Sleep Disorders in Dementia

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Update on the Diagnosisand Management of SleepDisturbances in DementiaBradley F. Boeve, MD

Sleep disturbances in patients who have demen-tia are common and are a major cause of reducedpatient, and particularly caregiver, quality of life,often leading to patient institutionalization. The lit-

erature has several excellent reviews on sleep distur-bances in dementia. The principal goals of thisarticle are to (1) review the most common and per-tinent sleep disturbances in the home/ambulatorysetting, (2) provide a simple diagnostic schemefor clinicians (and caregivers) to determine thelikely cause or causes of the sleep disturbances,and (3) provide a summary of nonpharmacologicand pharmacologic strategies for managing the dis-

turbances. The ultimate purpose of such a review is

to maximize quality of life for patients and theirbed partners, and to enable patients who have chal-lenging sleep disturbances to remain in the homeenvironment as long as possible.

Cognitive impairment and dementia have severaldozen causes. The principal causes of irreversibledementia are shown in Box 1; the reader is directedto other sources for a more complete discussion ofirreversible dementing illnesses [13].

Alzheimers disease (AD) is the most commonsuch cause, with the dysfunctional proteins in thisdisorder being amyloid (the major constituent ofneuritic plaques) and tau (the major constituent

of neurofibrillary tangles). Thus, AD is considered

S L E E PM E D I C I N E

C L I N I C S

Sleep Med Clin 3 (2008) 347360

Center for Sleep Medicine and Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN55905, USAE-mail address: [email protected]

- Diagnostic approach- Symptom complex: insomnia

Dementing illnessSleep disordersMedication effectsDepressionCircadian dysrhythmia

- Symptom complex: hypersomniaDementing illnessSleep disordersMedication effects

DepressionCircadian dysrhythmia

- Symptom complex: excessive motoractivity at night

Dementing illnessSleep disordersMedication effectsCircadian dysrhythmia

- Symptom complex: nocturnalhallucinations/behavioral problems

Dementing illness

Nocturnal agitation/behavioraldyscontrol

Sleep disordersMedication effectsCircadian dysrhythmia

- References

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1556-407X/08/$ see front matter 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.jsmc.2008.04.010sleep.theclinics.com
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an amyloidopathy and also a tauopathy. De-mentia with Lewy bodies (DLB) and Parkinsonsdisease with dementia (PDD) are the primary de-

mentia syndromes associated with underlyingLewy body disease (LBD). The choice of the DLB

versus PDD label relates to the timing of the onsetof dementia and parkinsonism; DLB is applied tothose who develop dementia prior to the onset ofparkinsonism or within 1 year of the onset ofparkinsonism, whereas PDD is applied to those

who develop dementia anytime after 1 year fromthe onset of parkinsonism. Alpha-synuclein is theprimary dysfunctional protein in the Lewy bodiesand Lewy neurites of LBD, and LBD, along withmultiple system atrophy and primary autonomicfailure, are collectively considered synucleinopa-

thies. LBD is now considered the second most com-mon irreversible cause of degenerative dementia,accounting for approximately 15% to 25% of cases.

Frontotemporal lobar degeneration (FTLD) isa spectrum of disorders that principally affect thefrontal and temporal lobes. It typically manifestsclinically as a behavioral/dysexecutive syndrome(known as frontotemporal dementia [FTD]) or anaphasic syndrome (known as primary progressiveaphasia). FTLD likely accounts for 5% to 15% ofdementia cases. Among those who have dementia,

whose onset of cognitive decline begins before age65, the FTLD disorders are particularly common(in the 20%50% range). Picks disease, cortico-basal degeneration, progressive supranuclear palsy,argyrophilic grain disease, and the rare, geneticallymediated disorder of FTD with parkinsonism

linked to chromosome 17 associated with muta-tions in the gene encoding microtubule-associatedprotein tau are collectively considered tauopa-

thies. FTLD with ubiquitin- and TAR-DNA bindingprotein-43-positive inclusions, FTLD with motorneuron disease, and FTD with parkinsonism linkedto chromosome 17 associated with mutations inthe gene encoding progranulin are considered tar-dopathies. Approximately 40% of patients present-ing with an FTD or primary progressive aphasiasyndrome have an underlying tauopathy, 40%

have a tardopathy, and the other 20% have eitheratypical AD or a more obscure disorder. Hunting-tons disease is an uncommon, genetically medi-ated disorder associated with the dysfunctionalgene product from huntingtin. Therefore, a spectrum

of disorders and their associated proteinopathiescan underlie the symptoms of the neurodegenera-tive disorders that present in an insidious fashionand have a slowly progressive course. The primary

symptoms and inherent sleep disturbances arelikely linked to the dysfunctional proteins and asso-ciated topography of neurodegeneration and neu-

rochemical alterations.Multi-infarct dementia is now considered within

the spectrum of vascular dementia (VaD). Althoughthe prevalence of VaD continues to be debated, andcerebrovascular disease is common in cognitivelyimpaired and cognitively normal elderly individ-uals [4,5], pure VaD as the sole cause of dementiaappears to be uncommon. Several sets of criteriaexist for the diagnosis of VaD, with the main con-cept being the onset of dementia occurring within

the 3 months after a cerebral infarct, particularly

when the infarct involves the neocortex orthalamus.

