Myoclonus epilepsy with ragged-red fibers
Jun. 10, 2021
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Disordered sleep and dementia are 2 neurologic issues that are found in many of the same patients and may indeed interact. Insomnia, hypersomnia, circadian rhythm disorders, and sleep-disordered breathing are more prevalent in dementia patients than in age-matched controls. REM sleep behavior disorder can herald a synucleinopathy, such as dementia with Lewy bodies or Parkinson disease. The treatment of excessive daytime sleepiness and insomnia in dementia patients is not well described because many medications have risks that outweigh their benefits. Nevertheless, REM sleep behavior disorder has been shown in clinical trials to respond to both clonazepam and melatonin. Continuous positive airway pressure therapy can improve cognition in some cases of obstructive sleep apnea.
• Various sleep problems such as insomnia, hypersomnia, circadian rhythm disorders, sleep-disordered breathing, and REM sleep behavior disorder are more prevalent in patients with dementia than in age-matched controls.
• In the preclinical stages of Alzheimer disease, excessive daytime sleepiness and poor sleep efficiency appear to be associated with greater cerebral beta-amyloid burden, as measured by amyloid PET imaging. Excessive daytime sleepiness is also associated with greater cerebral Lewy body burden, as documented in autopsy studies.
• Polysomnography is valuable as a diagnostic tool in dementia patients with sleep disorders, as relatively common sleep disorders, such as obstructive sleep apnea and REM sleep behavior disorder, are diagnosed based on the sleep study results.
• Bright light therapy, walking with family members, and melatonin have all been used effectively to manage the sundown syndrome and poor sleep quality, which are relatively common complaints in patients with dementia with Lewy bodies, Alzheimer disease, Parkinson disease, and other dementing illnesses.
• REM sleep behavior disorder is more common in patients with synucleinopathies such as dementia with Lewy bodies and Parkinson disease. In combination with excessive daytime sleepiness, idiopathic REM sleep behavior disorder is a predictor for mild cognitive impairment and motor dysfunction after 6 to 12 years of follow-up.
• Melatonin and clonazepam are both effective in reducing symptoms of REM sleep behavior disorder. Melatonin can improve sleep quality in patients with mild to moderate Alzheimer disease.
Sundown syndrome. “Sundowning,” or the nocturnal exacerbation of delirium, agitation, and aggressiveness has been recognized since the time of Hippocrates. Cameron first explored sundowning experimentally and reported that dementia patients brought into a dark room during the daytime were likely to become agitated and confused (17). The terms “sundown syndrome” or “cognitive fluctuations” are now broadly used to describe a set of neuropsychiatric symptoms that begin in the afternoon or early evening, including confusion, inattention, anxiety, pacing, wandering, and resistance to redirection (125; 67; 18; 71).
Hypersomnia. Excessive daytime sleepiness is common in the synucleinopathies, such as Parkinson disease and dementia with Lewy bodies (136), or it can be caused by sleep disordered breathing (89; 92). In Parkinson disease, hypersomnia can be related to the disease process itself, advanced age, dopaminergic medications, or to other sleep disorders such as restless legs syndrome (137; 60).
Insomnia. Chronic insomnia is the most prevalent sleep disorder in the general population (104). It is manifested by difficulty in getting to sleep, staying asleep, and in reduced quality of sleep with daytime consequences. Parkinson disease and insomnia can be aggravated by mood disorders, tremors, and nocturia (136).
REM sleep behavior disorder (RBD). This condition is either primary or secondary. Idiopathic REM sleep behavior disorder was initially described in humans in 1985 (101). It is manifested by violent behaviors, dream re-enactment, vocalizations, or involuntary leg movements during rapid eye movement (REM) or dreaming sleep. Secondary REM sleep behavior disorder has been strongly linked to a set of neurodegenerative disorders known as the synucleinopathies, which include Parkinson disease, dementia with Lewy bodies, and multiple system atrophy (03; 34; 57).
Restless legs syndrome (RLS). This condition is either primary or secondary. Patients with restless legs syndrome feel the urge to move their legs whenever they sit down or lie down. Idiopathic restless legs syndrome does not predispose patients to develop Parkinson disease or 1 of the synucleinopathies in the way that REM sleep behavior disorder does (87). Secondary restless legs syndrome occurs in 21% of Parkinson disease patients. Compared to idiopathic restless legs syndrome, it begins later in life, is less likely to be associated with a positive family history, and is less likely to be associated with a low serum ferritin level (87).
Sleep-disordered breathing. Symptoms of obstructive apnea or sleep-disordered breathing can vary from significant snoring with frequent arousals to complete airway obstruction with apneas. There has been mixed evidence in the past concerning the association of sleep-disordered breathing with dementia because it is hard to know about the directionality of the association (Plassman et al 2007; 05; 30; 28; 70). The difficulty with the older studies was their cross-sectional design. Prospective studies have documented a cause and effect relationship between sleep-disordered breathing, intermittent hypoxemia, and the risk of mild cognitive impairment and dementia (135; 89).
