Sleep Disturbances in Patients with Alzheimer's Disease - Springer Link

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CNS Drugs 2001; 15 (10) 777-796 1172-7047/01/0010-0777/$22.00/0 © Adis International Limited. All rights reserved.

Sleep Disturbances in Patients with Alzheimer’s Disease Epidemiology, Pathophysiology and Treatment Michael V. Vitiello and Soo Borson Department of Psychiatry and Behavioral Sciences, School of Medicine, University of Washington, Seattle, Washington, USA

Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Sleep in Alzheimer’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1 Biological Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2 Clinical Correlates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3 Sundowning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.4 Behavioural and Environmental Factors . . . . . . . . . . . . . . . . . . . . . . 1.5 Interactions Between Biological Changes and Environmental Situations . . . 1.6 Other Causes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.6.1 Physical Illness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.6.2 Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.6.3 Concurrent or Complicating Neuropsychiatric Disorders . . . . . . . . 1.6.4 Delirium and Other Confusional States . . . . . . . . . . . . . . . . . . . 1.6.5 Primary Sleep Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Identifying the Cause of Disturbed Sleep . . . . . . . . . . . . . . . . . . . . . . . . 3. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1 Sleep Disorders Associated with Medical Illness . . . . . . . . . . . . . . . . . 3.2 Sleep Disorders Intrinsic to Dementing Diseases . . . . . . . . . . . . . . . . . 3.3 Disrupted Sleep in the Context of Psychiatric or Behavioural Pathology . . . 3.4 Primary Sleep Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5 Symptomatic Treatment of Insomnia . . . . . . . . . . . . . . . . . . . . . . . 3.5.1 Ethical Issues in the Use of Sleep-Promoting Medications in Dementia 3.6 Nonpharmacological Interventions . . . . . . . . . . . . . . . . . . . . . . . . 3.6.1 Behavioural Interventions . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6.2 Light Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6.3 Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6.4 Other Approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Older adults represent an ever-growing proportion of the population of the industrialised nations, with a corresponding increase in the numbers of patients with dementing disorders. A common complaint in both normal aging and the dementias is that of significant sleep disturbance. The major causes of sleep disruption in aging and dementia include: (i) physiological changes that arise as part of normal, ‘non-

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pathological’ aging; (ii) sleep problems due to one of many physical or mental health conditions and their treatments; (iii) primary sleep disorders; (iv) poor ‘sleep hygiene’, that is, sleep-related practices and habits; and (v) some combination of these factors. Disrupted sleep in patients with dementia is a significant cause of stress for caregivers and frequently leads to institutionalisation of patients. It should be a target of clinical management when the goal is sustained home care, and when it is associated with disturbances of mood or behaviour. While the neuropathology of dementia can directly disrupt sleep, sleep disturbances in patients with dementia often have multiple causes that require systematic evaluation. Thorough assessment of associated psychopathology, day-time behaviour, medical disorders, medications, pain and environmental conditions is needed for optimal management. Differential diagnosis of a sleep problem in dementia is the basis of rational pharmacotherapy. However, patients with dementia are likely to be more sensitive than elderly persons without dementia to adverse cognitive and motor effects of drugs prescribed for sleep. Clinicians need to: (i) evaluate sleep outcomes when treating medical, psychiatric and behavioural disorders in older adults; (ii) be alert to emerging behavioural and environmental approaches to treatment; (iii) combine nonpharmacological strategies with drug therapies, when required, for added value; and (iv) avoid use of multiple psychotropic medications unless they prove essential to the adequate management of sleep disturbances.

Nearly 40 million Americans, 13.3% of the national population, are 65 years of age or older.[1] The majority of people who reach retirement age can expect to live into their 80s.[2] This increase in the aged population is associated with a sharp rise in the numbers of persons with dementing diseases, as age is the major risk factor for the most common dementias of adults. Recent studies estimate that between 2 and 4 million older adults in the US have Alzheimer’s disease, a number estimated to quadruple over the next 50 years.[3] This progressive neurodegenerative disorder accounts for approximately two-thirds of all dementias worldwide. Both normal aging and Alzheimer’s disease are associated with disturbances in the daily sleepwake cycle. The major causes of sleep disruption in aging and dementia include: (i) physiological changes that arise as part of normal, ‘nonpathological’ aging; (ii) sleep problems due to one of many physical or mental health conditions and their treatments; (iii) primary sleep disorders; (iv) poor ‘sleep hygiene’ or sleep-related habits, which can include © Adis International Limited. All rights reserved.

patterns of day-time sleeping established over long years of night-shift work that become maladaptive in the retirement years; and (v) some combination of these factors. Each of these causes of sleep disruption may lead to impaired day-time functioning and seriously compromise quality of life. Sleep disturbances are common among patients with Alzheimer’s disease, affecting up to 44% of clinic-based or community samples in cross-sectional studies.[4-6] For patients with Alzheimer’s disease, sleep disturbance adds an additional burden to the compromised functioning and quality of life directly attributable to dementia. For caregivers, disturbances in the patient’s sleep and night-time behaviour, particularly reduced night-time sleep time, increased night-time wakefulness and wandering requiring caregiver attention, are a significant source of physical and psychological burden and are often cited as a reason for a family’s decision to institutionalise a patient with dementia.[7-11] As a consequence, research into more effective management of sleep disturCNS Drugs 2001; 15 (10)

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bances in patients with Alzheimer’s disease is a priority.[12] 1. Sleep in Alzheimer’s Disease 1.1 Biological Factors

The sleep disturbances that accompany early stage or mild dementia are remarkable in that they appear to be exacerbations of the sleep changes found with ‘normal’ aging, rather than unique disease-related phenomena.[13] In patients with Alzheimer’s disease, sleep is marked by an increased duration and frequency of awakenings, decreased slow-wave sleep (SWS) and rapid eye movement (REM) sleep, and more day-time napping.[13,14] Polysomnographic study of patients with relatively advanced Alzheimer’s disease who were living in a dementia special care unit found that sleep was moderately disturbed during about 25% of nights, but that severe sleep disruption was present less than 10% of the time; severity of dementia predicted severity of sleep disruption.[15] Similar studies have not been done in community-dwelling patients with milder dementia. Damage to neuronal pathways that initiate and maintain sleep is the most likely cause of the acceleration of these age-related sleep changes in patients with Alzheimer’s disease. The ‘circadian pacemaker’, or internal clock, in the suprachiasmatic nucleus (SCN) of the hypothalamus is believed to generate circadian rhythms independent of environmental cues,[16] but uses light and physical activity, and perhaps social interaction and food, to synchronise these internal rhythms with the 24-hour cycle that is normal in humans.[17] Synchronisation of the activity of the SCN with external and internal cues is accomplished via neuronal projections from the retina, other hypothalamic nuclei, limbic forebrain, raphe nuclei and reticular formation, and also in response to the ambient hormonal milieu. The efferent pathways of the SCN neurons, through which it exerts its timekeeping functions, are poorly understood in humans, but animal studies have identified projections to many brain regions implicated in the © Adis International Limited. All rights reserved.

