Introduction
Adults with Down syndrome have a variety of comorbid medical conditions which require frequent monitoring from providers as they age.[1] Sleep disorders are highly prevalent across the lifespan in individuals with Down syndrome and are often underrecognized or untreated. The most common sleep disorders include obstructive sleep apnea (OSA), restless leg syndrome/periodic limb movement disorder, irregular sleep wake rhythm disorder (circadian shift), and insomnia. In this article, we review the evidence for sleep difficulties in adults with Down syndrome, the risk factors for these sleep problems, and the associated functional outcomes. Finally, we discuss how sleep disorders are diagnosed and treated in this group.
We know that sleep impacts mental health, brain functioning, and overall quality of life. In individuals with Down syndrome, who are already at high risk for early-onset Alzheimer’s disease (AD), there may be further complications when sleep deficits are left untreated.[2] In total, the evidence suggests that adults with Down syndrome may benefit from sleep treatments, which can enhance short-term functioning and modify longer-term sequelae (e.g., reduce the rate of AD-related decline).[3]
Association Between Sleep Disturbances, AD Neuropathology and Cognition in Individuals with Down Syndrome
Research in adults without Down syndrome has provided meta-analyses and population studies[41][5] detailing the impact of sleep disturbances and OSA on cognition, behavioral functioning, and risk for AD. Specifically, these reports have shown that reduced sleep duration is associated with increased cortical neuropathology, notably increased cortical β-amyloid.[5] Similarly, a US population sample from the Health and Retirement Study showed that OSA was significantly associated with cognitive impairment and AD diagnosis.[4] These studies show clear associations between sleep and AD-related decline in typical individuals, who are generally at less risk for these diagnoses as compared to individuals with Down syndrome.
Consistent with these findings, studies of individuals with Down syndrome have also shown significant associations between sleep disturbance, cognitive deficits, and Alzheimer’s neuropathology. In a study of 29 adults with Down syndrome without a dementia diagnosis, sleep efficiency and OSA were related to the integrity of white matter tracts in the brain[6], an important biomarker for the progression of neurological diseases, including AD. Another study of 116 individuals with Down syndrome examined Alzheimer’s disease biomarkers, finding significant correlations between AD risk factors and OSA. Using positron emission tomography (PET) and magnetic resonance imaging (MRI) to examine white matter, OSA was found to be associated with greater cortical and striatal β-amyloid burden and signs of white matter disease.[7] This work, however, did not find an association between AD diagnostic group assignment from a neurologist screening.
An additional study demonstrated that length of night-time awakenings was positively associated with striatal β-amyloid accumulation and deficits in both motor planning and executive function.[8] These data suggest that the neuropathologic findings of AD may be accelerated by sleep disturbances in individuals with Down syndrome, and that treating the OSA or other sleep disturbances may help maintain brain health and prevent cognitive decline.
Impact of Sleep Disturbances on Mental Health and Quality of Life in Individuals with Down Syndrome
Studies of individuals with Down syndrome have shown associations between sleep and cognition across the lifespan. For example, lack of sleep can be correlated with reduced language expression and understanding,[9][10] a key functional capacity for everyday engagement and long-term success in educational and vocational settings. In adults with Down syndrome, sleep disturbances can increase anxiety, depression, excessive daytime sleepiness, and aggression, among other behavioral problems. Regarding quality of life, OSA in individuals with Down syndrome is associated with more frequent physician visits and respiratory problems, while behavioral sleep disturbances are associated with poorer overall health, more frequent hospitalizations, and more emergency department visits.[11][12] In a 2019 study,[11] 56% of the caregivers of adults with Down syndrome reported disturbed sleep related to their caregiving responsibilities, suggesting that sleep problems could impact the home environment broadly.
Given the strong associations between sleep and health, in the following sections we review the sleep disorders that appear to be the most relevant to adults with Down syndrome, how they are diagnosed, and treatments that may be appropriate.