Sundown syndrome. Caregivers often complain that dementia patients can become acutely confused and agitated, and that they tend to wander, particularly during the early evening hours (sunset) or at night (67; 18; 62). Evidence demonstrates that sleep-wake disruption (sundown syndrome) can occur early in the course of Alzheimer disease and may even precede the development of cognitive symptoms (84). Cognitive fluctuations are a diagnostic core feature of dementia with Lewy bodies and they also occur in Parkinson disease (120; 81). Severe cognitive fluctuations in patients with dementia are often associated with impaired ability to engage in activities of daily living (117). Some patients with disrupted circadian rhythms can have complete reversal of their 24-hour rest-activity pattern, so that they are active all night and sleepy all day (71).
Hypersomnia. Excessive daytime sleepiness can be secondary to the dementing illness itself or be a symptom of obstructive sleep apnea (92). In a large longitudinal study of Parkinson disease, 12% of patients had excessive daytime sleepiness at baseline, then the frequency of excessive daytime sleepiness rose to 23% after 5 years of taking anti-Parkinson medications (Tholfsen et al 2015). In decedents enrolled in the Honolulu-Asia Aging Study, excessive daytime sleepiness was most prevalent among those who had severe Lewy body pathology (02). In the Baltimore Longitudinal Study of Aging (mean age of normal adults at baseline = 60 yrs), excessive daytime sleepiness was associated with 2.75 times the odds of beta-amyloid deposition in the brain by the time of the 15-year follow-up visit (data were adjusted for age, sex, education, and BMI) (112).
Insomnia. The diagnosis of insomnia should include a 2-week sleep log and an Epworth Sleepiness Scale to identify comorbid sleep-disordered breathing or other medical conditions (104). In a large systematic review, insomnia increased the risk of Alzheimer disease, but not vascular or all-cause dementia (106). In a large, case-control study of 51,734 patients with primary insomnia and 258,715 patients with nonprimary insomnia as a reference group, the primary insomnia patients had more diabetes, hypertension, and chronic kidney disease (50). After adjusting for these comorbidities, the primary insomnia group continued to be at greater risk for dementia (HR=2.14; 95% CI, 2.01-2.29) (50).
REM sleep behavior disorder. This condition is manifested by the loss of normal muscle atonia during REM sleep, and it presents with dream re-enactment. In acting out their dreams, REM sleep behavior disorder patients can either fall out of bed, scream, talk, or have loud vocalizations (19). It may be the first presenting clinical sign of a synucleinopathy (dementia with Lewy bodies, Parkinson disease, or multiple system atrophy). Inclusion of REM sleep behavior disorder improves the diagnostic accuracy of autopsy-confirmed cases of dementia with Lewy bodies (34), and it is now 1 of the 4 core diagnostic features of this disease (81). The majority of patients with REM sleep behavior disorder will go on to develop symptoms of a synucleinopathy, and on autopsy, roughly 90% will have signs of a synucleinopathy (14; 100; 81). In a longitudinal study of older patients with idiopathic REM sleep behavior disorder, 27.9% went on to develop a neurodegenerative disease after 6 years and those with excessive daytime sleepiness were twice as likely to make that conversion (137).
Restless legs syndrome. This condition manifests itself by the urge to move the legs, as well as by an uncomfortable prickling or crawling sensation in the legs (48). These feelings usually develop when the person sits down or lies down and can be relieved by standing up and pacing about the room. During sleep, the restless legs syndrome patient also experiences periodic movements of sleep (these are slower movements than either chorea or myoclonus). Primary restless legs syndrome is familial in more than 50% of cases. Secondary restless legs syndrome can be due to neuropathy, COPD, iron deficiency anemia, Parkinson disease, or chronic renal failure. Antihistamines and antidepressants can make restless syndrome symptoms worse. Nocturnal smoking is more prevalent among those with restless legs syndrome than controls (95).
Sleep-disordered breathing. This condition, which is characterized by recurrent arousals from sleep and intermittent hypoxemia, is common in older adults and affects 50% to 60% of elderly populations (89). Patients with obstructive sleep apnea often present with memory complaints and problems with attention and executive function (68). The cognitive problems of those with sleep-disordered breathing may vary, according to older age, severity of apnea, and lower level of education (43; 44). In a prospective study of older women, those with sleep-disordered breathing had an increased risk of developing mild cognitive impairment or dementia, compared to those without sleep-disordered breathing (135). A systematic review and a large cohort study have both revealed that sleep-disordered breathing was associated with a higher incidence of Alzheimer disease (106; 70).
Sundown syndrome. In 1 group of 215 mild to moderate Alzheimer patients, diurnal rhythm disturbances were shown to correlate with aggressive behaviors, as measured by the BEHAVE-AD rating scale (82). Cognitive fluctuations are not only a management challenge but can lead to fluctuations in a patient’s decision-making capacity (120). No study to date has prospectively examined the changes in circadian rhythms that occur with the progression of Alzheimer disease (71).
REM-sleep behavior disorder. About 81% of older men initially diagnosed with idiopathic REM sleep behavior disorder were later diagnosed with either Parkinson disease or dementia with Lewy bodies (100). In an autopsy series, 90% of cases initially diagnosed with iRBD showed histological evidence of synucleinopathy, primarily diffuse Lewy bodies (14). Additionally, REM sleep behavior disorder is an important predictor of mild cognitive impairment and dementia in Parkinson disease patients (04; 57). Ways to identify iRBD patients who are likely to transition to secondary RBD (Parkinson disease or dementia with Lewy bodies) are to measure: a) reduced autonomic function, b) reduced uptake of presynaptic dopamine transport on a DAT scan, c) mild cognitive impairment, d) olfactory deficit, or e) color vison abnormalities (72; 94).