Sleep disturbances are also common in the priondisorders (eg, Creutzfeldt-Jacob disease, fatal famil-ial insomnia, and Gerstmann-Straussler-Scheinkerdisease), and marked insomnia is a defining featureof fatal familial insomnia.

Most of the literature on sleep disturbances in de-mentia involve patients clinically diagnosed with

AD. However, as noted earlier, a few patients whohave typical AD clinical features do not have AD

when examined postmortem, and instead have henon-AD disorders listed in Box 1. Therefore, readersof this literature must keep in mind that these stud-ies have likely included cases with non-AD disor-

ders and thus the findings may not be specific forAD. Despite these inconsistencies, ample data and

Box 1: Principal causes of irreversibledementia

Degenerative Alzheimers disease Dementia with Lewy bodies

Parkinsons disease with dementia Picks disease Corticobasal degeneration Progressive supranuclear palsy Argyrophilic grain dementia Frontotemporal dementia with parkinson-

ism linked to chromosome 17 associatedwith mutations in the gene encoding micro-tubule-associated protein tau

Frontotemporal lobar degeneration withubiquitin- and TAR-DNA binding protein-43-positive inclusions

Frontotemporal lobar degeneration with

motor neuron disease Frontotemporal dementia with parkinsonism

linked to chromosome 17 associated withmutations in the gene encoding progranulin

Huntingtons disease

Vascular Vascular dementia

Prion Creutzfeldt-Jacob disease Fatal familial insomnia Gerstmann-Straussler-Scheinker disease

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clinical experience exist from which to developstrategies for managing common, and often chal-lenging, clinical problems in the dementedpopulation.

Diagnostic approachThis article provides data and strategies that are up-dated from an earlier article [6] using a diagnosticapproach, as shown in Box 2. Essentially, all sleepdisturbances in dementia relate to one of four pri-mary symptom complexes: insomnia, hypersom-nia, excessive motor activity at night, andnocturnal hallucinations/behavioral problems.

Within each symptom, the author reviews howthe symptom relates to the dementing illnessesthemselves, which primary sleep disorders may be

at play, which medications used for dementia mayimpact on the symptom, the role of depression inthat symptom, and finally, how circadian dysrhyth-mias can underlie that symptom. Pharmacologic

and nonpharmacologic management strategies arethen reviewed. Details regarding specific medica-tions are presented in Table 1.

Symptom complex: insomnia

Dementing illness

The incidence and prevalence of insomnia, per se, inpatients who have dementing illnesses are notknown, although sleep disturbances, in general,are known to exist in patients who have AD [79].

Such disturbances, which include insomnia, circa-dian dysrhythmia, nocturnal awakenings and agita-tion, and nocturnal wandering, can causeconsiderable caregiver burden and lead families todecide on nursing home placement [7,10,11]. Themedications used to treat these disturbances can

worsen obstructive sleep apnea (OSA) and daytimesymptoms [12]. Thus, the management of sleep dis-turbances in patients who have dementia is a com-

plicated and important clinical and societalproblem. Issues relating to specific sleep distur-bances are described in the following sections. In-somnia as an isolated disturbance may improve

with one or more of the agents presented in Table1. Studies using sodium oxybate and ramelteon inpatients who have dementia and insomnia areunderway.

Sleep disorders

Restless legs syndrome The incidence and prevalence of restless legs syn-drome (RLS) in patients who have AD and other de-menting conditions are not known, nor do anystudies address the safety and efficacy of variousagents in this population. Insomnia or hypersom-nia can result from untreated RLS. RLS is a clinicaldiagnosis and is purely based on a patients symp-toms. If a patient who has dementia does not al-

ready carry an RLS diagnosis, one must rely on

the patients response, which, by virtue of his/herillness, may or may not accurately reflect whetherany symptom is present or not. One must therefore

rely on the bed partners determination of the de-gree of restlessness at night, rather than solely bas-ing ones impression on the patients recall oftypical RLS symptoms. The authors clinical experi-ence suggests that RLS occurs with frequency in pa-tients who have AD, DLB, FTD, and VaD. Severalagents (eg, carbidopa/levodopa, pergolide, prami-pexole, and gabapentin [see Table 1]) appear to

be generally well tolerated and efficacious. How-ever, the dopaminergic agents should be used

with caution in patients who have psychotic fea-tures because these agents can escalate hallucina-tions and delusions.

Clinicians should keep in mind the associationbetween iron deficiency and RLS; when these coex-ist, it is often challenging, if not impossible, to treat

RLS effectively. One should not rely on routine re-sults obtained from a standard complete bloodcount; it is the ferritin level that is most important.

Those who have RLS and ferritin levels below50 ng/mL typically have limited responses to ther-apy. In such patients, daily use of iron supplemen-tation is recommended (ferrous fumarate plus

vitamin C is particularly well tolerated) for at least2 months, and perhaps longer, to achieve and

Box 2: Diagnostic approach for assessingsleep disturbances in patientswho have dementia

Essentially, all sleep disturbances in patientswho have dementia fall into one of four major

symptom complexes. Within each symptomcomplex, one can then consider five potentialunderlying causes for that symptom, whichcan then be pursued further and managed.