Obstructive Sleep Apnea
Obstructive sleep apnea (OSA) is very common in adults with Down syndrome with an estimated prevalence of 78-100%.[13][14][15][16][17] OSA is associated with significant impairments to quality of life, behavior and cognitive abilities. Despite the high prevalence, less than 50% of adults with Down syndrome are evaluated for OSA by their primary care provider.[18]
Diagnosis: Parental reporting of OSA is sometimes used in general clinical practice, but is highly unreliable, with parents often unable to detect even severe OSA.[19] The gold standard diagnosis for OSA is in-lab polysomnography. Polysomnography captures detailed information on multiple sleep metrics including respiration, oxygenation, limb movements, and heart rate. For adults with suspected OSA, several insurance providers may require a home sleep test in lieu of a polysomnogram, with a polysomnogram only covered if the home sleep test does not show the presence of OSA. Home sleep tests, however, typically measure only respiration and oxygenation and have decreased accuracy compared to in-lab polysomnography.
Alternatively, there are devices that can be worn on the hand which use cardiovascular surrogate markers to diagnose OSA. These devices may be best for individuals who cannot tolerate in-lab polysomnography or home sleep tests that directly measure breathing. One such device, the WatchPAT, detected OSA in 95% of participants, but this was not validated using polysomnography. Curiously, only 61% of participants wearing this device returned usable data, which is unexpected given the less invasive design.[20] Nevertheless, this approach may be worth considering for individuals unable to tolerate other sleep study approaches.
Treatment: The gold standard treatment for OSA in adults with and without Down syndrome is positive airway pressure therapy (PAP), typically continuous positive airway pressure therapy (CPAP), although bi-level PAP may also be used. For individuals who can use CPAP successfully, OSA is nearly completely resolved and OSA-related impairments such as daytime sleepiness are greatly improved. Unfortunately, CPAP therapy may be challenging for many individuals to tolerate. In large population studies, approximately 50% of people are adherent to CPAP, defined as using CPAP for 4 or more hours on 70% of nights in a 30-day period.[21] It appears that adults with Down syndrome have similar adherence rates to adults without Down syndrome.[22][23] For some individuals, a structured CPAP desensitization program can be helpful in improving adherence. As an example, CPAP may be used at bedtime for 1-2 minutes the first night, 3-4 minutes the second night, and so on, gradually increasing the time until the individual is wearing CPAP for most of the night. It is important to use CPAP for the planned duration, not adding extra time (even if the individual is doing well) and similarly not reducing time (even if the individual is uncomfortable). Desensitization should be personalized to the individual based on their initial comfort with CPAP.
For individuals unable to tolerate CPAP therapy, hypoglossal nerve stimulation has emerged as an FDA-approved alternative. Clinical trials of adults without Down syndrome as well as adolescents (age 10-21 years old) with Down syndrome have shown that hypoglossal nerve stimulation leads to approximately a 50% reduction in OSA severity, as well as improved quality of life.[24][25] Studies of adolescents with Down syndrome also suggest that hypoglossal nerve stimulation may improve cognition and behavior.[26] A small 11-person study of hypoglossal nerve stimulation to treat OSA in adults with Down syndrome has similarly shown a significant 79% reduction in OSA severity.[27] Hypoglossal nerve stimulation is generally well-tolerated, though some individuals may find the sensation of the nerve stimulation unpleasant, which may be difficult for those with limited communication abilities to express. In its current form, this approach requires replacement of an implanted battery approximately every 10 years.[28] Ear, nose, and throat (ENT) physician referral can be considered for individuals who do not tolerate PAP therapy, as surgical interventions other than hypoglossal nerve stimulation may sometimes be appropriate.