Sleep-disordered breathing. In a large 5-year study of community-dwelling men and women in the United States, the presence of sleep-disordered breathing was associated with a younger age of onset of mild cognitive impairment (mean = 72.6 years), compared to the mean age of onset in the comparison group that had no sleep-disordered breathing (x=83.7 years) (89). In a large population-based study of older adults in Switzerland who underwent complete sleep evaluation, those with cognitive impairment had more sleep-disordered breathing, higher apnea/hypopnea indices, and higher oxygen desaturation indices (45). Among 101 hospitalized geriatric patients with mild dementia, 47.6% had moderate-severe signs of sleep-disordered breathing and only 12.2% showed absence of sleep-disordered breathing on overnight polysomnograms (44). Those with sleep-disordered breathing were more likely to have medical comorbidities such as congestive heart failure.
A 73-year-old man complained of violent dream-related behaviors where "I go through the motions of what I'm dreaming about" (29). His wife also reported that he "flopped" his legs throughout the night and had problems with nocturnal choking.
His past medical history included a myocardial infarction, and the family history was positive for heart disease. The exam revealed evidence of recent blunt trauma with right infraorbital hematoma that he suffered during a dream, subsequently running into some furniture.
Polysomnography, with time-synchronized video recording, revealed significant periodic limb movements and an unusual increase in muscle activity during REM sleep (REM sleep without atonia). On 1 occasion during REM sleep, he exhibited running movements, after which he awoke and immediately reported having a dream where "I was chasing cattle."
The patient was diagnosed with REM sleep behavior disorder, and his violent dreams completely resolved after taking clonazepam, 1 mg po qhs. Over the next 8 years, he experienced significant cognition decline and developed a shuffling gait. Formal neurocognitive tests documented mild-to-moderate dementia. He was diagnosed with Parkinson disease, and he was treated with levodopa-carbidopa. Eventual daytime hallucinations and falls necessitated his institutionalization. The patient subsequently died from unspecified reasons before he could undergo a scheduled polysomnography to address growing concerns of obstructive sleep apnea.
Alzheimer disease. In this type of dementia, neuronal death is thought to occur as a result of the diffuse accumulation of amyloid-beta and tau protein in the cerebral cortex (09). In mild to moderate Alzheimer patients, increased daytime sleepiness and insomnia have been reported in as many as 25% to 40% of patients (82). Those who have amnestic mild cognitive impairment (early Alzheimer disease) have changes in sleep patterns recorded on electroencephalography, with lower sleep efficiency, less time spent in slow-wave sleep, less time spent in REM sleep, and longer REM sleep latencies (26; 91). Chen and colleagues showed that in those who have amnestic MCI or Alzheimer disease, sleep duration was either shorter (less than 6 hours/night) or longer (greater than 8 hours/night) than that recorded in normal age-matched controls (7 hours/night) (20). Weissova and colleagues demonstrated that Alzheimer disease patients who still lived at home took more daytime naps than age-matched controls and had dampened melatonin profiles (127). In the Framingham Heart Study (mean age = 72 yrs), transitioning to a longer sleep duration (greater than 9 hours/night) over 13 years was associated with an increased risk of developing Alzheimer disease (HR=2.20; 95% CI=1.17-4.13) (128). In Korean elderly subjects, longer sleep duration (greater than 8 hours/night) was demonstrated to be a predictor for future mild cognitive impairment in a 4-year follow-up study (114). In a systematic review of 7 studies, longer sleep duration increased the risk of Alzheimer disease by 63% (HR=1.63; 95% CI=1.24-2.13) (33). In a large (n=3140) Greek study of elderly participants using 3-day actigraphy, longer total daily sleep time (mean=8.2 hours) was recorded in Alzheimer dementia patients whereas shorter periods were noted in those with mild cognitive impairment (mean=7.3 hours) and cognitively normal age-matched controls (mean=7.4 hours) (10). Within the amnestic mild cognitive impairment group, those that slept longer had more cognitive impairment.
In 1 prospective cohort study of 698 older adults without dementia, better sleep consolidation was a factor that could attenuate the presence of an APOE-e4 allele on the risk of future Alzheimer disease and on the severity of neurofibrillary tangle (tau protein) density later found at autopsy (74). Studies in community-dwelling older adults have shown a greater cerebral amyloid burden in those who have lower sleep quality, whether the amyloid burden is measured by amyloid PET imaging (113), or by CSF A-beta 42 levels (58). When MRI markers and sleep habits were analyzed in the large (n=457) Lothian birth cohort in Scotland (mean age=76 years), increased perivascular spaces on MRI (a marker for decreased waste clearance) were demonstrated to be associated with interrupted sleep patterns (06). Longitudinal studies are needed.
Alzheimer pathogenesis. In live adult mice, natural sleep leads to an increased clearance rate of CSF levels of beta-amyloid (133). In a mouse model of Alzheimer disease, sleep deprivation leads to a decrease in tau phosphorylation and synaptic integrity, as well as a decrease in memory performance (27). Cognitively normal people with obstructive sleep apnea have higher CSF levels of phosphorylated tau, and their apnea hypopnea indices (AHI) correlate with serum levels of beta amyloid (16). Healthy adults who have their slow wave sleep purposely interrupted have increased levels of CSF beta-amyloid, suggesting that sleep may play a role in Alzheimer pathogenesis (76; 59). In live adult mice, natural sleep leads to an increased clearance rate of CSF levels of beta-amyloid (133).