Symptom complex Insomnia Hypersomnia Excessive motor activity at night Nocturnal hallucinations/behavioral problems

Underlying causes Dementing illness and its associated neuro-

nal degeneration/ischemia/death and alter-

ations in neurochemical systems Primary sleep disorder Medication effect Depression Circadian dysrhythmia

Diagnosis and Management of Sleep Disturbances 349


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Table 1: Management of sleep disorders, hallucinations, and nocturnal agitation in patientswho have dementia: selected medications with suggested dosing schedules

Symptom/behavior/disorder Medication

Startingdose

Suggestedtitratingschedule

Typicaltherapeuticrange

Insomnia Trazodone 25 mg qhs Increase in 25-mg incrementsevery 37 d as necessary andtolerated, up to 300 mg/night

50200 mg/night

Chloral hydrate 500 mg qhs Increase in 500-mg incrementsevery 37 d as necessary andtolerated, up to 1500 mg/night

5001000 mg/night

Melatonin 3 mg Increase in 3-mg incrementsevery 37 d as necessary andtolerated, up to 12 mg/night

312 mg/night

Ramelteon 8 mg 8 mg 3060 minutes beforebedtime; may require 34 wkof nightly use to determineefficacy

8 mg/night

Zolpidem 2.5 mg qhs Increase in 2.5-mg increments

every 37 d as necessary andtolerated, up to 10 mg qhs

2.510 mg/night

Zolpidem CR 6.25 mg If standard zolpidem iseffective at inducing sleep,but effect lasts


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Table 1: (continued)

Symptom/behavior/disorder Medication

Startingdose

Suggestedtitratingschedule

Typicaltherapeuticrange

Dextroamphetamine 5 mg qam Increase in 5-mg increments

every 35 d as necessary andtolerated in bid dosing (AM andnoon), up to 40 mg bid

5 mg qam20 mg

bid (AM and noon)

Dextroamphetamine 5 mg qam Increase in 5-mg incrementsevery 35 d as necessary andtolerated, up to 40 mg bid

520 mg qam

Amphetamine/dextroamphetamine

5 mg qam Increase in 5-mg incrementsevery 35 d as necessary andtolerated in bid dosing (AM andnoon), up to 40 mg bid

5 mg qam20 mgbid (AM and noon)

REM sleepbehaviordisorder

Clonazepam 0.25 mg qhs Increase in 0.25-mg incrementsevery 37 d as necessary andtolerated, up to 2 mg qhs

0.251 mg/night

Melatonin 3 mg Increase in 3-mg increments

every 37 d as necessary andtolerated, up to 12 mg/night

312 mg/night

Carbidopa/levodopa 25/100 CR 1 tab qhs; increase to 2 tabs1 wk later if necessary

12 tabs/night

Quetiapine 25 mg qhs Increase in 25-mg incrementsevery 37 d as necessary andtolerated, up to 300 mg qhs

25100 mg/night

Nocturnalhallucinationsor delusionsor behavioraldyscontrol oragitation/aggression or

nocturnalwandering ordisinhibition

Donepezil 5 mg qam Increase to 10 mg qam24 wk later

510 mg qam

Rivastigmine 1.5 mg bid Increase in 1.5-mg incrementsfor both doses every 24 wk,to a maximum 6 mg bid

1.5 mg bid6.0 mgbid

Rivastigminetransdermal

4.6 mg/24-hpatch daily

Increase to the 9.5 mg/24-hpatch 24 wk later

4.6 mg/24 h9.5 mg/24 h

patch qamGalantamine 4 mg bid Increase in 4-mg incrementsfor both doses every 24 wk,to a maximum 12 mg bid

4 mg bid12 mg bid

Galantamine ER 8 mg qam Increase in 8-mg incrementsevery 24 wk, to a maximum24 mg qam

824 mg qam

Memantine 5 mg qd Increase gradually over34 wk, up to 10 mg bid

5 mg qd10 mg bid

Melatonin 3 mg Increase in 3-mg incrementsevery 37 d as necessary andtolerated, up to 12 mg/night

312 mg/night

Quetiapine 25 mg qhs Increase in 25-mg incrementsevery 37 d as necessary and

tolerated, up to 300 mg qhs

25100 mg/night

Olanzapine 5 mg qhs Increase in 5-mg incrementsq7 d in bid dosing (AM and hs)

5 mg qhs10 mg bid

Disclaimer and important points: The choice of which agents to use and which dosing schedules to recommend must be in-dividualized. It is the responsibility of the clinician to consider potential sideeffects, druginteractions, allergic response, life-threatening reactions, dosing changes due to renal or hepatic dysfunction, and so forth, before administering any drug toanypatient, including those listed above. Dr. Boeve, Mayo Foundation, and the publisher will not be responsible for any ad-verse reactions of anykind to anypatient regardingthe contentof this information. TheFood andDrug Administration (FDA)has issuedwarnings about the increased frequency of hyperglycemia/diabetes, stroke,and mortality associated with someorall of the atypical neuroleptics, and increased mortality associated withgalantamine in patientswho havemild cognitive im-pairment. (For these and otherwarnings, refer to the FDA Web site [www.fda.gov].)The FDA has also issued a warning aboutthe increased frequency of cardiac dysrhythmia, other morbidity, and death associated withpsychostimulant use. Clinicians,patients, and their families must carefully weigh the risks and benefits before commencing any of these agents.

