Clifford Singer, MD

Changes in sleep are inevitable as people age, though some sleep symptoms may be due to diseases rather than aging itself (Foley et al., 1999). For example, 41% of a study sample of older adults with ≥4 medical conditions considered themselves to be fair or poor sleepers as compared to 22% with one to three conditions and only 10% of those with none (Foley et al., 2004). In this same study, poor sleep was most strongly associated with heart disease, depression, arthritis and obesity. However, even healthy seniors experience reductions in slow-wave sleep ("deep sleep") and have lower sleep efficiency with more nighttime awakenings than younger adults (Bliwise, 1993).

Patients with Alzheimer's disease (AD) may have the same sleep disturbances seen in other seniors, and, early in the course of AD, their sleep may not differ markedly from age-matched controls (Vitiello et al., 1990). In some cases, however, the sleep disturbance may be a marker for early AD. For example, investigators have reported that insomnia is an independent risk factor for cognitive decline over a three-year follow-up period (Cricco et al., 2001). Sleep-related problems generally increase as AD progresses (Moe et al., 1995). Patients with AD experience more frequent nighttime awakenings, daytime sleep increases, and both slow-wave sleep and rapid eye movement (REM) sleep are decreased (Bliwise, 1993; Prinz et al., 1982; Vitiello and Borson, 2001; Vitiello et al., 1992). Subjective sleep disturbances occur in up to 54% of patients with AD who live in the community (Carpenter et al., 1995; Chen et al., 2000; Hart et al., 2003; McCurry et al., 1999). McCurry et al. (1999) reported that 24% of caregivers report being awakened at night by the patient with AD and 40% report that patients with AD sleep more than usual.

Sleep disturbances tend to occur in patients with AD and other neuropsychiatric symptoms, such as anxiety and psychosis (Friedman et al., 1997; McCurry et al., 1999). Beyond these symptoms, disruptive nighttime behaviors secondary to confusion often develop, including nocturnal wandering, agitation, combativeness, disorientation or even delirium (Bliwise, 1993). The term 

 is sometimes used to refer to these nighttime behaviors and erroneously used as a synonym for 

 in patients with AD, but sundowning and sleep disorders are distinct syndromes. However, it is the nighttime behaviors while awake that prove distressing to patients and caregivers alike and, indeed, have been documented as the most significant contributing factor in institutionalization of patients with AD (Gaugler et al., 2000; Hope et al., 1998; Pollak and Perlick, 1991). In one study, caregivers reported that sleep disturbances were among the most distressing of all AD-related symptoms (Hart et al., 2003). In fact, of patients with AD who awaken their caregivers at night, 70% of the caregivers reported the awakenings to be moderately to severely distressing (McCurry et al., 1999).

Daytime function of patients with AD may be adversely affected by poor nighttime sleep, but there may also actually be a primary arousal problem in AD that impairs daytime alertness. Daytime sleepiness may be an early manifestation of AD, just as insomnia is. Adjusting for age and health status, older adults with daytime sleepiness are more than twice as likely to develop dementia after a three-year follow-up (Foley et al., 2001). Daytime sleepiness clearly impacts daily function in non-demented older adults (Gooneratne et al., 2003) and can be logically presumed to have at least as great an effect in patients with AD. Not surprisingly, although 38% of caregivers report moderate-to-severe distress from hypersomnia, this percentage is only half that of caregivers distressed by nighttime sleep disturbance (McCurry et al., 1999).

Alzheimer's disease sleep investigators from several centers recently proposed diagnostic criteria for defining the core sleep disturbance of AD (Yesavage et al., 2003). By defining diagnostic criteria for insomnia and hypersomnia in patients with AD, the authors provided clear diagnostic guidelines for clinical intervention and research trials. Although patients with AD may experience all the sleep disorders of old age--periodic limb movement, restless legs syndrome and sleep-related breathing disorders--the proposed diagnostic criteria specify that there is a primary sleep disturbance of AD. It is important to note, however, that the sleep disturbances seen in AD are nonspecific and can also be seen in other neurodegenerative conditions, such as vascular dementia, dementia with Lewy bodies (DLB) and Parkinson's disease. These other dementing diseases are also associated with high rates of insomnia and daytime sleepiness. Parasomnias are also more likely to occur in non-AD disorders. Some patients with dementia experience loss of muscle atonia during REM sleep that can result in dramatic motor activity and dream-enactment behavior. The syndrome, called 

, is not typically seen in AD, but is characteristic of DLB. Its development may even precede the dementia (Boeve et al., 1998).