Vascular cognitive impairment. Some authors have suggested that “vascular dementia” be subclassified into subtypes, which include post-stroke dementia, mixed Alzheimer and vascular dementia, subcortical vascular dementia, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (105). Others advise using the term “vascular cognitive impairment” to include the continuum of cognitive disorders from mild cognitive impairment to dementia in which 1 or more types of vascular brain injury (large vessel infarcts, small vessel infarcts, subcortical white matter changes, etc.) involve regions that are important for memory, executive function, and other cognitive skills (56; 51). The most severe form of vascular cognitive impairment (vascular dementia) causes cognitive deficits that are sufficient to disrupt instrumental activities of daily living. There must be signs of vascular brain injury on MRI to meet the criteria for vascular dementia. Moderate to severe obstructive sleep apnea has been positively associated with multiple neuroimaging indicators of subcortical vascular dementia: white matter hyperintensities, cerebral microbleeds, and enlarged perivascular spaces (110).
Synucleinopathies. The addition of REM sleep behavior disorder to the 3 non-dementia symptoms of dementia with Lewy bodies (parkinsonism, fluctuations of alertness, and visual hallucinations) improves the diagnostic accuracy of autopsy-confirmed cases (34; 81). REM sleep disorder is also an important early nonmotor symptom of Parkinson disease and multiple system atrophy (100). In Parkinson disease, the frequency of insomnia complaints increases somewhat over the first few years (31% at baseline, then 49% at 1 year) (118). The sleep maintenance subtype of insomnia in Parkinson disease steadily increases with time, whereas the sleep initiation subtype of insomnia falls. The presence of REM sleep disorder in Parkinson patients predicts faster motor and cognitive decline (90). It is also associated with greater alpha-synuclein and amyloid pathology.
Frontotemporal dementia. This dementia subtype is due to accumulation of the tau protein in neurons in frontal and temporal lobes of the brain. Sleep disorders such as chronic insomnia and excessive daytime sleepiness are common problems for patients who have frontotemporal dementia (79). REM sleep behavior disorder is rare in this condition, which may be confused with a circadian rhythm disorder, such as the sundown syndrome. Neuropsychiatric symptoms are required to make the diagnosis of the behavioral variant of frontotemporal dementia (23).
Genetics. Two genome-wide association studies had previously suggested that chronic insomnia and restless legs syndrome might share a common genetic basis, but another study demonstrated that there were significant differences between those who have chronic insomnia and those insomnia patients who also have restless legs syndrome (32). This study suggested that the MEIS1 genotype was only associated with restless legs syndrome.
Neurotransmitters. The neural mechanisms underlying insomnia, sleepiness, and delirium in dementia are complex and may involve activation of dopaminergic, serotoninergic, glutamatergic, and gamma-aminobutyric (GABA) systems, as well as activation or inhibition of the cholinergic system (37). Degeneration affecting the GABA “sleep switch” located in the ventrolateral preoptic nucleus of the hypothalamus, or the monoaminergic waking centers (the histaminergic tuberomammillary nucleus, the serotonergic dorsal raphe, and the noradrenergic locus coeruleus), can respectively lead to insomnia and sleepiness (30). In Parkinson disease, degeneration of dopaminergic cells in the substantia nigra and cholinergic neurons in the basal forebrain may also lead to hypersomnolence (30).
Orexin (hypocretin). In the laboratory, links between Alzheimer disease and melatonin and orexin (also known as hypocretin), both linked to sleep-wake cycle, have been delineated. In vitro, melatonin blocks both amyloid metabolism and aggregation (93). These findings are echoed by finding in Alzheimer disease patients. Uchida and colleagues found that a higher proportion of Alzheimer disease patients showed absence of diurnal variation in melatonin rhythm relative to elderly controls (121), and Liu and colleagues reported that postmortem CSF of Alzheimer disease patients was characterized by melatonin levels about 20% of controls, with this effect being most pronounced in the APO-E 4/4 genotype (75). In transgenic mice, sleep deprivation is linked with increased central nervous system interstitial amyloid levels and plaque deposition. These findings were reversed by sleep and an orexin receptor antagonist, suggesting elevated orexin levels as an intermediate step in this process (63). Further research has demonstrated higher levels of orexin in the cerebrospinal fluid of those with moderate to severe Alzheimer disease compared to controls, and the research has found a correlation of these higher levels with increased levels of tau (73).
Midbrain and pontine respiratory centers. Animal models suggest that in some neurodegenerative disorders, an interruption of the REM-atonia pathway and/or disinhibition of brainstem motor pattern generators, can lead to REM sleep behavior disorder (77). Animal studies and human stroke reports suggest co-localization of atonia and locomotor systems in the sublateraldorsal nucleus (an area of the brainstem medial to the locus coeruleus) (77; 131). In fact, neuronal inclusions of Lewy bodies and accumulation of insoluble alpha-synuclein protein in brainstem nuclei, the hypothalamus, and limbic structures that are involved in sleep circuitry have a significant association with disturbed sleep in patients with Parkinson disease (61).