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regulation of sleep and wakefulness, arousal and other behaviours.[18,19] The SCN is also known to regulate secretion of the ‘sleep hormone’ melatonin via projections to the sympathetic superior cervical ganglion and, in turn, to the pineal gland. This forms the basis for the postulated clinical utility and popularity of melatonin for the treatment of circadian disruptions of jet lag and as an inducer of sleep.[20-22] Certain neuronal pathways originating in subcortical regions also regulate arousal and sleepwake cycles, including the cholinergic basal forebrain nuclei, serotonergic raphe nuclei, dopaminergic nigrostriatal and pallidostriatal pathways, and noradrenergic locus coeruleus. These regions may, like the SCN, undergo extensive neurodegenerative change in Alzheimer’s disease, as may the cortical regions that generate electroencephalogram (EEG) slow-wave activity during sleep. Current theories implicate all of these regions in the aetiology of sleep disorders in patients with Alzheimer’s disease, and clinical studies using actigraphic methods and behavioural observations find evidence of deterioration in circadian timing systems in both healthy elderly individuals and patients with dementia.[23-25] Sleep in dementias other than Alzheimer’s disease is often also disrupted, and shows similar patterns of increased night-time awakenings, and decreased REM sleep and SWS.[26] For the most part, disturbances in sleep are a nonspecific symptom of a variety of neurodegenerative conditions affecting differing but often overlapping brain structures.[26] However, some brain disorders are also associated with specific, characteristic sleep changes (e.g. the increased frequency of nightmares in some patients with Parkinson’s disease taking levodopa). Further, two recent studies have suggested that the disrupted sleep patterns seen in patients with frontotemporal degeneration and dementia with Lewy bodies may differ reliably from those seen in patients with Alzheimer’s disease.[27,28] However, neither of these studies utilised polysomnography, but rather based their conclusions on actigraphy or questionnaire data. CNS Drugs 2001; 15 (10)

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1.2 Clinical Correlates

A cross-sectional clinical study using caregiver reports to evaluate sleep in 108 patients with Alzheimer’s disease living at home, who did not have major depression as a confounding diagnosis, found that 13% had occasional to frequent difficulty with night-time sleep and 8% usually or always had difficulty.[29] Considering only the most severe sleep impairments, the most common disturbances were: excessive awakening (2 to 5 times per night; 23%), early morning awakening (11%), excessive day-time sleepiness (10%), and napping for more than an hour a day (14%). Eleven percent of patients in this naturalistic home study regularly used sleep-inducing agents. Certain clinical features of dementia were associated with poor sleep at night-time, most prominently day-time behavioural disturbances. The severity of cognitive impairment, duration of dementia, and severity of impairment in basic activities of daily living were not significantly related to sleep problems in this group of relatively young patients (mean age 71 years). McCurry et al.[5] examined a population-based sample of 205 patients with Alzheimer’s disease living at home. Using caregiver reports of problems occurring at least once a week, these investigators found that hypersomnia and early morning awakening were the most common sleep changes, affecting 40 and 31% of patients, respectively. Night-time awakenings that disturbed family members were present in 24%. Night-time awakenings and reduced total sleep time were the most disturbing to caregivers, but all other sleep problems were also associated with reports of at least moderate distress for caregivers. Sleep disturbance was associated with severity of behavioural problems and, to a lesser extent, with severity of cognitive impairment. Other studies have found that sleep disturbances are associated with more severe cognitive and functional impairment in community-dwelling patients with Alzheimer’s disease, as well as with more rapid cognitive decline.[5,30,31] It is unclear how often this accelerated cognitive decline is the © Adis International Limited. All rights reserved.

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result of sleep deprivation, and therefore potentially reversible with interventions directed at sleep, and how often disrupted sleep, behavioural disturbances and rapid disease progression are correlated markers of particularly aggressive forms of neurodegenerative disease in individual patients. In the later stages of their disease, patients with Alzheimer’s disease may spend up to 40% of their time in bed awake and a significant proportion of their day-time hours asleep.[14,26,32] Further, this increased day-time sleep consists almost exclusively of stage 1 and 2 sleep and does not replace or even remotely compensate for the night-time losses of SWS and REM sleep.[14] There is considerable evidence that sleep disturbance grows more severe with increasing severity of Alzheimer’s disease.[13,15,30,33] However, two crosssectional studies have reported an inverted U-shaped profile, with patients who have moderate dementia showing more impaired sleep than persons who are in the early or advanced stages of disease.[34,35] This moderate stage of the disease is when most other behavioural disturbances occur with peak frequency.[31,36] Shifts in the basic circadian sleep-wake rhythm of patients with dementia can be severe, and in extreme cases may lead to complete day/night sleep pattern reversals. In end-stage Alzheimer’s disease, patients may appear to sleep throughout most of the day and night, awakening only for brief periods. However, as of this time there have been no prospective longitudinal studies of sleep in patients with Alzheimer’s disease, and this remains an important gap in our understanding of both the biology and therapeutics of sleep disturbances in patients with dementia. 1.3 Sundowning

‘Sundowning’ is a commonly used generic term to describe a constellation of increasing behavioural disturbance in patients with dementia late in the day. The prevalence of sundowning has been estimated as 12 to 25% in institutionalised elderly patients, with estimates by in-home caregivers of 24 to 28%.[37] CNS Drugs 2001; 15 (10)

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Sundowning typically begins in the late afternoon or early evening, when other demands on caregivers’ energy reserves are high. It has received little systematic study despite its clinical importance in the care of patients with dementia. Sundowning behaviours can include agitation, reduced ability to maintain attention to external stimuli, disorganised thinking and speech, a variety of motor disturbances such as wandering and pacing, perceptual disturbances such as illusions and hallucinations, and emotional disturbances such as anxiety, fear and anger.[37-41] The temporal pattern of sundowning has been thought to reflect a deterioration in the maintenance of normal diurnal rhythms and/or a manifestation of fatigue. However, sundowning is not universal in dementia; there is increasing evidence that patients vary widely in the timing and robustness of their rhythms of agitation and that these variations may relate directly to the sleep-wake cycle.[20,39,42,43] While sundowning cannot be directly equated with sleep disturbances in Alzheimer’s disease, it can be associated with disrupted night-time sleep;[44] sometimes treatment of the nocturnal sleep problem greatly ameliorates sundowning, but formal studies of this phenomenon are lacking. It is likely that a more detailed understanding of the periodicity with which agitated behaviours occur will ultimately provide clinically useful clues important for the evaluation and management of sleep disturbances in this population. 1.4 Behavioural and Environmental Factors

Sleep quality in non-demented elderly individuals and in patients with dementia has been linked to a variety of behavioural and environmental factors, including bedtime rituals and habits, amount of time spent in bed, ambient light levels, amount of day-time activity, and night-time noise.[20,35] All of these and others factors have been shown to have a potentially negative impact on sleep quality and to be amenable to appropriate intervention is selected patients. This topic is addressed in greater detail in section 3.6.1. © Adis International Limited. All rights reserved.

