before and after clinically indicated adenotonsillectomy, 22 children (28%) met DSM-IV criteria for ADHD preoperatively, compared with 7% of controls. On postoperative follow-up 1 year later, 11 of the 22 children who had ADHD (50%) no longer qualified for that diagnosis. Surprisingly, standardized PSG measures, such as AHI, did not predict baseline neurobehavioral morbidity or postoperative improvement in any areas apart from sleepiness, whereas a validated
questionnaire better predicted initial hyperactivity and its subsequent improvement for this cohort [81]. Other studies have also suggested that the relationship between SDB and ADHD is complex and cannot be predicted based solely on the frequency of respiratory disturbances detected by standard PSG. Some investigators have identified higher sleepiness and hyperactivity scores for children who had suspected SDB compared with controls, but found that these scores did not differ between subjects who had OSA and those who had primary snoring [82]. In a cohort of 5- to 7-year-old children who had parentally reported ADHD symptoms, children who had mild ADHD symptoms were most likely to have PSG-confirmed OSA (26%) compared with children who had significant ADHD symptoms (5%) or controls (5%) [29]. This poor correlation between AHI and neurocognitive consequences in patients who have OSA suggests that the causative mechanism is not reliably demonstrated by standard PSG techniques. It is hoped that new technologies designed to increase sensitivity of PSG for subtle airway obstruction and microarousals may provide improved predictive value in this area [83]. It remains uncertain what proportion of patients who have ADHD have clinically significant SDB as a sole or contributing underlying cause. In recent pediatric series assessing children meeting DSM-IV criteria for ADHD, the prevalence of associated OSA varied substantially depending on the AHI criteria used for the diagnosis of OSA. Studies using low AHI cutoffs identified high rates of OSA: 56.8% for Huang and colleagues (OSA defined as AHI>1) and 50% for Golan and colleagues (RDI>2) [27,28]. Sangal and colleagues [26,84] reported that none of 40 children who had DSM-IV ADHD had OSA defined as AHI>5; however, 57.5% of these subjects demonstrated AHI>1. Although these and other studies suggest that a large proportion of children who have ADHD have associated SDB, further large-scale studies using standard, contemporary criteria for the diagnosis of ADHD and OSA will be required to better define the strength and frequency of this association.
Other sleep disorders associated with attention deficit hyperactivity disorder symptoms Data regarding the association of RLS and PLMD with ADHD have been derived primarily from pediatric studies. Although the prevalence of RLS/PLMD in children has not been precisely defined, leg restlessness was reported for 17% of children in a large cross-sectional survey and up to 45% of adult RLS
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patients reported onset of symptoms before age 20 [85,86]. Several lines of investigation support the premise that childhood RLS/PLMD may be associated with ADHD symptoms. First, there is compelling evidence that ADHD is overrepresented among children who have PSG-confirmed PLMD. In a retrospective review of 129 children and adolescents who had PLMD (PLMI>5 on PSG), 117 (91%) met DSM-IIIR or DSM-IV criteria for ADHD [87]. The association was particularly strong for the children whose PLMI exceeded 25, 15 of whom (94%) had ADHD. Second, children who have restless legs symptoms are more likely to be rated as hyperactive than children who do not have leg restlessness. In a cohort of 866 children recruited from community-based pediatrics clinics, 18% of children who had restless legs symptoms were found to have high hyperactivity index scores compared with 11% of children who did not have leg restlessness (P<.05) [86]. In a separate account describing 32 children who had clinically diagnosed RLS, inattentiveness was reported for 8 (25%) [88]. Finally, multiple studies suggest that children meeting DSM-IV criteria for ADHD are more likely to have excessive periodic limb movements than other children. In an early report, Picchietti and colleagues [89] compared 14 consecutive children who had newly diagnosed ADHD to 10 control subjects. Nine of 14 (64%) children who had ADHD demonstrated PLMI greater than 5 during PSG compared with none of the controls (P<.0015). All 9 of the children who had ADHD with excessive PLMS had a longstanding history of sleep problems and met ICSD criteria for PLMD. Excessive PLMS during PSG of children who had DSM-IV ADHD compared with controls were also reported by Huang and colleagues (10% versus 0%) and by Golan and colleagues (15% versus 0%) [27,28]. Data regarding the association between RLS/ PLMD and adult ADHD are scant. Wagner and colleagues [90] prospectively evaluated 62 adults who had RLS and found that 26% met DSM-IV criteria for ADHD compared with 6% of patients who had insomnia and 5% of control subjects. Among the patients who had RLS, the RLS symptom severity score was greater for patients who had ADHD compared with those who did not (P<.04). Data regarding the impact of RLS/PLMD treatment on ADHD symptoms are even more limited. In an uncontrolled, seven-patient series assessing children who had RLS/PLMD and DSM-IV ADHD, dopaminergic therapy was associated with significant improvements of ADHD symptoms as measured by the Conners’ Parent Rating Scale
(P<.04), with three children no longer meeting criteria for ADHD following treatment [91]. Detailed examination of the impact of other sleep disorders on waking neurocognitive function is beyond the scope of this article; however, daytime inattention and hyperactivity have also been reported in children who have narcolepsy [92,93], delayed sleep phase syndrome [72], and insufficient nighttime sleep [94,95].
Sleep and attention deficit hyperactivity disorder: potential pathophysiologic links Clinical and experimental evidence support the notion that deficient levels of arousal may underlie some of the neurocognitive impairments common to ADHD and sleep disorders. MSLT studies of children who have rigorously diagnosed ADHD have reported high rates of sleepiness compared with controls [28,32], consistent with cross-sectional studies showing strong associations between sleepiness and ADHD behaviors [76]. Although the concept that hyperactive and inattentive children are actually sleepy seems counterintuitive, it is highly consistent with findings from studies of pediatric sleep restriction that have reported inattention, hyperactivity, and impaired reaction times as prominent waking symptoms in sleep-deprived children [94–96]. The current theoretic framework regarding central nervous system mechanisms linking OSA and ADHD primarily focuses on the prefrontal cortex, which subserves many aspects of executive function, including attention and working memory [33]. The hypothesis that the behaviors associated with ADHD result from aberrant executive regulation by the prefrontal cortex is supported by positron emission tomography studies of patients who had ADHD demonstrating abnormal dopaminergic metabolism in this area [97]. Data indicating that the cognitive and emotional deficits that result from sleep disruption also localize to the prefrontal cortex [98,99] lend further support to this theory. It remains uncertain whether the effects of OSA on the prefrontal cortex are mediated by disruption of sleep quality, sleepiness, intermittent hypoxia, or alternative mechanisms [100]. Models linking RLS/PLMD with ADHD are presently less well developed than those for OSA. One hypothesis is that daytime inattention and hyperactivity resulting from RLS/PLMD may represent nonspecific manifestations of disturbed sleep quality and daytime sleepiness similar to those exhibited by sleep-deprived children. Another is that RLS/PLMD and ADHD may both result from underlying central nervous system disturbances of dopamine metabolism [90]. An intriguing
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possibility suggested by Cortese and colleagues [22] is that diurnal restlessness and motor activity secondary to RLS might mimic the symptoms of ADHD to the point that the waking symptoms are misclassified.
Summary Existing research suggests that a close but complex relationship exists between the daytime behaviors that define ADHD and disturbances of nighttime sleep. Present data suggest that substantial, but not precisely defined, numbers of children presenting with symptoms of ADHD may in fact have sleep disorders as a primary underlying cause or treatable comorbid condition. Further work is required to better elucidate the common pathophysiologic mechanisms underlying these conditions and more clearly define their impact as important and treatable public health problems.
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