Abbreviations: AM, morning; CR, controlled release; ER, extended release; qam, every morning; qhs, every night.

http://www.fda.gov/http://www.fda.gov/http://www.fda.gov/http://www.fda.gov/http://www.fda.gov/http://www.fda.gov/http://www.fda.gov/


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maintain ferritin levels well above 50 ng/mL. It isreasonable to also administer a dopaminergic agentor gabapentin over this same time period, and somepatients no longer require continued use of dopa-minergic therapy or gabapentin once ferritin levelsexceed 50 ng/mL.

The same logic as that for assessing iron defi-ciency and treating it with iron replacement therapyapplies to periodic limb movement disorder

(PLMD) (see section on excessive motor activitya night).

Central sleep apneaCentral sleep apnea (CSA) can cause profound hy-persomnia or insomnia; this topic is discussed inthe section on hypersomnia.

Medication effects

The only agents approved by the United States Foodand Drug Administration for the management ofdementia are the acetylcholinesterase inhibitors(AChEIs) (ie, tacrine, donepezil, rivastigmine, andgalantamine) and the N-methyl-D-aspartate(NMDA) antagonist memantine. The AChEIs actby blocking acetylcholinesterase activity, therebyleaving more acetylcholine in the synaptic cleft tocontinue activating the postsynaptic neuron. Mem-antine blocks NMDA receptors and is believed to

provide benefits by decreasing glutaminergic excito-toxicity. The usual starting doses and titrationschedules are shown in Table 1. The AChEI agents

and memantine can improve cognitive and neuro-psychiatric symptoms and functional abilities; evi-dence is not convincing that any of the agentsslow the course of any of the dementing conditions.

It is common practice for patients to be com-menced on either an AChEI or memantine firstand, once the maintenance dose is achieved, tothen add the other class or agent such that a combi-

nation of memantine and one of the AChEIs is be-ing administered. Although the clinical benefitfrom these agents is typically modest at best, rarepatients do experience rather dramatic improve-ment in symptoms and functional abilities,

particularly with the AChEIs. Based on head-to-head studies and clinical experience, none ofthe AChEIs appears to be superior to the others.

However, the clinical benefits and side effects are variable for each individual, so changing fromone AChEI to one of the others is reasonable, de-pending on the response to therapy. Despite the of-ten disappointing efficacy of these agents, andpotential side effects that can impact sleep andalertness, the progressive nature and universally fa-tal result of the irreversible dementing disorders cer-tainly justify using the AChEIs or memantine at

least for trial periods to determine if efficacy war-rants continued use.

TacrineTacrine was the first AChEI marketed for the man-agement of cognitive impairment in AD, but it is

rarely used anymore because of liver toxicity andthe need for frequent dosing during the day. Insom-nia can occur with this agent.

DonepezilDonepezil was the second AChEI to become avail-able on the market, and it is widely used in theUnited States and abroad. Donepezil affects acetyl-cholinesterase activity. The manufacturer recom-mends that it be dosed at night to minimize thedevelopment of nausea, although many clinicians

now dose this agent with breakfast because nauseatends to be mild and infrequent, and insomnia,nightmares, and nocturnal hallucinations can beproblematic for some patients.

RivastigmineRivastigmine affects acetylcholinesterase and butyl-cholinesterase activity, and this agent is also widelyused in patients who have dementia. Oral and

transdermal formulations are available. The manu-facturer recommends that the oral form be admin-istered twice daily, and most patients take the pill

with breakfast and supper. If insomnia is problem-atic with this agent, the latter dose can be taken ear-lier in the day, such as with lunch. The transdermalformulation should be applied each morning, withthe previous days patch removed and the currentdays patch placed on a different location of theskin (often changed after a patient takes a showerin the morning).

GalantamineGalantamine affects acetylcholinesterase and nico-

tinic receptor activity. This agent comes in liquidand capsule (given twice daily) and extended-

release capsule (given once daily) formulations. The extended-release pill should be given in themorning. If insomnia is problematic with the liquidor standard capsule formulations, the latter dosecan be taken earlier in the day, such as with lunch.

MemantineMemantine is an NMDA receptor antagonist, and itis often used in combination with one of the

AChEIs mentioned earlier. The medication is typi-cally titrated upward over 3 to 4 weeks to a mainte-nance dose of 10 mg twice daily. Although efficacyhas been demonstrated in placebo-controlled trials,

clinical experience has shown that improvement incognition and neuropsychiatric issues is typically

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subtle, rather than dramatic. Side effects are uncom-mon and minor. Insomnia due to memantine israre; when it does occur, taking the latter dose ear-lier in the day, such as with lunch, often alleviates it.