Alzheimer's disease results in degenerative changes to brain stem nuclei and cortical pathways that in all probability contribute to the breakdown in sleep and its diurnal pattern, though the actual pathological processes remain unknown (Vitiello and Borson, 2001). Decreased cholinergic input to the cerebral cortex secondary to neuronal loss in the nucleus basalis may affect both daytime arousal and REM sleep propensity (Chokroverty, 1996). The circadian breakdown in the sleep-wake cycle commonly seen in AD may be due to degeneration of the suprachiasmatic nucleus (or circadian pacemaker or "body clock") (Swaab et al., 1985). The cholinesterase inhibitors commonly prescribed to patients with AD can improve daytime alertness but may also contribute to insomnia (Stahl et al., 2003). High rates of sleep-disordered breathing (obstructive hypopneas and apneas) may also contribute to the daytime sleepiness and agitation in people with dementia (Ancoli-Israel et al., 1991; Gehrman et al., 2003). Gehrman et al. (2003) found that 63% of the dementia subjects had apneas or hypopneas of probable clinical severity; a strikingly high rate that contrasts with the 4% to 8% prevalence rate in non-demented elderly.

Assessment of sleep symptoms requires help from family or caregivers. Simple sleep diaries or sleep logs in which the caregiver records sleep times, describes nighttime awakenings and estimates sleep quality can be very helpful to the clinician. Validated rating scales of sleep symptoms can also be helpful, both in the initial assessment as well as follow up for treatment interventions. The Sleep Disorders Inventory (SDI) is an easy-to-use instrument that has been validated in a cohort with AD (Tractenberg et al., 2003). Based on the Neuropsychiatric Inventory (NPI) (Cummings et al., 1994), the SDI evaluates the frequency, severity and caregiver distress of eight sleep-related symptoms. The Epworth Sleepiness Scale (ESS) can be helpful in evaluating daytime sleepiness, particularly in less impaired, community-residing patients (Johns, 1991).

Wrist actigraphs provide nonintrusive technology to provide objective data on the sleep-wake cycle in patients with AD. They are worn like a wristwatch, and although they only measure movement, they are useful for long-term studies and can have excellent reliability and validity against sleep electroencephalogram (Ancoli-Israel et al., 2003; Singer et al., 2003). However, actigraphs are expensive and are generally used only by sleep labs or sleep researchers. Some investigators are experimenting with pressure sensors under the beds of long-term care residents to obtain longitudinal data on time in bed. This technology may be of some assistance to clinicians and researchers in the future.

The gold standard of sleep assessment is polysomnography (PSG). This technology is the only way to obtain diagnostic information critical to the assessment of obstructive sleep apnea, periodic limb movement and parasomnias such as REM behavior disorder, but it is expensive and not always practical for more severely demented patients. Polysomnography should be reserved for those patients with daytime somnolence that cannot be attributed to insomnia, medications or acute illness, and then only if the patient can tolerate the procedure. Some sleep labs will allow a caregiver to remain in the lab with the patient, improving the likelihood of a successful study. In-home studies are available in many areas, and performing the study in the familiar environment of home makes it much easier on the patient with dementia.

. Diagnosis of the underlying cause of insomnia or daytime sleepiness is a necessary first step in treatment. Although AD itself can cause sleep symptoms, other medical, psychiatric and environmental causes of sleep disturbance in old age need to be considered (

). If the dementia is far advanced, some of these problems (e.g., obstructive sleep apnea) can be approached very conservatively. Pain and comfort issues, of course, would be actively managed, regardless of the stage of dementia. Routine administration of analgesics at bedtime can be very helpful. Restless legs syndrome and periodic leg movements can be treated with benzodiazepines, opioids or dopamine agonists (Boeve et al., 2002). The potential for these agents to affect cognition and behavior has to be considered. Patients in long-term care facilities are especially likely to spend excessive amounts of time in bed during the day, potentially contributing to poor nighttime sleep (Ancoli-Israel et al., 1989). Structured daytime activity has been shown to improve sleep in these patients (Alessi et al., 1999).

It is necessary to define goals before prescribing for sleep disorders. In most cases, the goal should be to improve daytime alertness. There are times, however, when it may be appropriate to target improved nighttime sleep for the purpose of relieving caregiver distress at home or reducing nighttime disruption that endangers the patient or other residents in long-term care facilities.

Approaches to primary insomnia and daytime sleepiness are discussed below.

. Benzodiazepine and non-benzodiazepine sedative-hypnotics are commonly prescribed for older adults, and they have been extensively studied in short-term, controlled trials in this population (Reynolds et al., 1998; Wortelboer et al., 2002). These agents have been proven to modestly increase sleep time. Short-acting agents, such as triazolam (Halcion) and temazepam (Restoril), are associated with less risk of daytime confusion and morning hangover. Even short-acting agents, however, may increase risk for nighttime falling and confusion. The risk of worsening obstructive sleep apnea also exists. The non-benzodiazepine hypnotics (e.g., zaleplon [Sonata] and zolpidem [Ambien]) may be safer than benzodiazepines, though they can clearly cause the same types of problems. No large, controlled trials of these agents have been conducted in patients with dementia, but they are frequently used. There is some evidence that hypnotic medications may not significantly improve sleep symptoms in long-term care residents, many of whom have dementia (Englert and Linden, 1998; Monane et al., 1996).

Prescribing regulations in nursing homes and many pharmacy benefit plans limit the use of these medications to 10 to 14 nights per month, making treatment of persistent insomnia problematic. The development of tolerance to the hypnotic effects of these agents sometime requires changing to as-needed or controlled-interval therapies (Wortelboer et al., 2002).