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1.5 Interactions Between Biological Changes and Environmental Situations

Studies of patients living in institutional settings provide much of the available information about sleep disorders in cognitively impaired patients, where dementia and snoring are the strongest predictors of disrupted sleep (see review by Ancoli-Israel et al.[45]). Environmental factors that promote circadian dysregulation in patients with dementia living in such settings include light, noise, activity schedules, and the needs of staff. Ambient light levels are too low in many congregate care facilities to support natural light–dependent internal rhythms, and noisy conditions, especially during the night, are inimical to sleep for many residents. Activity and staff schedules in many facilities caring for patients with dementia may be driven less by the needs of individual patients than by compliance with federal and state requirements governing nursing home operations. Regulatory requirements in general do not yet incorporate many of the positive evidence-based practices found to be beneficial for residents with dementia, focusing more attention on feeding and bathing schedules, injury prevention, and detection of medical problems than on sleep and other issues related to quality of life. Several studies show fragmentation of restactivity cycles in heterogeneous groups of institutionalised elderly and in patients with Alzheimer’s disease and vascular dementia specifically.[14,37] Detailed studies of sleep in patients with Alzheimer’s disease living at home are rare and thus far have not confirmed this finding.[46] Moreover, the natural history of sleep disturbances and their behavioural correlates in patients with dementia are not well understood. 1.6 Other Causes

Since the majority of persons who develop Alzheimer’s disease are older adults, it is likely that the sleep quality of most patients with the disease is influenced not only by the disease, but by the CNS Drugs 2001; 15 (10)

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factors that are known to contribute to sleep disturbances in non-demented elderly individuals. Since population-based studies examining the incidence and persistence of sleep disturbances in patients with Alzheimer’s disease are lacking, little is known about the risk factors for their development. Consequently one must look to the literature concerning sleep disturbance in elderly persons without dementia, and combine this with clinical assessment of individual patients to make informed inferences to the Alzheimer’s disease population and arrive at effective treatment interventions for individual patients. 1.6.1 Physical Illness

Many elderly persons, whether demented or cognitively intact, have medical conditions that disrupt sleep. There is increasing evidence that sleep disturbances in older adults are more strongly associated with medical and psychiatric comorbidity than with age per se. The multisite longitudinal Established Populations for Epidemiologic Studies of the Elderly (EPESE) project found that sleep complaints in community-dwelling elderly were associated with symptoms of respiratory disease, physical disabilities, nonprescription medication use, and poor perceived health.[47] Further, over a 3-year follow-up, the strongest predictor of remission in reported insomnia was improvement in perceived health.[48] In contrast, untreated insomnia and day-time sleepiness have been associated with nursing home placement and mortality.[49,50] Medically ill older adults admitted to acute care hospitals are particularly vulnerable to sleep disruptions, which appear to be created as much by the various treatments and procedures, unfamiliar routines and environmental conditions, as by the pain, anxiety and discomfort associated with their underlying medical condition.[51] Medical conditions especially likely to disrupt sleep are congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), Parkinson’s disease, gastro-oesophageal reflux disease, arthritis and nocturia. © Adis International Limited. All rights reserved.

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Uncompensated CHF is thought to cause sleep disruption because of nocturnal respiratory distress or recumbent nocturnal diuresis,[52,53] but circulatory factors affecting brain function have not been explored. COPD is associated with both sleep apnoea and REM-related oxygen desaturation, and hypoxaemia caused by either form of sleep-disordered breathing can lead to progression of pulmonary encephalopathy and potentially further impair sleep. In Parkinson’s disease, sleep disturbance affects the majority of patients during the course of the disease, and may be a function of disease severity.[54] Disrupted sleep in Parkinson’s disease is associated with nocturia, pain and stiffness, and difficulty turning over in bed, and may also be caused by levodopa therapy. Moreover, dementia associated with Parkinson’s disease may have independent effects on sleep-regulating centres in the brain. Parkinson’s disease has been found to be associated with REM sleep behaviour disorder (RBD), which can be an early sign of the neurodegenerative process.[55] Substitution of sustained-release levodopa preparations, use of nasal vasopressin to control nocturia, temperate use of benzodiazepines, and, for patients with depression, antidepressant medications, have been suggested as approaches to treating sleep problems in patients with Parkinson’s disease.[56] Gastro-oesophageal reflux disease, one of the most common ‘benign’ conditions of older adults, can disrupt sleep by causing bronchospasm due to reflux of acid stomach contents, and by causing oesophageal discomfort.[57] Nocturnal asthma which is related to gastro-oesophageal reflux disease is easily overlooked in patients who do not have daytime respiratory symptoms. Arthritic conditions can disrupt sleep through several different mechanisms, including increased pain due to joint immobility during sleep, abnormal joint mechanics that make it difficult to find a comfortable sleeping position or to change positions normally while sleeping, and lower ambient temperatures during the night that increase joint stiffness. Decreased elasticity of soft tissues with CNS Drugs 2001; 15 (10)

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age, even in the absence of arthritis, may also contribute to poor sleep quality when diminished movement during sleep further diminishes flexibility and causes discomfort. Awakening to urinate is a symptom frequently endorsed by elderly persons, and in men is commonly attributed to enlargement of the prostate. However, older persons experience pressure to urinate from a variety of causes, including nocturnal diuresis due to excessive night-time fluid intake, CHF or poorly timed diuretic medications, and autonomic sensory disturbances due to anxiety, depression or neurological diseases. Neurological diseases may cause nocturia due to impaired inhibition of bladder sensation and tone, and increased responsiveness of the bladder detrusor mechanisms that initiate micturition. Such ‘upper motor neuron’ impairments of bladder function commonly cause day-time urinary urgency in patients with vascular brain disease and some neurodegenerative disorders that may not be fully suppressed during sleep. However, these disorders have not been well studied to date as causes of sleep disruption in older adults. Excessive night-time waking apparently due to the need to urinate should not necessarily be accepted at face value. In a sample of patients examined in a sleep disorders centre, the great majority of awakenings were found to be due to a primary sleep disorder (sleep apnoea, periodic limb movements or snoring) but were often attributed by patients to a need to urinate.[58] While patients’ reports should be accepted as valid perceptions, it is important to recognise that certain primary sleep disorders, most prominently sleep apnoea with hypoxaemia, are associated with increased autonomic arousal that may account for the sensation of a need to urinate, even when urine volumes are relatively low and might not prompt the need to void during day-time wakefulness. Reports of excessive nocturia (more than 1 to 2 times per night) should prompt close examination for occult medical and neurological causes, including primary sleep disorders.[58] © Adis International Limited. All rights reserved.