Depression

Depression is common in patients who have de-mentia, and can cause insomnia in demented indi-

viduals, similar to those who do not have anycognitive impairment. Antidepressant medicationscan also lead to insomnia, particularly those withactivating properties such as fluoxetine, venlafax-ine, and bupropion. The choice of when to treat de-pression and with which agent is up to the clinician,but because tricyclic antidepressants have mild tosevere anticholinergic side effects, these agents

should generally be avoided in patients who havedementia. Sertraline also has some anticholinergicactivity and is not ideal for patients who havedementia.

Circadian dysrhythmia

Although precise data on the incidence and preva-lence of circadian dysrhythmia in the dementedpopulation do not exist, several groups have ob-

served a high frequency of sleep fragmentation

and circadian dysrhythmia in the institutionalizedelderly [8,9,13,14]. The symptoms of insomniaand hypersomnia can reflect a primary circadian

dysrhythmia. Degenerative changes in the supra-chiasmatic nucleus of the hypothalamus and de-creased melatonin production are thought to becontributing factors in the circadian dysrhythmicabnormalities in patients who have AD and otherdementing conditions [15,16].

Two primary management strategies centeraround this knowledge: exogenous melatonin and

phototherapy. Data from small numbers of patientswho have dementia suggest that melatonin can im-prove sleep continuity and lengthen total sleep time[17,18]. A multicenter, placebo-controlled trial us-ing 2.5 mg slow-release and 10 mg formulations

of melatonin failed to demonstrate efficacy overplacebo, although individual patients clearly ap-peared to benefit from melatonin [19]. Studies

with ramelteon for the management of circadiandysrhythmia in patients who have dementia are inprogress, and clinical experience thus far has

yielded variable efficacy but good tolerability. Pho-totherapy has shown some promise in the manage-ment of circadian dysrhythmia in dementedindividuals, although the optimal timing and dura-tion of phototherapy and illumination intensityhave not yet been determined [2023].

Symptom complex: hypersomnia

Dementing illness

The incidence and prevalence of hypersomnia inthe various dementing conditions are not known,and reports of hypersomnia directly related to anunderlying degenerative dementing disorder havenot been published. Experience at the authors cen-ter indicates that some individuals who have DLBor FTD have objective evidence of hypersomno-lence, as measured by the multiple sleep latencytest, that is not associated with another primarysleep disorder, and such hypersomnolence can im-prove with psychostimulant therapy. More recent

evidence in DLB patients from the authors centerhas revealed marked hypersomnolence (mean ini-tial sleep latencies less than 5 minutes), sometime

associated with two or more sleep-onset rapid eyemovement (REM) periods, on the multiple sleep la-tency test, suggesting a narcoleptic profile (Fer-man and colleagues, unpublished data, 2008).Low-dose methylphenidate (5 mg or less) has beenshown to improve alertness in older patients resid-ing in nursing homes [24], and recent evidence sug-gests methylphenidate in older individuals mightreduce fall risk[25]. In the authors experience, mod-afinil, methylphenidate, dextroamphetamine, anddextroamphetamine/methamphetamine have beenhelpful in managing hypersomnolence in patients

who have dementia, without inducing untoward

neurobehavioral or cardiovascular side effects (see

Table 1). The anatomicophysiologic underpinningsof hypersomnia in dementing conditions are un-clear, although alterations in hypocretin production

or physiology may be at play[26].

Sleep disorders

Obstructive sleep apneaThe relationships among OSA, cognitive status, and

dementia are complex and not fully understood. Al-though OSA and dementia appear to be associated,data are conflicting as to whether OSA is causally re-lated to dementia [2732]. Because intracranialpressure increases markedly and cerebral perfusion

changes during apneic events [33,34], one wouldexpect that if OSA is causally related to any etiologicmechanism for dementia at all, VaD would most

likely be related. Evidence accumulated over thepast 20 years indicates that untreated OSA in thenondemented population causes cognitive impair-ment, excessive daytime somnolence (EDS), and di-minished mood and quality of life, and thattreatment of OSA (particularly with nasal continu-ous positive airway pressure [CPAP]) improves cog-nitive performance, EDS, mood, and quality of life[3550]. Neuropsychologic analyses have revealed



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that in patients who have OSA, cognitive flexibility,attention, processing speed, and memory all im-prove with CPAP therapy[39,46,51]. The challengeis that many patients who have OSA do not experi-ence an obvious clinical benefit from CPAP therapy,or cannot tolerate nightly CPAP use, so compliance

with CPAP therapy, even in nondemented individ-uals, is far from ideal.