. Tricyclic antidepressants should not be used for insomnia in patients with AD because of their anticholinergic effects. Trazodone (Desyrel) and mirtazapine (Remeron) can be tried, but no controlled trials have been reported, so safety, efficacy and dosages have not been established. However, these agents are in widespread clinical use (Walsh and Schweitzer, 1999) and many clinicians are strong advocates.

. Diphenhydramine is frequently seen as a benign sedative in older adults, yet its anticholinergic effect impacts cognition in non-demented elderly people, and it should be avoided in patients with AD.

. Antipsychotic medications have long been used to treat neuropsychiatric symptoms in patients with AD. Although these medications have not been approved by the U.S. Food and Drug Administration for treating agitation and psychosis in patients with AD, there are large, randomized, controlled trials to support their use (Tariot et al., 2004). Similar data do not exist to support their use to treat insomnia in AD, though the sedative effect of the more-antihistaminic agents (e.g., quetiapine [Seroquel] and olanzapine [Zyprexa]) is commonly used for this purpose. The safety and efficacy of this practice, or its effect on daytime function, is unproven, especially over the weeks or months patients are usually treated.

. Despite promising results in small pilot studies in participants with AD, melatonin failed to separate from placebo by wrist actigraph-scored sleep in two large placebo-controlled trials (Serfaty et al., 2002; Singer et al., 2003). Interestingly, in the larger of these trials, melatonin did show a positive trend on actigraph-scored sleep, a significant effect relative to placebo on the caregivers' rating of participants' sleep and a dramatic effect on one patient with a reversed sleep/wake cycle (Singer et al., 2003). One can conclude that in doses ranging from 2.5 mg to 10 mg, melatonin has, at best, a modest effect on sleep in patients with AD. By way of perspective, however, no other agent has either been as well studied or has proven safety or efficacy in this population.

No controlled data on safety or efficacy are available to support the use of other supplements for sleep disturbance in AD. Valerian (

), a popular supplement used for sleep, does not appear to have sedating effects in older adults (Glass et al.. 2003).

. The theoretical reasons for increased bright light exposure improving sleep-wake cycle are compelling, given that people with dementia may have light exposure that is inadequate to maintain robust circadian rhythms (Ancoli-Israel et al., 1997). Although bright light exposure may change the circadian timing of sleep, it may not improve the quality of sleep (Ancoli-Israel et al., 2002). This remains an area of active investigation, and increased exposure to natural light is still recommended by AD sleep experts.

. Cognitive-behavioral therapy for insomnia in older adults is at least as effective as medication and has more persistent effects (Morin et al., 1999). This intervention may be less successful in memory-impaired patients, but environmental and behavioral approaches, including reducing noise and other disruptions at night, reducing nocturia and incontinence, increasing exercise, and reducing time in bed during the day, may all be of potential benefit. An ongoing study of these interventions is underway, and several case reports of successfully treated patients have been published (McCurry et al., 2004). However, there is also evidence that interventions to reduce noise and light in the nursing home have only modest effect (Schnelle et al., 1999). Examples of sleep hygiene and environmental interventions are presented in 

 and reflect generally accepted sleep hygiene measures thought to be effective in both young and old adults. Caregivers of patients with dementia can be successfully trained to institute these measures, though education alone may be insufficient and active assistance may be needed (McCurry et al., 2004).

. Methylphenidate (Concerta, Metadate, Ritalin) and modafinil (Provigil) have potential to be helpful in improving daytime sleepiness in patients with AD (Boeve et al., 2002). Controlled trial data have not yet been published, but some clinicians believe this is an effective way to improve daytime function in these patients.

Patients with AD suffer the same age- and disease-related changes to sleep as their age-matched peers. As the dementia progresses, however, even more severe disturbances develop, with impairments in both nighttime sleep continuity and daytime alertness. Thoughtful assessment can usually allow the clinician to make an accurate diagnosis, though some cases may require referral to a sleep laboratory. Data from controlled trials for sleep disorders in this population have been disappointing to date, leaving clinicians to either use therapies that have demonstrated safety and efficacy in non-demented older adults or therapies for which there is substantial clinical experience and anecdotal evidence of efficacy. Finally, effective treatment over the long term may require a holistic approach with environmental and behavioral interventions to augment sleep medications.

Dr. Singer is associate professor of psychiatry and neurology at Oregon Health and Science University (OHSU). He is clinical director of geriatric psychiatry and medical director of the Oregon Geriatric Education Center.

Ms. Bahr is a fourth-year medical student at OHSU and plans to pursue a career in geriatric medicine.

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Articles

Patients with Alzheimer's disease may suffer the same age- and disease-related changes to sleep as their age-matched peers. However, as the dementia progresses, even more severe disturbances develop, with impairments in both nighttime sleep continuity and daytime alertness. This article focuses on long-term, holistic approaches to treatment, including environmental and behavioral interventions to augment sleep medications.

Author | Clifford Singer, MD

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Assessing and Treating Sleep Disturbances in Patients With Alzheimer's Disease