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1.6.2 Medications

Many prescription and over-the-counter medications and social drugs (caffeine, nicotine, alcohol) can disrupt sleep.[59,60] However, there are no population-based studies relating insomnia or night-time waking to specific drug classes. Prescribing information for many psychotropic and other drugs often highlights sleep disturbance as a potential adverse effect in individual patients. In those with Alzheimer’s disease, clinical experience dictates that such potential drug effects should always be considered when sleep is disturbed. 1.6.3 Concurrent or Complicating Neuropsychiatric Disorders

Sleep in the elderly may also be affected by psychiatric morbidity. Psychiatric disorders, particularly major depressions, are not only associated with disturbed sleep[61-63] but can also greatly impact both self-report and objective ratings of sleep quantity and quality.[64] Depressive symptoms are common in older adults, especially among persons who are medically ill, bereaved or cognitively impaired, but they are by no means always associated with disrupted sleep. Foley et al.[48] found depressed mood to be one of the strongest correlates of insomnia in the EPESE sample of 6800 older adults, elevating risk to 2.5 times that of persons without depressed mood. However, 72% of new insomnia cases developing over a 3-year period occurred independent of depressed mood, and 73% of patients with depression did not develop insomnia. On the other hand, self-reported sleep complaints have been shown to be a robust predictor of future depression in a large sample of older persons.[65] The prevalence of depression in patients with Alzheimer’s disease seen in clinical settings is estimated at about 50%, roughly evenly distributed between major depression and milder chronic depressive disorders.[66] A recent large populationbased study examining psychopathology in patients with dementia[67] used a caregiver-rated instrument and found that significant depressive symptoms were present in 20% of patients with Alzheimer’s disease and in 32% of those with vasCNS Drugs 2001; 15 (10)

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cular dementia, although these symptoms do not necessarily imply the presence of a major depression. Nevertheless, depression should always be evaluated as a possible contributor to the sleep disturbances encountered in patients with dementia. Other neurobehavioural symptoms and syndromes are at least as important as depression as psychopathological correlates of sleep disturbances in Alzheimer’s disease. A wide range of behavioural and psychological disturbances occur much more often in elderly persons with dementia than in those without dementia.[67] Day-time apathy, depression, anxiety, agitation and aggression, irritability, loss of normal behavioural inhibition, and motor overactivity may all be clinically associated with disturbed sleep, although the mechanisms may differ; no studies to date have explicitly addressed these associations. 1.6.4 Delirium and Other Confusional States

Few studies have examined the interactions between age-related medical illnesses and sleep and night-time disturbances in Alzheimer’s disease. One exception is the known role of delirium in older adults with dementia. Delirium is a neuropsychiatric syndrome characterised by fluctuating levels of consciousness, inattentiveness, perceptual disturbances, cognitive impairment, and changes in the sleep-wake cycle, and, often, behavioural disturbances. Delirium may be caused by specific medical disorders, medications, or acute withdrawal from addictive substances, and its full or subsyndromal forms often contribute to sleep disturbances in acutely or seriously ill older adults. Dementia has been shown to be a principal risk factor for development of delirium among elderly hospitalised patients.[68] Other important correlates of delirium include drug toxicity, acute medical illness, sensory impairment, malnutrition or dehydration, depression, and use of physical restraints.[69,70] By and large, delirium is understood as a syndrome of acute, reversible brain failure for which identifiable causes can usually be found; however, sometimes no definitive aetiology can be identified, and, in some cases, impairment of brain func© Adis International Limited. All rights reserved.

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tion apparently initiated by a delirium becomes chronic and unremitting, particularly in patients with dementia.[71] 1.6.5 Primary Sleep Disorders

In addition to the sleep disturbances that result from normal aging or brain disease, sleep quality may be impaired by primary sleep disorders, some of which themselves may be age-related. Sleep disordered breathing (sleep apnoea), periodic limb movement disorder (PLMD) and RBD are such primary sleep disorders for which there is clear evidence of increasing prevalence with age. Sleep apnoea syndrome is characterised by the repeated cessation of breathing (apnoea) for 10 seconds or longer. This results in multiple episodes of hypoxaemia (often below 80% blood oxygen saturation), multiple brief awakenings, complaints of excessive day-time sleepiness, and impaired daytime functioning. Major risk factors include male gender and obesity. It has been observed that 24 to 62% of community-dwelling older adults have sleep-related breathing disturbances, although the true clinical implications of these observations are unclear.[72] Nevertheless, sleep apnoea should be considered in the differential diagnosis when older adults report poor sleep and when cognitive impairment is discovered for the first time. PLMD is characterised by a rapid, stereotypical, periodic flexion of the leg and foot that is associated with repeated awakenings throughout the night. These repeated disruptions of sleep result in sleep maintenance insomnia. PLMD commonly presents together with restless legs syndrome (RLS).[73] PLMD and RLS are not synonymous. RLS is a clinical symptom while PLMD is a polysomnographic finding. The great majority of individuals with RLS have PLMD, but the reverse is not true. RLS is characterised by a very strong pre-sleep urge to move one’s legs and is often described as a ‘pulling’, ‘searing’ or ‘crawling,’ which can lead to sleep onset insomnia. PLMD, depending on its severity, may or may not have clinical significance. Recently it has been suggested that PLMD is not a disorder per se but a manifestation of sleep disorders such as RLS that CNS Drugs 2001; 15 (10)

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involve dopaminergic impairments.[74] PLMD often occurs in conjunction with sleep apnoea,[75] and has been reported to be present in up to 45% of community-dwelling older adults.[76] PLMD and RLS may be familial, metabolic, vascular or neurological in origin.[73,77] RBD is seen most frequently in older men. RBD is characterised by a relative absence of the atonia characteristic of REM sleep. This lack of atonia permits the physical acting out of dream mentation, particularly dreams involving confrontation, aggression and violence. RBD occurs in both acute and chronic forms. Acute RBD can occur during withdrawal from alcohol or hypnosedatives. RBD has also been induced by tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs) and venlafaxine.[55] The chronic form of RBD may occur as part of an identifiable underlying neurological disorder, but typically is idiopathic. RBD may also be an initial manifestation of parkinsonism.[55] Although it might be expected that the incidence of the primary sleep disorders would increase in patients with dementia because of the CNS dysfunction underlying these disorders, studies comparing the rates of sleep apnoea and PLMD in patients with dementia and age-matched controls have not found consistent differences.[78-81] Nevertheless these conditions may interact with the dementia syndrome to further worsen sleep quality as well as cognitive and functional abilities. For example, some studies have shown that sleep apnoea is associated with increased morning confusion in patients with Alzheimer’s disease (see review by Janssens et al.[82]). 2. Identifying the Cause of Disturbed Sleep

The first steps in successful treatment of a sleep problem in an older patient with dementia are a thorough evaluation of the pattern of sleep disruption and associated psychiatric, behavioural and medical factors, and a broad assessment of possible environmental causes. © Adis International Limited. All rights reserved.