Medullary respiratory centers. Finally, in dementia, the degenerative process may affect brainstem respiratory centers as sleep-related breathing disorders have frequently been reported in patients with mild cognitive impairment and dementia (135; 89; 26). Normal involuntary breathing is dependent on the medullary respiratory center, which is comprised of a dorsal respiratory group (composed of inspiratory cells from the solitary tract nucleus) and a ventral respiratory group (formed by the nucleus ambiguus and the nucleus retroambiguus) and contain neurons for inspiration and expiration (28). Central sleep apnea has been shown to occur after stroke of the solitary tract nucleus, and obstructive sleep apnea has been reported after injury to the ventral respiratory group of nuclei; as such, neural degeneration of these areas in dementing processes might also lead to sleep-related breathing disorders.
Dementia. In the United States, 1 large study of insured patients found that the cumulative risk for dementia varies according to race, being 38% for African Americans, 32% for Latinos, 30% for whites, and 28% for Asian Americans (78). Racial/ethnic inequalities in this study persisted after adjustment for vascular comorbidities but differences in education were not taken into account. The most common type of dementia in the elderly is Alzheimer disease, followed by vascular dementia, dementia with Lewy bodies, and frontotemporal dementia (24).
Sundown syndrome. In all likelihood, some component of sundowning affects most demented patients at some point in their illness. Volicer reported that 11 of 25 (44%) Alzheimer disease patients sometimes or usually experienced sundown syndrome (123). This study noted that there was a higher incidence of the sundown syndrome in the fall and winter months, possibly related to lower levels of sunlight. Walker and colleagues defined cognitive fluctuations by including patients who have: a) day-to-day changes in MMSE scores, b) daytime confusional spells, and c) episodic stupor (125). They found the prevalence of fluctuating cognition to be highest in those who have dementia with Lewy bodies (89%), followed by those with vascular dementia (64%) and Alzheimer disease (23%).
Hypersomnia. Excessive daytime sleepiness (as measured by an Epworth Sleepiness Scale score > 10) is more prevalent among those who have mild dementia with Lewy bodies (81%) than among those who have the behavioral variant of mild frontotemporal dementia (47%) or mild Alzheimer disease (45%) (12).
Insomnia. This is the most prevalent sleep disorder in the general population (104). In a systematic review and metaanalysis, de Almondes and others showed that chronic insomnia was associated with a significant risk of all-cause dementia (RR=1.53; 95% CI=1.17-2.18) (25). In the large Canadian Longitudinal Study on Aging, 3.7% of those over 45 had probable insomnia disorder; they had more adverse medical and psychiatric problems such as diabetes, anxiety, and depression (21). They also had more problems with memory on formal cognitive tests.
REM sleep behavior disorder. In patients with idiopathic REM sleep behavior disorder, the estimated 5-year risk of developing Parkinson disease or dementia with Lewy bodies is 17.7%, and the 12-year risk is 52.4% to 73.5% (34; 94). In patients with dementia with Lewy bodies, REM sleep behavior disorder precedes visual hallucinations and parkinsonism by 7 to 8 years. When imaging with dopamine transporter (DAT)-SPECT was used as a marker of synucleinopathy, 58.6% of patients with idiopathic REM sleep behavior disorder were identified as having baseline DAT deficits, and 28.7% developed DAT deficits within 5 years of idiopathic REM sleep behavior disorder onset (52).
Restless legs syndrome. This is the most common of all movement disorders because it affects 3% to 10% of the general population (48). It is more common in older adults (10% of 30- to 79-year-olds) compared to younger adults (3% of 18- to 29-year-olds). Secondary restless legs syndrome is seen in 20.8% of Parkinson patients (87).
Sleep-disordered breathing. Older individuals with sleep-disordered breathing are more likely to develop signs of mild cognitive impairment at an earlier age (89). The prevalence of obstructive sleep apnea in those over 65 years is at least 20% (41).
Chronic obstructive pulmonary disease. In a large (n=4735) 3-year study of chronic obstructive pulmonary disease patients and controls, the incidence of mild cognitive impairment and dementia was higher in those who had chronic obstructive pulmonary disease at baseline than in the controls. After adjusting for covariates, the hazard ratio for mild cognitive impairment was 1.49 for dementia and the hazard ratio for dementia was 1.90 (132). The risks were even higher for those chronic obstructive pulmonary disease patients who were current smokers (HR=2.28 for MRI and 3.38 for dementia).
Medication review. Whenever mild cognitive impairment or dementia patients show signs of memory loss, cognitive fluctuations, or the sundown syndrome, their medication list needs to be examined, and they need to be assessed for iatrogenic events, such as bladder infections (18; 39). Narcotics, sedative-hypnotics, histamine-2 receptor blockers, antiparkinsonian medications, and anticholinergics are commonly associated with delirium in dementia patients. Data suggest that anticholinergic medications in cognitively impaired patients should always be used with caution (42).
Well-lighted environment. A study of demented elderly patients in nursing homes suggested that the best predictors of circadian sleep-wake cycle maintenance were daytime physical and psychosocial activity (116) and light because sundowning tends to be worse in the winter, when illumination levels are lower. Exposure to bright light may help to optimize the sleep-wake cycle in dementia, and light treatment may be useful for some agitated Alzheimer patients (62).
