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Introduction
“One minute, Sam Cohen, 80, points to photos of his kids and talks about how his son wanted to become an actor. The next minute, he unravels. Cohen, a former New Jersey taxi driver and ironworker, is convinced his family will steal his money. He talks about escaping to Israel. He ignores his grown children’s pleas to take his medication—he tells them they’ve been brainwashed. And he threatens his wife, Haya. ‘He is starting to make Charlie Sheen look rational,’ said his son, Michael Cohen, about his dad’s Alzheimer disease (AD). Earlier this month, he went from paranoid to physically violent.”1
Sundown syndrome, or sundowning, is a ubiquitous and startling pattern of disruptive behavior in elderly dementia patients in the early evening that impacts the quality of life for patients, caregivers, and families. We have gained some understanding of the pathophysiology of this condition, but a clear cause and specific treatments have remained elusive over the last 75 years. Large scale data collection to develop a predictive model of sundowning and to more comparably test therapeutics is sorely needed.
New developments in methods to analyze gene changes in rhythmic conditions such as sundowning offer new potential avenues for studying the genetic determinants of sundowning and may direct us toward new therapies. The aim of this review is to bring the reader up to date on pertinent historical points, recent research regarding sundown syndrome and its treatments.
Definition
Our current definition of sundowning is rooted directly from Ewen Cameron’s 1941 Studies in Senile Nocturnal Delirium, “The delirium usually appears after retiring to sleep… complete disorientation; frequently some degree of agitation and panic is apparent.”2 The concept of sundowning is multifactorial and remains formally undefined, though most people who work routinely with an elderly population, particularly those with dementia, readily know what is meant by the word “sundowning.”
Sundowning is difficult to define because it represents a collection of neuropsychiatric symptoms that can present in patients with a background of neuropsychiatric disease, most frequently dementia. The symptoms may include increased confusion, restlessness, hallucinations, verbal outbursts, and wandering, all of which can occur during a specific part of the day.3 The exact timing of sundowning behaviors is contested, but most can agree that it occurs in the late afternoon and/or early evening.4
Sundowning is not thought to be a reflection of an acute disease process but rather a sign of underlying chronic neurodegenerative disease or environmental stress, or some combination.5 Interestingly, the behavioral and psychological manifestations of sundowning share many similarities with delirium, but unlike delirium, it takes a more chronic course, is not associated with an acute medical problem, and is not associated with increased mortality risk in institutionalized individuals.6,7
Further complicating the definition of sundowning, there are different schools of thought as to whether it should be classified as a behavioral and/or biological problem. Those who classify it as a behavioral problem, point to causes of sundowning as a product of the chaos of providers’ shift-changes and other environmental factors.8 However, with increasing frequency, the study of sundowning as a biological phenomenon seems to predominate the research space and it is frequently associated with sleep disorders linked to aging and dementia.9
The prevalence of sundowning among nursing home patients ranges from 10-25% defined by afternoon agitation, with only 2.4% having a circadian abnormality.10 In AD the rates are likely much higher with a per evaluation risk of a behavioral disturbance found at 83%.6 Though with some dispute in the literature, in 1993, Bilwise and colleagues found that there is a seasonal effect in sundowning. They write that it’s more common in the time of the year when daylight hours are shorter ergo winter (though seasonal affective disorder may be a confounding factor).11 Martin and colleagues, on contrary, did not report a seasonal association.10
As noted above, the most commonly noted risk factor for developing sundown syndrome is the presence of underlying dementia. Alzheimer and Lewy body dementia are the two conditions most routinely studied in relation to sundowning.12,13 Sundowning’s severity and incidence is thought to be reflective of worsening AD.14
Pathophysiology
To date, no unifying explanation of the pathophysiology of sundowning has emerged in the literature. However, one of the most accepted biological mechanisms involves the dysfunction of the body’s circadian rhythm in sundowning. The part of the nervous system that controls circadian rhythms, and thus sleep-wake cycles, is the suprachiasmatic nucleus (SCN), which receives sensory input from photosensitive cells in the retina via the retino-hypothalamic tract.15 It has been shown that patients with severe dementia have neuropathological changes in the SCN. It has been hypothesized that these changes may be linked to the disordered circadian rhythm that many clinicians observe in patients with severe dementia.16,17
Treatment Modalities
There are three main treatment approaches geared toward ameliorating sundowning: improving the patient’s environment, minimizing comorbidities which may negatively affect the mental state of the patient, and pharmacotherapies to improve symptoms and slow the progression of AD.