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Detailed clinical assessment requires information from informed and observant caregivers, as patients with dementia are often unable to provide reliable or valid information about their sleep, and sleep problems are frequently caused by several interacting factors. Many patients with dementia whose sleep is abnormal are not aware of it and do not appear distressed by this, while anxious, agitated, psychotic or depressed individuals may experience significant distress and fatigue. Caregivers who must awaken to assure the safety of their patient, or whose sleep is interrupted by nocturnal activity of a wakeful patient, may become seriously sleep deprived themselves. Although patients with more than minimal memory impairment cannot be considered reliable sources of historical information about their sleep, most can provide valid verbal or behavioural responses to specific inquiries (e.g. about pain, sadness, loneliness, anger or irritation) if examined at the time a problem is occurring. This information can be of decisive value in defining causes and treatment options for sleep problems, and caregivers can be taught to elicit it. When the cause of a sleep problem is not obvious, a structured approach to evaluation, using comprehensive assessment tools combined with informant interviews and appropriate laboratory investigations, is the preferred approach to evaluating these problems as well as to other behavioural problems.[83] In home settings, day-time routines, mood and behavioural problems, the quality of interactions with caregivers, and realistic threats to safety must be assessed. For example, conflictual relationships with caregivers may cause, as well as result from, sleep problems in patients. In addition, patients with mild dementia living alone in neighbourhoods no longer safe may sleep poorly due to night-time hypervigilance. In institutional environments, routines of care, staffing patterns and duties, staff-resident interactions, the behaviour of other residents, and the location of residents’ rooms in relation to sources of light and noisy night-time activity should be exCNS Drugs 2001; 15 (10)

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plored as possible contributors to sleep problems in individual patients. Interviews with staff and administrators may provide clues that would otherwise go unnoticed when assessment is limited to clinical features alone. 3. Treatment 3.1 Sleep Disorders Associated with Medical Illness

Identifying medical disorders that cause poor sleep, followed by changes in management to optimise results, is the best initial approach, but may not be sufficient to reverse an associated sleep problem. Simple measures may, however, be highly effective in selected cases. For example, pre-bedtime use of analgesics may greatly improve the sleep of patients awakened at night by pain. Nighttime use of a proton pump inhibitor to block gastric acid secretion can prevent waking due to nocturnal reflux asthma.[84] Avoiding late-evening use of levodopa may ameliorate a sleep problem in patients with Parkinson’s disease.[54] In selected patients with sleep disturbance due to an overactive bladder, careful use of anticholinergic medications that target bladder receptors may reduce waking. However, even the most selective of available anticholinergic agents may have systemic effects that further impair brain function and contribute to night-time waking in patients with dementia. Other possible pharmacological causes of sleep disturbance in the medically ill should also be considered, including the use of high-potency diuretics or drugs with CNS stimulant activity (e.g. caffeine, amphetamines, methylphenidate and newer stimulants) too late in the day, and multiple medications with the potential for pharmacokinetic or pharmacodynamic interactions that can affect brain function and sleep rhythms.[59] 3.2 Sleep Disorders Intrinsic to Dementing Diseases

Oral acetylcholinesterase inhibitors, including donepezil, rivastigmine and galantamine, are cur© Adis International Limited. All rights reserved.

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rently the standard of care for treating cognitive disorders in Alzheimer’s disease, and are increasingly used by specialists in treating a wide variety of dementing diseases. These drugs may improve sleep patterns in some patients. They are believed to act by enhancing cholinergic transmission in the brain. The involvement of both forebrain and brainstem cholinergic nuclei in regulating sleep-wake cycles and arousal, forms the rationale for expecting both positive and negative effects of these agents on sleep. Insomnia, vivid dreaming and bladder stimulation have been observed in a small percentage of patients treated with acetylcholinesterase inhibitors.[85] Animal studies implicate brainstem cholinergic stimulation in the promotion of REM sleep,[86] but studies of acetylcholinesterase inhibitors in healthy volunteers have produced conflicting findings. Tacrine (tetrahydroaminoacridine; an older cholinesterase inhibitor no longer considered a first-line drug for Alzheimer’s disease) shortens REM latency in healthy younger adults in a dose-dependent manner.[87] Rivastigmine has been found to increase REM density without affecting REM latency or SWS.[88] In contrast, galantamine reportedly shortens REM latency, increases REM density and reduces SWS.[89] In patients with Alzheimer’s disease, tacrine was found to have no effect on sleep.[90] However, the newer agents have not been similarly investigated to date in patients with Alzheimer’s disease, the principal group in whom acetylcholinesterase inhibitors are used. An intriguing single-case report describes the successful treatment of severe insomnia and profound day-time apathy in a patient with Alzheimer’s disease with the stimulant, methylphenidate.[91] 3.3 Disrupted Sleep in the Context of Psychiatric or Behavioural Pathology

Pharmacological treatment of mood or behavioural disorders associated with sleep disturbances in patients with Alzheimer’s disease frequently improves sleep patterns, although controlled clinical CNS Drugs 2001; 15 (10)

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trials focusing specifically on this dimension are lacking. In psychotic or severely agitated or aggressive patients, antipsychotics are frequently the drugs of choice. Atypical antipsychotic agents with low potential for causing extrapyramidal signs and symptoms are preferred, and may include risperidone, olanzapine or quetiapine. All of these can be used as single doses at night-time and titrated to clinical efficacy or toxicity. Typical effective dosages for patients with dementia and agitation are risperidone 1 to 1.5 mg/day,[92] olanzapine 5 to 10 mg/day,[93] and quetiapine 25 to 100 mg/day beginning with an initial dose of 12.5 to 25mg at bedtime.[94] For patients with psychosis and sleep disorder associated with Parkinson’s disease, quetiapine or clozapine may be preferred agents; they have useful sedative as well as antipsychotic properties and their potential for increasing parkinsonism is relatively low. However, reports of efficacy and safety of these agents has been mixed (see review by Friedman and Factor[95]). 3.4 Primary Sleep Disorders

If there is reason to suspect that a patient with Alzheimer’s disease may have a primary sleep disorder (usually based on caregiver reports of snoring, breathing cessation or excessive limb movements), referral to a certified sleep disorders centre for diagnostic evaluation is the most appropriate course of action. Treatment of obstructive sleep apnoea includes behaviour modification to minimise sleeping on the back, bodyweight loss for obese patients, avoidance of respiratory depressant drugs (hypnosedatives and alcohol), and the use of nasal continuous positive airway pressure (CPAP).[96] Apnoea can also be treated with a variety of surgical interventions including tracheostomy, although these approaches are typically not first-line treatment[97] and carry significant morbidity and mortality risk.[96] For most cases of clinically significant obstructive sleep apnoea, CPAP remains the treatment of choice. However, adherence to CPAP can © Adis International Limited. All rights reserved.