Avoid night-time awakening. One study showed that healthy adults without sleep disorders who were awakened during slow-wave sleep showed increased production of spinal fluid levels of amyloid-beta (59). This acute effect was specific for an increase in amyloid-beta (not for total protein, tau, or hypocretin). Although slow-wave disruption acutely increases the production of amyloid-beta, poor sleep quality over several days correlated with increased spinal fluid levels of tau. The authors suggested that these effects were mediated by changes in neuronal activity during disrupted sleep. From a practical point of view, these findings suggest that we should refrain from awakening nursing home patients in the middle of the night for vital signs, or for the administration of medications.
Prevent daytime napping. This method has been shown to increase the duration of nocturnal sleep in the nondemented geriatric population and may be as effective in the demented population because the homeostatic regulation of sleep and wakefulness appears preserved even in the late stages of dementing illness. However, Sloane and colleagues (109) presented data suggesting that nursing facilities that routinely put patients in bed during the afternoon for naps had lower rates of agitation relative to facilities that did not employ this routine. Other elements of a nursing home environment, such as difficulty in maintaining quiet and in minimizing undue lighting at night, may also contribute to interruption of sleep, but these elements may be difficult to control (22; 103). Others have shown that a short-term nap and light physical exercise increased sleep efficacy and reduced nocturnal wake time (65).
Protect the environment. In patients who have REM sleep behavior disorder, the bedroom environment should be protected. If the patient has a history of falling out of bed, then consideration should be made for having the mattress placed on the floor and removing all sharp objects from the bedroom. Overstimulation, competing priorities, and unrealistic expectations (of caregivers) can lead to sleep disruption and worsening of symptoms of the sundown syndrome in nursing home patients with dementia (62).
Smoking cessation. Reducing nocturnal cigarette use is likely to reduce symptoms of restless legs syndrome because nocturnal smoking has been shown to be more prevalent in these patients (95).
Sundown syndrome. Nocturnal delirious states in dementia patients (sundown syndrome) can occur in a wide variety of infectious, toxic, metabolic, and drug-induced conditions (18; 62). When a dementia patient develops the cognitive fluctuations or the sundown syndrome for the first time, medications need to be reviewed, and the possibility of pain, fatigue, hunger, depression, bladder infection, fecal impaction, or other new medical problems need to be considered as possible contributing factors. Cognitive fluctuations in Parkinson disease dementia or dementia with Lewy body patients can occasionally be explained by orthostatic hypotension; these patients have been shown to respond favorably to the addition of midodrine (96).
Chronic insomnia. Clinical guidelines for evaluation of chronic insomnia in adults have emphasized the need to rule out comorbid medical and psychiatric problems (104). Although decreased sleep duration was shown in a large longitudinal study to be associated with an increased risk of incident dementia, the results did not remain positive after there was an adjustment for the presence of depression (46). Therefore, older patients who report insomnia need to be screened for symptoms of depression, and a trial of 1 or more sedative antidepressant drugs should be considered before attributing the insomnia to a new cognitive disorder.
Medication review. Assessment of chronic insomnia needs to include a review of all medications, as well as the total daytime use of caffeinated beverages (104). Evaluation for nocturnal delirium should involve a complete medication review with special consideration of drug interactions, even when these drugs are taken in therapeutic dosages (18). Anticholinergics, benzodiazepines, antipsychotics, opioids, and proton pump inhibitors should all be scrutinized because they can increase the risk of cognitive fluctuations and the sundown syndrome (81; 129). Suspending at least 1 of these drugs can improve sleep quality and reduce the risk of hospitalization. Routine blood chemistries and a complete blood count should be obtained for the possible presence of uremia, diabetes and other endocrinopathies, liver dysfunction, vitamin B12 and folate deficiency, systemic infection, and anemia. Alcohol or benzodiazepine withdrawal and the effects of recent surgery are other potential contributors to sleep disturbances.
Polysomnography. Signs and symptoms suggesting REM sleep behavior disorder or obstructive sleep apnea should be fully addressed with a complete sleep history and polysomnography when indicated. Polysomnography is valuable in diagnosing REM sleep behavior disorder (03). The International Classification of Sleep Disorders definition of REM sleep behavior disorder using polysomnography demands the presence of REM sleep without atonia. Although it is not a diagnostic demand, periodic limb movements in sleep can be seen in up to 75% of patients with REM sleep behavior disorder. Approximately 25% of patients with subclinical REM sleep behavior disorder will develop REM sleep behavior disorder (03). A longitudinal study of older adults using home-based polysomnography showed that lower percentages of REM sleep and longer latencies to REM sleep were both associated with a higher risk of incident dementia (91). Guidelines have outlined the situations where polysomnography is preferred over home sleep apnea testing for the diagnosis of obstructive sleep apnea (64).
The first step in practical management of disordered sleep in dementia is to take a good sleep history and to remediate potential exacerbating factors. This should include such things as excessive or poorly timed caffeine and alcohol intake, nocturnal smoking, use of sedating medications, medical issues that directly impact sleep such as respiratory problems acid reflux, and pain, mood issues, and sleep hygiene (95; 98). For instance, renal and hepatic disease, systemic infection, hypovolemia, acid-base and electrolyte imbalances, and hypovitaminosis should be corrected if possible. Special attention should also be focused on the patient's behavior and level of alertness during the daytime hours.