In some instances, patients have been diagnosed

with delirium [52,53], dementia (not otherwisespecified) [54], and a degenerative dementing ill-ness [55], who are found to have untreated OSA,and delirium or dementia disappears with CPAPtherapy. Hence, OSA can be considered one of thereversible causes of delirium and dementia. The fre-quency of such cases is not known, but the fact thatsome individuals have dramatic functional and

neuropsychometric improvement with CPAP ther-apy, and the high prevalence of OSA in the elderly[28], underscore the need to consider OSA in anypatient who has cognitive impairment. Further-more, because CPAP therapy has now been shown

to improve the sleep quality in bed partners of pa-tients who have OSA [56], caregivers of patients

who have dementia and OSA could enjoy improvedquality of sleep/quality of life with their bed part-

ners use of CPAP therapy.Recent data show that cognition and alertness

improve with CPAP therapy in patients who have

OSA and a coexisting dementing illness, and thatCPAP therapy is tolerated in demented individuals[57,58]. No published data exist on the effects ofCPAP therapy on the bed partners/caregivers of pa-tients who have OSA and dementia. Experience atthe authors center has also revealed the followingregarding patients who have dementia and OSA:(1) a few patients do experience significant func-tional and mild neuropsychometric improvement

with CPAP therapy, (2) a significant proportion of

patients do tolerate CPAP therapy and use it nightly,

(3) some patients who have positional OSA do tol-erate positional therapy and experience mild clini-

cal improvement, and (4) some caregivers ofpatients enjoy less fragmented sleep and less EDS

while their bed partners who have dementia useCPAP therapy. Therefore, importantly, it shouldnot be assumed that patients who have dementiaand OSA cannot tolerate or benefit from CPAP ther-apy; most deserve a polysomnography (PSG) andCPAP trial, similar to any individual who doesnot have dementia.

Central sleep apneaCSA is known to occur in patients who have pri-mary cardiac and primary central nervous system

dysfunction. The dysregulation of the brainstem re-spiratory neuronal networks is presumed to be

responsible for CSA in degenerative dementing ill-nesses, and likely contributes similarly in VaD.

The frequency of CSA in the degenerative and vas-cular dementing conditions is not known, but inthe authors experience, it is far less common thanOSA in those who have mild to moderate dementia.

As in CSA related to cardiac dysfunction, manage-ment can be challenging. Nasal CPAP therapy, bile-

vel positive airway pressure therapy, adaptive

servoventilation devices, supplemental oxygen,benzodiazepines, or a combination of two or threeof these can provide symptomatic improvement in

some cases. Therapeutic trials typically require 1 or2 nights of PSG to determine which single therapyor combination of therapies provides the maximalbenefit.

Complex sleep apnea syndromeSome patients who have OSA develop a high fre-quency of central apneas or a disruptive Cheyne-Stokes respiratory pattern after application ofCPAP, which has been termed complex sleep ap-nea syndrome (CompSAS) [59,60]. Adaptive ser-

voventilation has been shown to be effective intreating CompSAS [61]. The incidence and preva-lence of CompSAS in patients who have dementia

have not been well studied, but in the authors expe-rience, this disorder does occur with some fre-quency in the dementia population, and adaptive

servoventilation can be tolerated and effective.

Periodic limb movement disorderSee section on excessive motor activity at night.

Medication effects

The AChEIs rarely cause hypersomnia, but in thosewho do experience this side effect, it may be worthwhile to change to another agent in this class be-cause it is rare to experience hypersomnia as

a side effect across all of the AChEIs. Hypersomnia

due to memantine is also rare.

Depression

Hypersomnia related to underlying depression cancertainly occur and, if suspected, an antidepressant

with few or no sedating properties could be used.


See the section on insomnia. Also, wake-promotingagents can be used effectively and without side ef-fects in patients who have hypersomnia, whetherrelated to a circadian dysrhythmia or not. Some-times, strategies directed at minimizing insomnia(eg, a sedative/hypnotic or phototherapy) plusa wake-promoting agent during the day can providethe best response.

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Symptom complex: excessive motoractivity at night

Dementing illness

See the section on nocturnal hallucinations/agita-tion for more details.

Sleep disorders

Rapid eye movement sleep behavior disorderREM sleep behavior disorder (RBD) is characterizedby simple or complex limb movements or vocaliza-

tions during REM sleep, and such behaviors typi-cally mirror the content of the dream whena patient is awakened and questioned [62]. Behav-

iors can be violent, and patient and bed partner in-juries can occur. The frequency and severity of RBD

varies among patients and during the course ofsymptoms in individual patients, but when RBD

is associated with a neurodegenerative disorder,the symptoms tend to wane as the degenerative ill-ness progresses. Differentiating RBD from noctur-nal wandering, somnambulism, and sleep terrorscan usually be done by taking a careful history[63]. RBD is more short lived, involves more vigor-ous limb movement, and is often associated with

vocalizations; dream content mirrors behaviors,the dream often involves a chasing or attacking

theme, and behaviors tend to occur more in the sec-

ond half of the night when more REM sleep typi-cally occurs. Nocturnal wandering is typicallymore prolonged, less violent, and not associated

with any apparent dream, and has a pacing or rum-maging quality. Somnambulism is less violent andmore prolonged, tends to occur in first half of thesleep period when more non-REM sleep occurs,and is not associated with any dream recall. Sleepterrors are typically not associated with any dream,involve more vocalization than limb activity, andoccur in the first half of the sleep period. Some pa-

tients have elements of more than one of these dis-tinct non-REM sleep parasomnias. When thediagnosis is in question, particularly when the po-tential for injury is present, PSG is warranted andis preferably performed with additional electro-

myogram leads on the arms and with synchronousvideo/PSG monitoring.