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be problematic, particularly in patients with dementia; those with significant cognitive impairment may be unable to understand the value of treatment or learn to use or tolerate it, and nocturnal confusion may lead to automatic removal of the device. RLS and PLMD have been successfully treated with benzodiazepines (clonazepam, temazepam) and opiates. However, dopaminergic agents (e.g. levodopa, pramipexole) are the current treatments of choice.[55,98] It has been observed that iron deficiency may be present in a significant percentage of patients with RLS, and could be involved in the development of the condition.[99] Such patients may respond well to iron supplements. One should also be aware that antipsychotics have been shown to cause or at least exacerbate RLS, as well as akathisia.[100,101] RBD is very responsive to clonazepam, although the use of this agent has not been approved by the US Food and Drug Administration.[55] 3.5 Symptomatic Treatment of Insomnia

When insomnia is not caused by, or fails to respond to treatment of, another medical or psychiatric condition, pharmacological treatment with hypnosedatives may be considered as symptomatic therapy. Controversies regarding the use of such medications in patients with dementia revolve around issues of efficacy and potential toxicity, neither of which have been resolved by appropriately comprehensive empirical study. There is evidence, however, that hypnosedatives as a class may be inappropriately prescribed or overprescribed in patients with dementia. A recent 2-year longitudinal study of 76 elderly patients with Alzheimer’s disease or vascular dementia in assisted-living homes found that 24% used regular prescription hypnosedatives at baseline. This proportion remained relatively stable over time, while prescribing of ‘as-needed’ hypnosedatives increased from 3 to 17% after 1 year and to 13% at 2 years.[102] The total number of prescriptions for all drugs also rose over time, indicating an increasing potential for drug interactions due to CNS Drugs 2001; 15 (10)

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polypharmacy. Notably, antidepressant medications were used in fewer than one-fifth of patients, although depressive symptoms were present in over three-quarters. While this descriptive study did not assess the efficacy of medications for sleep, or attempt drug withdrawal to assess the need for continued therapy, the findings suggest that hypnosedative agents are often prescribed without thorough assessment of the elderly patients to whom they are given. A recent study in residents of 18 skilled nursing facilities found that hypnosedatives accounted for 13% of all incidents and 18% of those considered preventable.[103] In a now-classic paper, Avorn et al.[104] reported that the use of hypnosedatives could be substantially reduced by a targeted intervention in nursing homes without apparent deterioration in residents’ clinical status (although detailed data on sleep and dementia diagnosis were not reported). The hazards of excessive sedation for patients with dementia, including increased impairment in cognition, gait and balance, and the consequent risk of falls, have been widely publicised but have been surprisingly poorly studied. Presumably, currently available hypnosedatives of either the benzodiazepine or non-benzodiazepine classes are effective, at least in part, because of diffuse effects on brain activity mediated through benzodiazepine receptors that are widely distributed in the brain, rather than by specific effects on a putative ‘sleep centre’. Because of this, the common adverse effects of both classes of hypnosedatives are part and parcel of their impact on sleep. Several recent studies have shown that the use of prescription drugs does not necessarily improve subjective and objective ratings of sleep quality in community-dwelling or institutionalised older patients.[105-108] However, no controlled clinical trials have evaluated the efficacy or toxicity of benzodiazepines or the newer non-benzodiazepine, imidazopyridine hypnosedatives (such as zolpidem or zaleplon) in groups of patients with dementia. The properties of these newer agents have recently been compared with benzodiazepine hypnosedatives in © Adis International Limited. All rights reserved.

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a comprehensive review.[109] Evidence suggests that there may be significant differences between these newer hypnosedatives, with zaleplon producing less adverse effects on psychomotor and cognitive function than zolpidem (or benzodiazepines) in doses equipotent for sleep.[109] In a report of two patients with especially severe insomnia (sleeping an average of only 2 to 3 hours/night) and night-time wandering unresponsive to benzodiazepines, trazodone or antipsychotics, zolpidem was found to be effective and well tolerated during an uncontrolled 3-month trial.[110] In a study designed to define the effect of sedation with diazepam (for neuroimaging studies of patients with dementia), cerebral glucose metabolism was found to be reduced by an average of 20%,[111] a finding that suggests risk of increased cognitive impairment. In another study, seven patients with Alzheimer’s disease reported by their caregivers to have frequent night-time awakenings were treated with placebo and triazolam 0.125mg at bedtime in an A-B-A design.[112] Active drug therapy had no effect on sleep latency, total sleep time, number of arousals or day sleep time, and also had no significant effects on a memory task. This suggests that the standard geriatric dose of this agent is not an effective hypnosedative for patients with Alzheimer’s disease. Many sedating agents are currently in use for treating dementia-associated sleep disorders, all unproven in rigorous clinical or laboratory sleep research. Trazodone, in doses far below those required for the treatment of major depression, e.g. 25 to 100mg at bedtime, has become popular as a night-time sedative and is also commonly used to manage day-time agitation. However, caution is required in considering the use of trazodone in men because of its rare but potentially serious adverse effect of priapism. The use of anticholinergic antidepressants such as amitriptyline or doxepin to promote sleep in institutionalised older adults, including those with dementia, remains widespread,[113] despite the demonstrated susceptibility of patients with Alzheimer’s disease to increased functional impairCNS Drugs 2001; 15 (10)

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ment when exposed to even small increases in anticholinergic loads.[114] Antihistamines such as diphenhydramine, used for its sedative effects, also have significant anticholinergic activity. Federal nursing home regulations now explicitly caution against, but do not prohibit, the use of sedatives with anticholinergic effects to induce sleep. Mirtazapine, a newer antidepressant without anticholinergic effects, has become popular in low doses in clinical practice for its sleep-promoting effects, which are believed to be due to central histamine receptor blockade. The absence of controlled clinical trials of symptomatic treatments for insomnia in patients with dementia represents a serious and continuing gap in knowledge. Antipsychotic agents have long been considered important pharmacological treatment options for patients with Alzheimer’s disease who are agitated, sundowning behaviour and sleep disturbance. Recent randomised controlled trials of newer agents[92,93] have demonstrated efficacy for a number of behavioural disturbances often associated with sleep disorders. Unfortunately, these studies did not report sleep outcomes; however, somnolence was a relatively common adverse event encountered in these trials. There is no indication for the use of antipsychotic agents in sleepdisordered patients with Alzheimer’s disease who do not also have significant behavioural disturbances. Melatonin, the ‘sleep hormone’ secreted by the pineal gland, is widely available as a popular overthe-counter sleep aid. This is appealing as a ‘physiological’ sleep inducer but it is still under investigation. Research on the therapeutic efficacy of melatonin for sleep disorders has emphasised that different marketed preparations labelled as equivalent may contain highly variable amounts of or no active melatonin. This highlights the need for strict quality control in evaluating claims for and against its efficacy. When quality-controlled preparations are used in well-designed studies, timed administration of melatonin can shift circadian periods independent of light,[115] have soporific effects when given during the day, and mediate alignment of © Adis International Limited. All rights reserved.