Physical activity. Incorporation of physical activity into the patient's routine, exposure to outdoor sunlight, and a short-term nap during the day may be useful to treat insomnia and to reduce nighttime interruptions (Katagi & Miyai 2018). Data have shown that aggressive attempts at behavioral strategies emphasizing good sleep hygiene can be helpful in treating insomnia and other nighttime behavioral disturbances (83). The sundown syndrome and sleep quality both showed significant improvements in Alzheimer disease patients who walked routinely with family members (107). It is difficult to propose standardized schedules for physical activity but it is generally agreed that sleep quality improves when exercise is performed in the late afternoon or early evening (35).
Light. Light is a powerful cue given by the environment for the sleep-wake cycle in both demented and nondemented geriatric patients. Studies of light therapy have used 2000 lux to 10,000 lux for 2 hours to several hours per day. In broad terms, various forms of bright light therapy have not been proven to be beneficial for sleep, cognition, or mood in demented adults, as demonstrated in a Cochrane review (38). However, ongoing research is investigating specific interventions, such as use of bright bluish-white lighting in the daytime in the nursing home setting, which in 1 small study, did appear to improve sleep time and efficiency, mood, and behavior (36). Two authors now recommend a combination of bright light therapy and melatonin as a first line of treatment for sleep problems in dementia patients (88). One study treated Parkinson disease patients with excessive daytime sleepiness with a 14-day light intervention that consisted of 1 hour of exposure to bright (10,000 lux) versus dim (< 300 lux) light twice a day (122). The bright light intervention improved daily activities and reduced excessive daytime sleepiness significantly more than the dim light. Other trials with bright light therapy in Parkinson disease patients have demonstrated benefit in reducing insomnia, REM sleep behavior disorder, and anxiety (35). The newest form of light intervention is the “dawn-dusk simulator”, which is placed over a patient’s bed and has been shown to improve mood and quality of life in institutionalized patients with dementia (15).
Melatonin. Studies of early Alzheimer disease have shown that CSF melatonin levels fall in the preclinical stages before patients ever manifest cognitive impairment (111). Other studies have shown dampened melatonin profiles in the evening and night-time in Alzheimer disease patients compared to controls (127). In a 24-week study of mild-moderate Alzheimer disease patients, prolonged release melatonin was given in addition to other antidementia medications with beneficial cognitive and sleep effects (124). A meta-analysis of the use of melatonin for sleep disorders in dementia, primarily of the Alzheimer type, did show modest improvement in both sleep time and sleep efficiency. Melatonin was given orally at nighttime in these studies at a variety of doses ranging from 2.5 to 10 mg per day (134). Melatonin also improves the symptoms of REM sleep behavior disorder in patients who have dementia with Lewy bodies (13). There have been mixed results when melatonin was used to treat the sundown syndrome associated with either Alzheimer disease or vascular dementia, but open-label studies consistently documented a reduction of sundown syndrome symptoms at doses of 3 to 9 mg per day (18). In Parkinson disease, there is evidence that the combination of melatonin and bright light therapy is superior to either intervention alone in preventing insomnia or the sundown syndrome (35). Melatonin slightly improves sleep onset and sleep duration in elderly patients but product quality and efficacy may vary because it is considered an unregulated natural product (01).
Cholinesterase inhibitors. Treatment with recognized medications for dementia may help sleep quality, but the evidence is sparse to date. An open-label study of galantamine (vs. placebo) in patients who had dementia with Lewy bodies showed significant benefits at 24 weeks in night-time behaviors, visual hallucinations, and clinical global improvement of change (31). A study of sleep patterns in demented and nondemented elderly subjects with cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) had mixed results, with only galantamine showing a significant improvement in the Pittsburgh Sleep Quality Index (85). Experts in long-term care agree that cholinesterase inhibitors serve an important function in preventing agitation in patients with dementia (97).
Memantine. Two common sleep disorders are found among those who have dementia with Lewy bodies and Parkinson disease with dementia, so 1 small randomized placebo-controlled trial of memantine examined these patients in equal numbers using 2 sleep questionnaires (69). After 24 weeks, those treated with memantine (20 mg/d) were found to be significantly less active at night with respect to their REM sleep disorder symptoms compared to the placebo controls. Memantine had no significant effect on excessive daytime sleepiness. A small trial of Alzheimer disease patients with memantine showed longer total sleep time and higher sleep efficiency (53).
Benzodiazepines. Benzodiazepines often make agitation and other symptoms of the sundown syndrome worse, so they should not be used routinely in elderly patients (with the exception of low-dose clonazepam, which is sometimes needed to treat REM sleep behavior disorder) (18; 01). In a large 5-year longitudinal case-control study of participants 66 years and older, Billioti de Gage and others demonstrated that there was an increased risk of new Alzheimer disease among those who used benzodiazepines compared to age- and sex-matched controls; this occurred even after adjusting for the presence of anxiety, depression, and insomnia (OR 1.43; 95% CI=1.28-1.60) (11). In a metaanalysis, Islam and associates confirmed that the odds of dementia were much higher among those who used benzodiazepines than in age-matched controls (OR 1.78; 95% CI=1.33-2.38) (54). One could argue that these results were an example of reverse-causation because very early dementia patients often exhibit behavioral symptoms before cognition becomes impaired. Nevertheless, it is true that benzodiazepines may have a paradoxical effect on behavior in the elderly and therefore should be avoided.