Environmental Treatments
Caregiver Lead Therapies
Non-pharmacological interventions are able to provide a nearly risk-free intervention in a population that is highly sensitive to medications. Whereas these therapies show statistical significance, the magnitude of these effects, their aggregation and interaction remains unknown. Instead, a plethora of heterogeneously composed studies have shown a trend toward efficacy in reducing the behavioral abnormalities associated with AD; and as a logical extension, sundowning as well.18
Tailored activities based on the patient’s history, occupation, and interests have shown reduced agitation, arguing, and shadowing.19 Music therapy, one of the most pervasively used methods, has shown efficacy in reducing aggressiveness and agitation with live performances, sing-alongs, and instrumental play-alongs.20-22 Aromatherapy, specifically lavender, and aroma-acupressure may decrease agitation.23,24 There is conflicting evidence whether exercise improves behavior.18
Sleep Consistency and Quality
Management and promotion of regular high-quality sleep may be an important adjunct to the treatment and prevention of sundowning. As stated above, circadian rhythm is intimately related to sleep, and likely, to sundowning. As such, sundowning can be considered a sleep disorder that exists in patients with a concomitant neurodegenerative brain disease.
Interestingly, the relationship between disordered sleep and dementia seems to be bidirectional. It has been shown that chronic poor sleep quality leads to a pro-inflammatory state within the body.25 This pro-inflammatory milieu is linked to higher risk of cardiovascular disease and diabetes, which are thought to be independent risk factors for the development of Alzheimer dementia.26
Additionally, it has been suggested that amyloid beta production may be higher during times of poor sleep quality, further emphasizing the notion that high quality sleep and neurodegenerative brain diseases are intimately connected. Therefore, managing and promoting high-quality sleep in elderly populations may help to prevent dementia and sundowning.27
A recently published cohort study of 15 273 brain disease-free men, aged 58-93, showed that men who had a higher calorie consumption, higher intake of trans fats, high sodium intake, and lower intake of vegetables had a high association with non-restorative sleep and difficulty maintaining sleep.28 The point is that sleep quality is not only a consequence of sleep physiology itself, rather it’s also a consequence of the environment in which the patient sleeps, including their sleep hygiene. This includes preparing a comfortable environment for sleep, avoiding smoking, and consumption of alcohol and caffeinated drinks, eating too recently before sleep, going to bed hungry, minimizing light exposure at night and excessive noise/distraction, having daily walks,29 playing gentle music before bed,30 and including full spectrum light exposure in the morning.31
Mental State
Emerging evidence shows that Alzheimer patients report pain at lower levels, if at all, indicated on the Facial Action Coding System.32 This likely means an Alzheimer patient will chronically be underreporting pain. Undiagnosed/untreated pain, can contribute to sundowning. Factors that influence the mental state of patients that may also contribute to sundowning include boredom, social isolation due to evening shift changes, and depression.33,34 Constant vigilance and communication with the patient allows prompt interventions that can prevent perturbations in the patient’s mental state that can lead to sundowning.
Pharmacotherapies
Melatonin
Melatonin is a natural hormone produced in conjunction with circadian rhythms and has long been used as a sleep aid.35 Melatonin may protect neurons in AD from amyloid-induced neuro-toxicity due to its antioxidant and anti-amyloid properties.36 A systematic review of the literature in 2010 concluded that melatonin may improve both sundowning and sleep-wake cycles in patients with dementia, but these conclusions are derived from case reports and studies with limited sample size.37 Melatonin is well tolerated with common dose dependent side effects of drowsiness and somnolence the following morning.38
Melatonin Agonists
In the past year, another case study was published regarding the use of ramelteon (Rozerem), a melatonin agonist, in the treatment of sundown syndrome. In this case, a patient with dementia on a stable home dose of quetiapine (Seroquel) was admitted to the hospital for an infection. Despite clearing the infection in a matter of days and minimizing multi-drug interactions, this patient remained delirious and exhibited more disturbing behaviors at night. The authors attributed this behavior to sundowning.