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internal sleep drive with the diurnal rhythms expected in modern human society.[116] In small studies of patients with Alzheimer’s disease, endogenous melatonin levels are reportedly lower than in age-matched individuals without dementia, which are in turn lower than in young adults.[117] In patients with dementia who experience disrupted sleep, the effects of melatonin have been examined in uncontrolled trials (e.g. CohenMansfield et al.[118] and Jean-Louis et al.[119]). In one such trial, doses of 3 to 9mg given at bedtime to patients with Alzheimer’s disease of variable severity appeared to improve sleep, perhaps reduce evening agitation, and in some individuals allowed discontinuation of medications prescribed to treat agitation.[120] 3.5.1 Ethical Issues in the Use of Sleep-Promoting Medications in Dementia Who is the Patient?

Growing interest in the ethics of research and treatment of patients with impaired decisional capacity[121] has focused attention on distinctions between interventions that positively affect the patient’s quality of life and those administered to patients to make caring for them less difficult. Much of the debate has centred on nursing home residents, where federal regulations have been extended to limit the use of hypnosedatives and antipsychotics. It is generally accepted that medications for sleep should not be given merely to quieten a patient for the comfort of others. However, in practice, decision making must often consider the needs of caregiving families, and, in institutional settings, the needs of other patients and professional caregivers. When a patient with dementia has a sustained sleep disorder that interferes with the sleep of others but has no discernible effect on the patient himself/herself, nursing home placement or forced discharge from an assisted-care facility are real risks that may damage optimal outcomes, at least when a move is otherwise not in the patient’s best interest. Debate on this issue has not been resolved by scientific study of the trade-offs between patient and caregiver well-being when sleep-inducing CNS Drugs 2001; 15 (10)

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medications are used in these situations. However, the association between day-time behavioural disturbances and night-time sleep disruption is sufficiently strong that, for the majority of patients, treatment decisions need not be framed in such stark terms. Growing evidence for the efficacy and safety of specific medications for agitation, aggressive behaviour, psychosis and depression in patients with dementia (e.g. see study by Katz et al.[92]) that are often associated with disrupted sleep, supports the value of treatment of the psychopathology; unfortunately, the available studies have not examined sleep outcomes. The major ethical dilemma arises when sedative drugs are substituted for adequate day-time stimulation, activity and other nonpharmacological interventions with the potential to promote more normal sleep patterns. Recognising the risks of medication therapy as the mainstay of insomnia treatment in the elderly, the National Institutes of Health have formally encouraged the use of sleep hygiene measures in cases where sleep problems are not clearly traceable to a treatable medical or psychiatric condition.[122] Long-Term Drug Therapy for Chronic Insomnia

Experts in sleep medicine do not agree on whether long-term drug treatment of primary insomnia is effective and safe,[123-126] and the field has been dominated more by doctrine than data. If reliable data are sparse regarding the population at large, they are sparser still regarding the treatment of older adults with dementia. Buysse[127] has recently critically examined the state-of-the-art regarding the nature and treatment of chronic insomnia, proposing a clarifying view that may be applicable to studies of sleep in patients with dementia. He distinguishes insomnia as a symptom or complaint, and insomnia as a disorder or disease that causes functional impairment, and highlights evidence that otherwise healthy patients with insomnia have significant abnormalities in physiological function beyond the domains of complaint and sleep reduction. He constructs an approach to thinking about insomnia that calls for new avenues of research, for which the corner© Adis International Limited. All rights reserved.

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stones are development of neuropsychobiological models of insomnia, a reliable and valid nosology, and a sequential programme of intervention research beginning with nonpharmacological treatments and followed by drug therapies for nonresponders.[126] This agenda and the paradigm that supports it provide a helpful framework for learning about and treating sleep disorders in patients with Alzheimer’s disease. 3.6 Nonpharmacological Interventions

In situations where a sleep disturbance is not wholly the result of age-related sleep changes, a primary sleep disorder, or a specific medical or psychiatric disorder or complication of dementia, sleep may become chronically disrupted through the development of poor sleep habits, conditioned emotional responses or poor environmental conditions. These problematic habits and responses interfere with normal regulatory sleep mechanisms and may serve as inhibitors to sleep. A number of behavioural and environmental modification strategies, including sleep hygiene, sleep compression, relaxation training, stimulus control and multicomponent cognitive-behavioural therapy, have proven effective for enhancing sleep in older adults without dementing diseases, and some of their components can be helpful in patients with dementia. There is also an emerging body of literature indicating that light and exercise may also have a beneficial impact on sleep quality in both the healthy elderly and those with dementia. Overall, there is good evidence that nonpharmacological treatments can improve sleep quality and reduce the use of sleep medication in older adults (e.g. see study by Morin et al.[128]). However, the practising physicians most often responsible for treating patients with Alzheimer’s disease do not generally recommend these measures as the first intervention.[129] 3.6.1 Behavioural Interventions

Behavioural approaches are often recommended to alleviate sleep disturbances in both the healthy, sleep-disturbed elderly individuals and CNS Drugs 2001; 15 (10)

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those with dementia. Such approaches are appealing because they are inexpensive, readily available, and free of adverse effects. They are also theoretically compatible with behavioural interventions that have been used successfully to treat other dementia-related problems, such as depression and disruptive behaviours. Given their wide use and efficacy in older adults without dementia, it is not surprising that behavioural approaches are often recommended to alleviate sleep disturbances in patients with dementia, particularly when aimed at reducing day-time sleep and improving the sleep environment and routine. Studies have shown that time spent in bed during the day, institutional noise and light, and night-time incontinence care practices are important correlates of sleep disturbances in institutionalised older adults.[130-132] In a recent review, Alessi and Schnelle[133] concluded that improvement of the nursing home environment may be critical for the alleviation of sleep disturbances for nursing home residents. There is also increasing attention being paid to how physical environment, institutional routines and the quality of patient-staff interactions contribute to patient agitation and other behaviour problems in long-term care facilities.[134-137] Although this research has not been specifically focused on patient sleep per se, it is reasonable to expect that interventions designed to reduce agitation might also impact on sleep quality.