There are several alternative therapies available for OSA that lack data specific to individuals with Down syndrome but may still be of use. Positional therapy involves the use of body positioning aids to prevent sleeping in the supine position. This may be as simple as pinning a tennis ball to the back of a night shirt or acquiring other positioning devices available for purchase online. These are typically foam blocks to prevent one from sleeping supine, or an alarm that sounds when the individual turns on their back. There is some evidence that positional OSA (where OSA severity is more than twice as severe in the supine position compared to the non-supine position) may be common in individuals with Down syndrome.[29]
There are also dental options for the treatment of OSA. Mandibular advancement devices are mouthguards that protrude the mandible, which can open the airway and reduce OSA severity.[30] These devices work best for mild-moderate OSA in individuals who are not overweight. There are no published data related to the use of mandibular advancement devices for OSA treatment in individuals with Down syndrome.
Several medications have shown promise for treatment of OSA, though none have yet been FDA-approved. The combination of atomoxetine and oxybutynin has shown an approximate 50% reduction in OSA severity in children with Down syndrome[31] and adults without Down syndrome,[32][33] but specific data in adults with Down syndrome are lacking. Incretin therapies such as tirzepatide[34] and liraglutide[35] have shown promising results for both obesity and OSA (approximate 25-50% reduction in OSA severity) in adults without Down syndrome but no data are available specific to individuals with Down syndrome. Tirzepatide was recently approved for the treatment of moderate-severe OSA in adults with obesity and could be considered for some adults with Down syndrome that fit these criteria. However, its efficacy specific to individuals with Down syndrome is unknown at present. Further research and real-world experience are needed to explore these promising OSA treatment options.
Circadian Rhythm Disorders
There are limited data related to circadian rhythm disorders in individuals with Down syndrome. Individuals with Alzheimer’s disease as well as children with neurodevelopmental disorders are known to be at risk for irregular sleep-wake rhythm disorder (ISWR); thus, it is plausible that adults with Down syndrome are also at risk. ISWR is characterized by a lack of sleep consolidation. Instead, individuals often experience several periods of sleep (usually for several hours) scattered across day and night hours and have periods of wakefulness during the night. In essence, the circadian rhythm is functioning, but at a decreased amplitude or effectiveness. A study of children and young adults with Down syndrome found that sleep-wake rhythms became less stable with age,[36] which suggests an increased risk for development of ISWR. Treatment is focused on maximizing circadian cues by providing a consistent schedule, ensuring light exposure during the day and minimizing nighttime light exposure. Nighttime melatonin may also be considered.[37][38] Use of hypnotics or sedatives is generally discouraged as the risk of adverse events may outweigh the benefits, particularly in the setting of dementia.
Restless Leg Syndrome and Periodic Limb Movement Disorder
Restless leg syndrome (RLS) is a condition that occurs in approximately 10% of the population and is clinically significant in 2-3% of the population.[39][40] RLS is characterized by an urge to move the legs that is worse when staying still, better with movement, worse at night and not explained by another cause.[41] There are no specific data as to how adults with Down syndrome may describe their experience with RLS. Atypical descriptions such as “bubbles in my legs,” “ants crawling on my legs” or similar may represent RLS symptoms, particularly if this is only present at night. Periodic limb movement disorder (PLMD) is a similar disorder diagnosed when there are more than 15 periodic limb movements per hour seen on polysomnography. In the setting of disrupted sleep or excessive daytime sleepiness, treatment should be considered.
Treatment for both conditions needs to be personalized to the individual. Interestingly, iron deficiency is a very common contributing factor. For individuals with a ferritin level of ≤ 75, iron supplementation should be considered.[42]
Many anti-depressant medications are known triggers of RLS/PLMD. If appropriate, discontinuation of the medication may improve symptoms. Bupropion is a known exception to this rule and, if appropriate otherwise, may be a useful alternative for individuals with RLS/PLMD due to medications. Treatment of OSA may also improve or resolve RLS/PLMD. If necessary, gabapentin or dopamine agonists such as pramipexole may be used, but should only be considered after other reversible causes of RLS/PLMD have been addressed. Referral to sleep medicine should be considered if the diagnosis is unclear or for further management in individuals with adequate iron stores.