Treatment with ramelteon was initiated as an adjunct to the regular quetiapine to stimulate regular circadian rhythm cycling. Within a single night, the patient’s condition improved with full reversal of delirium by the 21st hospital day. The authors indicated that ramelteon may work synergistically with atypical antipsychotics to suppress central dopaminergic and nicotinic acetylcholine function, thus decreasing sundowning behavior in the delirious patient.39
While this study suggests that further research should be done to confirm these findings, it is not necessarily elucidative of how ramelteon would work for most patients who experience sundowning. As noted above, sundowning is usually present among patients with underlying dementia, not necessarily acute delirium. However, ramelteon, a melatonin agonist, could be a good target for future research in patients with non-delirium related sundowning behavior since melatonin supplementation has shown some success in this area.37
Other Pharmacotherapies
There has been discussion of other pharmacotherapies in the treatment of sundowning, but no randomized controlled studies have directly looked at their efficacy in sundowning. FDA-approved treatments for AD itself include cholinesterase inhibitors, donepezil, rivastigmine and galantamine, and the N-methyl-d-aspartate receptor (NMDAR) antagonist memantine.40 The best evidence comes from the use of cholinesterase inhibitors. One placebo-controlled trial utilizing Donepezil (23 mg/d) in AD has been shown to provide incremental cognitive benefits on the Mini-Mental State Examination, and possibly on sundowning symptoms.41,42
Future Directions
Seventy-five years after Ewen Cameron described sundowning, there is still not a consensus definition established in the literature. Some studies associate sundowning to the timing of lunch, some an arbitrary time in the afternoon, some after sundown, and some to post shift changes. These are clearly observational associations underpinning the definition of the term.
To be better able to monitor for improvements in the condition and make research more comparable, a statistical approach should be applied. A multicenter, ongoing database needs to be established with parameters that can help elucidate the influencing factors for sundowning and which populations are most at risk. Some variables to look at would be: the specific symptoms experienced, the time of day they occur, the duration of sleep, the quality of sleep, which therapies and medications were administered. These variables can be correlated with the patient’s past medical history, blood glucose levels, blood pressure, temperature, gender, race, and age, among other variables. Once established, this database could be used to develop a predictive model of sundowning given the variables. Also, this model could serve as the template for comparing various therapies for sundowning.
An exciting study of circadian patterns of gene expression in the human brain’s prefrontal cortex was published this year and may provide a new avenue to examine sundowning on a biological level. In this study, Chen and colleagues were able to use brain tissue from 146 deceased patients aged 16 to 96, using microarray analysis to ascertain levels of gene expression in the prefrontal cortex, which according to the authors, has been shown to demonstrate rhythmic changes important for cognition and executive functions. Tissues were collected and time of death was standardized to a coordinated universal time, which allowed the authors to reliably examine the time-sensitive expression of genes in the prefrontal cortex.
They identified many genes that exhibited temporal patterns of expression, but also identified genes that showed age-dependent rhythm changes. Interestingly, they found genes that lost chronicity, but also other genes that gained chronicity with age.43 The importance of this study is not necessarily that they identified specific genes, but that they demonstrated a new method, which the authors call time of death transcriptomic analysis, for understanding rhythmic gene expression within the human brain. This method will need to be validated in the future, but represents a significant opportunity for understanding the biology and pathophysiology of rhythmic conditions such as sundowning.
Conclusion
Sundowning is a complex multifactorial condition that has eluded rigorous understanding of its pathophysiological causes. However, strides have been made towards reducing sundowning, and new evidence has emerged backing cost effective therapies of examining a patient’s mental status, optimizing a patient’s environment, and administering medications. New research is focusing on the promise of understanding sundowning through genomic expression, opening new avenues of potential treatment. In addition, a more thorough understanding of those subsets of patients who are affected by the condition with epidemiological studies may improve surveillance and preventative measures for at risk populations.
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