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There is growing interest in the use of timed light exposure for the treatment of insomnia in older adults. A number of studies have examined whether increasing light exposure will improve sleep in institutional settings (see review by McCurry et al.[143]). Results have been promising; light therapy has been shown to increase total nocturnal sleep time, decrease day-time napping and reports of behavioural outbursts, and increase the stability of rest-activity rhythms on actigraphic reports. However, while early data are encouraging, further research is needed to accurately assess the efficacy of bright light therapy for treating sleep disturbances in institutionalised patients with dementia. Even less is known about the impact of timed bright light exposure on the sleep and night-time behaviour of community-dwelling patients with Alzheimer’s disease. While timed bright light exposure may help to improve sleep in patients with dementia, the one published study of light intervention in a typical home care setting failed to demonstrate improvements in sleep.[144] Light therapy interventions are demanding and compliance problematic even for motivated unimpaired elderly persons. Ultimately such interventions, although potentially efficacious, may prove to be impractical or too burdensome and expensive for use in community-dwelling patients with Alzheimer’s disease. 3.6.3 Exercise

3.6.2 Light Therapy

Many older adults are exposed to insufficient daily levels of ambient light to maintain stable sleep-wake circadian rhythms.[138,139] Lower levels of light are associated with decreased amplitude of the activity-rest cycle and more wakefulness at night.[140] Studies have shown that patients with dementia may be particularly underexposed to sufficient levels of bright light to maintain stable sleep-wake rhythms, with typical exposures to bright light being limited to 30 minutes or less a day for community-dwelling patients and less than 6 minutes a day for institutionalised patients with Alzheimer’s disease.[141,142] © Adis International Limited. All rights reserved.

Numerous studies have examined the effects of exercise on sleep in the elderly. Although the results are far from definitive, research indicates that sleep quality improves with improved physical fitness, suggesting that sleep in elderly persons may be enhanced by participation in routine exercise.[145,146] Although patients with dementia vary widely in their ability to follow a structured exercise programme, studies have shown that such individuals can participate in supervised, low-intensity exercise programmes.[147-151] Alessi and colleagues[152] recently reported that a combination of light physical exercise and other behavioural strategies (e.g. keeping patients out of CNS Drugs 2001; 15 (10)

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bed in the late afternoon and evening, or providing quiet and non-intrusive night-time incontinence care) produced significant improvements in sleep quality. Furthermore, there is evidence that highintensity activity is not needed to produce improvements in some sleep parameters. Naylor et al.[153] found that a programme of daily (morning and evening), structured social and physical activity in persons without dementia who were living in nursing homes increased sleep quality compared with elderly controls who did not take part in such a programme. Thus, reinforcement of regular social patterns of activity may be as important to sleep quality in the elderly as enhancement of aerobic capacity. Less attention has been paid to specific forms of exercise (e.g. stretching) and physical manipulation (e.g. massage) that are aimed at improving flexibility and reducing pain due to stiffness of soft tissues, rather than at improving fitness. Nevertheless, clinical experience indicates that both may improve comfort in patients with impaired mobility due to neurodegenerative diseases and may improve sleep. 3.6.4 Other Approaches

In addition to these physical but nonpharmacological approaches to improving sleep quality, other changes in day-time routine may be useful. Structured group adult day programmes tailored to the cognitive abilities and needs of patients with dementia have been shown to reduce anger, depression and other signs and symptoms of burden in caregivers,[154] and may therefore indirectly improve patients’ behaviour at home. As yet, findings from this study regarding changes in behaviour and sleep of patients with dementia have not been published, but observations of patients in ongoing clinical care for dementia suggest that participation in adult day programmes can help to reduce behavioural problems at home and normalise sleep patterns, particularly when day-time apathy and understimulation result in excessive day-time sleep. In summary, the findings reviewed suggest that the interactions between ambient light, physical exercise, structured day-time social activity, and © Adis International Limited. All rights reserved.

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sleep quality in patients with dementia warrant further study. Thus, despite literature recommending their use, and evidence that nonpharmacological interventions may be important in improving the sleep of both community-dwelling and institutionalised older adults, there is to date no information regarding the feasibility or efficacy of these treatments with community-dwelling patients with Alzheimer’s disease. 4. Conclusions

Evaluating and treating disturbed sleep in a patient with Alzheimer’s disease, while often complex, is ultimately rewarding. It requires an appreciation of the many ways that sleep can be disturbed in such individuals and the willingness to parse what those casual agents might be and marshall the most effective treatment for each of them. Effective assessment of sleep disturbances in patients with dementia can only be done in the context of associated medical disorders, current drug treatments, psychopathology, primary sleep disorders, and behavioural and environmental conditions. Thorough assessment of sleep problems takes time and may require serial evaluations and information from multiple sources. Accurate identification of underlying causes, their effective treatment, attention to behavioural and environmental conditions and, where possible, their correction coupled with appropriate and judicious pharmacotherapy when necessary, will best address most sleep disturbances in patients with Alzheimer’s disease. However, what is clear from this review is that the literature available to guide effective treatment of sleep disturbances in patients with Alzheimer’s disease is woefully insufficient. Major gaps in the literature exist. These include: • studies of longitudinal changes in sleep during the course of dementia • randomised controlled trials of treatments for behavioural disturbances using measures of sleep, day-time function and impact on caregivers, in addition to behavioural and psychiatric outcome measures CNS Drugs 2001; 15 (10)

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• randomised controlled trials to assess the comparative efficacy of specific pharmacological and nonpharmacological approaches to sleep management • studies of the long-term efficacy and safety of newer hypnosedative agents in patients with dementia who have sustained sleep disorders • an understanding of the impact of improved sleep quality on the cognitive function of patients with dementia • empirical validation of algorithms for assessing and managing sleep in patients with dementia • controlled health services trials of the effect of changes in institutional policies on residents’ sleep. Only once these gaps are filled can a definitive guide to treating sleep disturbances in patients with Alzheimer’s disease be written. Acknowledgements The authors wish to thank Ms. Erin Madar for her expert assistance in preparation of this manuscript. Dr Vitiello is supported by Public Health Service Grants KO2-MH01158, RO1-MH53575, RO1-AG12915, MO1-RR37 and the Department of Veteran’s Affairs. Dr Borson is supported by Public Health Service Grant PO1-AG 05136. The authors have no conflict of interest that are relevant to the contents of this article.

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Correspondence and offprints: Prof. Michael V. Vitiello, Department of Psychiatry and Behavioral Sciences, Box 356560, University of Washington, Seattle, WA 98195-6560, USA. E-mail: [email protected]

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