The association of RBD with neurodegenerative

disease is now well established and occurs particu-larly frequently in DLB, Parkinsons disease andPDD, multiple system atrophy, and pure auto-nomic failure (known collectively as the synuclei-nopathies) [6368]. The sensitivity andspecificity of RBD for DLB and PDD in the settingof dementia has not yet been determined, but de-tailed antemortem analyses and the lack of anypathologically confirmed cases of RBD in pure

AD, Picks disease, FTD, corticobasal degeneration,or VaD suggest that RBD may be predictive of un-derlying LBD in most patients who have dementia[68]. Recent analyses have also shown that in thosepatients who have dementia and RBD, the patternof impairment on neuropsychologic testing (eg, im-

paired visuospatial functioning, verbal fluency, andattention/concentration, with relative preservationof memory and confrontational naming) is consis-

tent and is parallel to what has been described inautopsy-proven LBD [69,70]. Therefore, a carefulsleep history and neuropsychologic testing may

provide diagnostically relevant information in theevaluation of patients who have dementia.

Ensuring safety in the sleep environment is thesimplest recommendation for managing RBD (ie,locate all potentially injurious objects away from

the bed, place mattress on floor next to bed, andso forth). Clonazepam has been the drug of choiceand is usually effective in the 0.25 to 1.0 mg/nightdose range (see Table 1) [71,72]. Because benzodi-azepines can precipitate or aggravate OSA, it is im-

portant to ensure that no OSA exists before usingthis agent, or that nasal CPAP therapy is successfullytreating OSA if it is present. Clinicians often expressconcern about using this long-acting benzodiaze-

pine in patients who have dementia but, in the au-thors experience, it has been tolerated well with fewor no cognitive side effects in most cases. Melatonin

has also been shown to be effective in minimizingRBD, either by itself or in combination with clona-zepam [73,74]. The author typically commences3 mg nightly and, depending on clinical responseand side effects (which are typically rare), titratesupward in 3 mg increments every 3 to 7 nights asneeded and tolerated, up to 12 mg/night (see Table1). In those rare individuals who have pervasiveRBD that is not responding adequately to clonaze-pam plus melatonin, adding quetiapine can be ef-fective. Some patients derive benefit from

controlled-release carbidopa/levodopa for RBD, soin those who have RBD plus RLS or periodic limb

movements (PLMs), this agent may be a good firstoption.

Periodic limb movement disorderAs in the other primary sleep disorders, the inci-dence and prevalence of PLMD in patients whohave dementia are not known. In the authors expe-rience, PLMD does occur with some frequency inthis population, and PSG is sometimes helpful di-agnostically in hypersomnolent demented patients

when they and their bed partners are entirely un-aware of the existence of PLMs. Some unresolved is-sues include the frequency of PLMs, and the

frequency of arousals due to PLMs, that may be con-sidered clinically significant. The snapshot that



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1 nights PSG provides is an approximation of thenightly presence and frequency of key sleep indices,so it is probably not necessary to rely on hard cut-offs for PLM frequency and PLM arousal frequencyto make treatment decisions.

If the sleep issue is patient hypersomnolence,

then a PLM arousal frequency of at least 5 or 10per hour (similar to the suggested arousal frequencyfor treating sleep-disordered breathing) would be

reasonable to treat. If the sleep issue is bed partnersleep disruption due to the patients excessive mo-tor activity at night, then the mere presence ofPLMs may be sufficient to warrant treatment.

As in RLS, treatment with carbidopa/levodopa,pramipexole, ropinirole, or gabapentin is generallyefficacious and well tolerated. Again, the dopami-nergic agents should be used with caution in pa-

tients who have psychotic features because theseagents can aggravate psychosis. Measuring ferritinmay also be worthwhile to ensure that relativeiron deficiency is not contributing to PLMs; for

values below 50 ng/mL, iron replacement therapy

is reasonable.

Medication effects

The cholinesterase inhibitors and memantine rarelyinduce or aggravate RBD or PLMs. If any appear todo so by the temporal association of worsening

RBD or PLMs with adding one of these drugs,then the timing of medication administration canbe altered. One report has suggested donepezilcan alleviate RBD [75].

Some antidepressants, particularly venlafaxineand mirtazapine, have been reported as inducingor aggravating RBD [76,77] but theoretically, any

agent designed to affect mood could alter RBD fre-quency and severity. It would be prudent to shyaway from these two agents if RBD is bothersomeand depression is sufficiently problematic to war-rant treatment. Because of its dopaminergic effects,

bupropion may be preferable to several otheragents in managing depression in patients whohave significant RBD, but no clinical studies havebeen carried out to prove its efficacy in this clinicalsetting. Although selective serotonin reuptake in-hibitors can also theoretically worsen PLMs, it israrely clinically significant.


In the setting of daynight reversal and other circa-dian dysrhythmic disorders, demented patients willtend to sleep more during the day and be activemore during the night. This increased motor activ-ity at night can result in significant caregiverdistress. Melatonin or phototherapy can be consid-ered (see discussion in section on insomnia).

Symptom complex: nocturnalhallucinations/behavioral problems

Dementing illness

Nocturnal hallucinations As patients develop more cognitive impairmentwith progression of the dementing illness, the dif-ferentiation among dream mentation, visuopercep-tual dysfunction, and reality can become blurred.