There are limited data describing individuals with Down syndrome who have RLS or PLMD. A study of 47 adults found 21% of participants had a periodic limb movement index of >5 and 2% of participants had a periodic limb movement index >15. A single study in children with Down syndrome found that 33% of children who underwent polysomnography had an elevated periodic limb movement index (>5), and 55% of those who had a ferritin result available were found to have a ferritin less than 50 ng/dL.[43] Most of these children had undergone polysomnography due to concern for OSA and the increased limb movement was an incidental finding. For individuals found to have PLMD but no associated impairments, it may be reasonable to assess ferritin level and offer supplemental iron if ferritin is ≤ 75 ng/dL, but not pursue further treatment given the lack of associated impairment.
Insomnia
In individuals with Down syndrome, insomnia is likely a common condition, with one study reporting 23% of individuals having a “behavioral sleep disturbance”.[12] These individuals were also reported to have increased behavioral and health concerns compared to those without a sleep disturbance. Another study found decreased sleep efficiency and increased daytime napping, but most participants had OSA which may explain this finding.[17] Insomnia symptoms appear more common in adults with Down syndrome and dementia compared to those without dementia, and these insomnia symptoms were associated with impairments in functions of daily living.[44] Insomnia may also be a presenting symptom of Down Syndrome Disintegrative Disorder (also referred to as Down Syndrome Regression Disorder) along with other significant behavioral changes.[45]
Management of insomnia in adults with Down syndrome is complex. As an initial step, evaluation for other disorders that may cause insomnia should be pursued, as treatment of these disorders may improve or resolve insomnia symptoms. These other disorders include OSA, restless leg syndrome/periodic limb movement disorder and circadian rhythm disorders, all of which may be present in adults with Down syndrome. After adequate treatment of other causes of insomnia, individuals with primary insomnia (insomnia not secondary to another disorder) may be candidates for either behavioral interventions or pharmacologic therapy.
The preferred behavioral treatment regimen for adults without Down syndrome is cognitive behavioral therapy for insomnia (CBT-I). This is a treatment package of behavioral interventions that may be highly successful. There are no published data regarding CBT-I for adults with Down syndrome, and component interventions would need to be tailored to the individual. However, many of the components of CBT-I would likely be adaptable for many adults with Down syndrome and may be successful. CBT-I web is a free online training program for clinicians to learn more about this regimen.
Medications may be considered for insomnia in adults with Down syndrome, but the decision to medicate and selection of medications must be tailored to the individual. Melatonin may be a reasonable first step, given the low cost and ready availability over the counter. Sedating anti-depressant medications such as trazadone or mirtazapine may be effective. Z-drugs such as zolpidem may be considered, but these carry considerable risks including an association with early onset of dementia, a particular concern for adults with Down syndrome. Orexin receptor agonists such as suvorexant, daridorexant and lumborexant have recently become available and target a different pathway than prior hypnotic medications. Given their recent approval, there are limited long-term safety data. Finally, it is important to consider that none of these medications have been specifically studied for individuals with Down syndrome.
Summary
In summary, treatment for sleep disturbances in individuals with Down syndrome can be safe and effective, with manageable side effects. The discomfort involved in sleep screenings has been lessened with more inclusive approaches, allowing for optimism that more adults with Down syndrome can be effectively screened and treated. Many individuals will benefit if allowed greater access to growing resources for sleep screening and treatment. Unfortunately, a recent survey of over 700 families suggested almost universal difficulty accessing sleep screening and treatment options. For instance, most respondents (84%) did not receive a repeated sleep assessment to monitor sleep disturbance in adulthood, even though rates of OSA and other sleep disorders increase substantially with age. Similarly, most respondents did not discuss FDA-approved alternate treatments, such as hypoglossal nerve stimulation, with their doctor.[46] Given these data, individuals with Down syndrome could greatly benefit from sleep treatments and all should receive routine sleep-related care across adulthood.