Other sedative drugs. Zaleplon and zolpidem were developed as sedative drugs with preferential binding to the GABAa receptor complex but there is no clear evidence for superiority of these agents over the traditional benzodiazepines for the treatment of chronic insomnia (99). Similarly, the novel dual orexin receptor antagonist, suvorexant, has not been shown to be safer than pre-existing sedatives. Nevertheless, a study demonstrated that suvorexant and ramelteon (a melatonin receptor agonist) improved sleep quality with less delirium in acute stroke patients (66).
Antipsychotic drugs. Clinicians should be cautious in using atypical antipsychotics for behavioral management of dementia, including sundowning, weighing both risks and benefits carefully in individual cases (18; 97). A multicenter double-blind, placebo-controlled trial using 4 arms (risperidone, olanzapine, quetiapine, and placebo) in 421 patients with Alzheimer disease with psychosis, aggression, or agitation showed no significant difference in outcome as measured by the Clinical Global Impression of Change, suggesting that other classes of drugs or nonpharmacological approaches might have been more effective in managing the agitated behaviors in these patients (102; 97). Some have cautioned that there is an increased risk of cerebrovascular disease in older patients taking risperidone (130), as well as a heightened risk of diabetes (86). In Parkinson patients, use of antipsychotic drugs is associated with an increased risk of mortality, according to a study from the Veterans Administration (126). The highest risk of mortality was with use of typical antipsychotic drugs, such as haloperidol (HR=5.08), compared to atypical agents, such as quetiapine (HR=2.16). If antipsychotic drugs are used as a “last resort” for the management of agitation, they need to be monitored on a regular basis. Renewed efforts at tapering these drugs need to be initiated every 3 to 6 months at least.
Clonazepam. REM sleep behavior disorder is a core feature of dementia with Lewy bodies (34; 81). Clonazepam successfully controls REM sleep behavior disorder symptoms in up to 90% of patients (77), and, within 7 days, 0.5 to 1 mg per day often results in marked improvements. Administration 2 hours before the preferred sleep time can also help to address concomitant issues of insomnia, in addition to helping decrease next-day sedative hangover effects.
Modafanil. This stimulant drug has been recommended by the American Academy of Neurology for use in treating the hypersomnia associated with Parkinson disease (136).
Trazodone. This antidepressant medication can be used at doses of 50 to 200 mg qhs to treat dementia patients or poststroke patients who have symptoms of anxiety, insomnia, or the sundown syndrome (47; 80; 23; 97). It increases the central availability of the neurotransmitter serotonin by acting as a serotonin antagonist reuptake inhibitor.
Dopaminergic drugs. According to the American Academy of Neurology, levodopa/carbidopa is probably useful in reducing the frequency of leg movements of idiopathic restless legs syndrome and the secondary restless legs syndrome associated with Parkinson disease (136; 08). Paradoxically, high daytime doses of levodopa/carbidopa have been associated with excessive daytime sleepiness (60). According to the American Academy of Sleep Medicine, the 2 dopaminergic drugs that are recommended as the standard of care for treating symptoms of restless legs syndrome are pramipexole and ropinirole (07).
Continuous positive airway pressure (CPAP). Finally, treating concomitant sleep-related breathing disorders, such as obstructive sleep apnea, may increase the quality of life in patients with dementia (88). A randomized double-blind, placebo-controlled trial was performed utilizing continuous positive airway pressure therapy (CPAP) in 52 men and women with mild to moderate Alzheimer disease and obstructive sleep apnea (05). Comparison of pre- and post-treatment neuropsychological scores after 3 weeks of CPAP showed significant improvements in cognition. As such, the authors stated that clinicians who care for patients with Alzheimer disease should consider CPAP when obstructive sleep apnea is present. In 1 large prospective study of older adults with sleep-disordered breathing, CPAP treatment was shown to significantly delay the age at onset of mild cognitive impairment by about 10 years (89). In a few small studies of poststroke patients with sleep disordered breathing, CPAP has been shown to correlate positively with good functional outcomes, good language scores, and improved daytime sleepiness scores (47). The new practice guidelines for obstructive sleep apnea give strong recommendations for using CPAP in those who have symptoms of excessive daytime sleepiness (92).
“Augmentation” can develop as a complication of chronic use (months-years) of dopamine agonist therapy for restless legs syndrome. In this situation, more and more agonist drug is needed over time to produce the same benefit. Several strategies can be used to counteract the effects of augmentation. One strategy is to check iron stores to be sure that iron supplementation is provided if needed (40). A second strategy is to switch from 1 class of agonist drug to another (from pramipexole to ropinirole, for example). A third is to use a longer-acting agonist drug, such as the transdermal patch rotigotine. Finally, an alternative to dopamine agonist therapies for restless legs syndrome is the use of gabapentin (150-300 mg qhs) (47).
Recent surgery may be a risk factor for developing symptoms of the sundown syndrome (108).
Institutionalization. Symptoms of the sundown syndrome can vary according to the amount of light exposure during the day, availability of nursing staff, and fatigue of the patient (18).
Linda A Hershey MD PhD
Dr. Hershey of the University of Oklahoma Health Sciences Center has no relevant financial relationships to disclose.See Profile
Evgeny V Sidorov MD PhD MHA
Dr. Sidorov of University of Oklahoma Health Sciences Center received honorariums from Abbvie and BioHaven as an independent contractor.See Profile
Antonio Culebras MD FAAN FAHA FAASM
Dr. Culebras of SUNY Upstate Medical University at Syracuse received an honorarium from Jazz Pharmaceuticals for a speaking engagement.See Profile
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