This blurring appears to be particularly evident inend-stage DLB and PDD (arguably the same under-lying substrate for dementia), although visual hal-lucinations, illusions, and misidentification canalso occur in AD and FTD. Whether the visual hal-

lucinations that occur with DLB and PDD representfragments of REM sleep invading into wakefulness

versus some other process is a matter of debate,

but some evidence in patients who have PD sug-gests the dream imagery of REM sleep may be con-tributing to daytime visual hallucinations [78].Patients may converse with or yell at, swing limbstoward, or kick toward apparent objects, animals,or people. When hallucinations are mild and notfrightening to patients, reassurance often suffices;pharmacologic intervention should be reserved forthose who are frightened or bothered by them.

One should ensure that no medical illness hasarisen (eg, urinary tract infection, pneumonia)and all medications with potential hallucinatoryside effects should be decreased or eliminated (eg,

levodopa, amantadine, selegiline). Although theAChEIs can aggravate hallucinations, some reports(confirmed by the authors experience) suggestthat they can significantly ameliorate hallucinations

and delusions (see Table 1) [7981]. Risperidoneand olanzapine are purported to be effective inmanaging these symptoms without causing extrapy-ramidal side effects, but this is not always the case.Clozapine can be effective in this setting, but theneed for frequent laboratory monitoring because

of rare agranulocytosis can pose inconveniencesfor patients, families, and clinicians. Quetiapine ap-pears similar in efficacy to clozapine, and becauseagranulocytosis is not an issue, no laboratory mon-itoring is necessary. This agent is costly but is now

widely used because it can provide adequate man-agement of hallucinations, delusions, and problem

behaviors, with tolerable side effects.Conventional neuroleptics such as haloperidol

should generally be avoided in patients who have

dementia, and they are absolutely contraindicatedin patients who have DLB, PDD, or PD [7981].

Nocturnal agitation/behavioral dyscontrol

One must consider medical issues such as pain, in-fection, and so forth, when agitation during day or

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night evolves, especially when it does so abruptly.One should also use behavioral techniques beforeproceeding to pharmacologic intervention. Tech-niques such as acknowledging the source of agita-tion if it can be identified, then using gentleredirection, can be effective, but the caregiver or

nursing home staff needs to be trained in how touse behavioral techniques, which some master butmany do not. Various medications can be effective

for managing nocturnal agitation (see Table 1). The AChEIs (eg, donepezil, rivastigmine, galant-amine), memantine, atypical neuroleptics (eg,olanzapine, quetiapine), antiepileptics (eg, carba-mazepine, valproic acid), benzodiazepines (eg, clo-nazepam), and trazodone and chloral hydrate, canbe considered if drug therapy is needed [1]. If agi-tated depression is suspected, psychiatric consulta-

tion for consideration of electroconvulsive therapycan be helpful.

Sleep disorders

Rapid eye movement sleep behavior disorderRBD is discussed in the section on excessive motor

activity at night.

Medication effects

Ample data indicate that the AChEIs and meman-

tine can improve hallucinations and agitation,

and cognition (se Table 1) [8286]. Yet some pa-tients appear to have hallucinations or agitation

precipitated or aggravated by one or more of thesedrugs; nocturnal hallucinations appear to be morecommonly associated with cholinesterase inhibitortherapy, especially when administered before bed-time. Decreasing the dose, moving the timing ofthe dose to earlier in the day, or discontinuing thedrug altogether may be necessary in such instances.


SundowningSundowning is a nebulous term. Delirium, confu-sion, disorganized thinking, impaired attention,restlessness, hyperactivity, wandering, agitation, in-somnia, hypersomnia, hallucinations, illusions, de-

lusions, anxiety, and anger have all been consideredfeatures of the sundowning syndrome [13,87].

The term implies that problem symptoms or behav-

iors develop during the evening or night. Althoughmany clinicians have heard caregivers or nursinghome staff describe the escalation of symptoms to-

ward the late afternoon or evening, little data sup-port that this escalation occurs [13]. Bliwise andcolleagues [13] suggested that some componentsof sundowning may reflect disruptive behaviors oc-curring with identical frequency throughout the daybut with differential impact upon nursing staff. The

same phenomenon could be occurring with care-givers of patients residing at home.

Several different physiologic substrates for the various problem symptoms and behaviors arelikely, and the optimal strategies for managementmay reflect the physiologic underpinnings, which

have yet to be fully characterized. Therefore, incommunicating among health care professionals,patients, caregivers, and researchers, it may be

more appropriate to use descriptive terms orphrases such as agitation and physically aggressivebehavior or wandering and pacing rather thansundowning. Furthermore, administering medica-tions to patients is only one facet of management;caregiver education, psychologic support, timeaway from patients by way of respite care, and soforth, are also critical.

Several modalities have been suggested to ame-liorate various features of the sundowning syn-drome (see excellent review by McGaffigan andBliwise [88].) Table 1 presents several agents thatare variably effective for problem symptoms and

behaviors. The dictums of therapy are (1) usea trial-and-error approach and (2) start low andgo slow. Combination therapy is sometimesnecessary.

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