Delirium Diagnostic and Classification Challenges in Palliative Care: Subsyndromal Delirium, Comorbid Delirium-Dementia, and Psychomotor Subtypes

Vol. 48 No. 2 August 2014 Journal of Pain and Symptom Management 199

Special Section: Studies to Understand Delirium In Palliative Settings (SUNDIPS)

Delirium Diagnostic and ClassificationChallenges in Palliative Care: SubsyndromalDelirium, Comorbid Delirium-Dementia,and Psychomotor SubtypesMaeve M. Leonard, MB, MRCPsych, MD, Meera Agar, MBBS, FRACP,Juliet A. Spiller, MBChB, MRCP (Edin), Brid Davis, BSc, MSc,Mas M. Mohamad, MB, BMed Sci, MRCPI, MRCPsych,David J. Meagher, MD, PhD, MRCPsych, and Peter G. Lawlor, MB, FRCPI, MMedScGraduate Entry Medical School (M.M.L., D.J.M.) and Milford Care Centre (B.D., M.M.M.),

University of Limerick, Limerick, Ireland; Discipline, Palliative & Supportive Services (M.A.),

Flinders University, Adelaide, South Australia; South West Sydney Clinical School (M.A.), University

of New South Wales; Department of Palliative Care (M.A.), Braeside Hospital, HammondCare,

Sydney, New South Wales, Australia; Palliative Medicine (J.A.S.), Marie Curie Hospice, Edinburgh

and West Lothian Palliative Care Service, Edinburgh, United Kingdom; Bruy�ere Research Institute

(P.G.L.), Bruy�ere Continuing Care; Division of Palliative Care (P.G.L.), Department of Medicine,

Epidemiology and Community Medicine, University of Ottawa; and The Ottawa Hospital Research

Institute (P.G.L.), Ottawa, Ontario, Canada

Abstract
Context. Delirium often presents difficult diagnostic and classification
challenges in palliative care settings.Objectives. To review three major areas that create diagnostic and classification

challenges in relation to delirium in palliative care: subsyndromal delirium (SSD),delirium in the context of comorbid dementia, and classification of psychomotorsubtypes, and to identify knowledge gaps and research priorities in relation tothese three areas of focus.

Methods. We combined multidisciplinary input from delirium researchers andknowledge users at an international delirium study planning meeting and relevantPubMed literature searches as the knowledge synthesis strategy in this review.

Results. We identified six (SSD), 33 (dementia), and 44 (psychomotorsubtypes) articles of relevance in relation to the focus of our review. Recentliterature data highlight the frequency and impact of SSD, the relevance ofcomorbid dementia, and the propensity for a hypoactive presentation of deliriumin the palliative population. The differential diagnoses to consider are wide andinclude pain, fatigue, mood disturbance, psychoactive medication effects, andother causes for altered consciousness.

Address correspondence to: Peter G. Lawlor, MB, FRCPI,MMedSc, Bruy�ere Continuing Care, 43 Bruy�ereStreet, Ottawa, Ontario, Canada K1N 5C8. E-mail:[email protected]

Accepted for publication: April 2, 2014.

� 2014 American Academy of Hospice and Palliative Medicine.Published by Elsevier Inc. All rights reserved.

0885-3924/$ - see front matterhttp://dx.doi.org/10.1016/j.jpainsymman.2014.03.012

Delta:1_given name

Delta:1_surname

Delta:1_given name

Delta:1_surname

Delta:1_given name

Delta:1_surname

Delta:1_given name

mailto:[email protected]

http://dx.doi.org/10.1016/j.jpainsymman.2014.03.012



200 Vol. 48 No. 2 August 2014Leonard et al.

Conclusion. Challenges in the diagnosis and classification of delirium in peoplewith advanced disease are compounded by the generalized disturbance of centralnervous system function that occurs in the seriously ill, often with comorbidillness, including dementia. Further research is needed to delineate thepathophysiological and clinical associations of these presentations and thusinform therapeutic strategies. The expanding aged population and growing focuson dementia care in palliative care highlight the need to conduct thisresearch. J Pain Symptom Manage 2014;48:199e214. � 2014 American Academy ofHospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.

Key Words
Delirium, palliative care, subsyndromal, diagnosis, assessment, dementia, psychomotor,classification and hospice
IntroductionDelirium is a common and distressing medi-

cal syndrome for people with advanced life-limiting illness, whether viewed from theperspective of the patient, their loved ones,or the health professionals caring for them.1e6

There are many challenges in achieving a pre-cise diagnosis in patients with possible deliriumin palliative care clinical settings (Table 1).These challenges reflect difficulties in theassessment process; issues of conceptual over-lap in relation to both the neurocognitive sta-tus of patients with pre-existing or evolvingdementia and overlap between delirium anddepression; the impact of extreme frailty andcachexia; and use of potent psychoactive med-ications, often in association with polyphar-macy.7,8 The relatively high frequency ofhypoactive presentations of delirium in pallia-tive care, whether as part of a mixed or purelyhypoactive psychomotor subtype of delirium,may present diagnostic challenges and increasethe risk of the disorder not being detected.4

The diagnostic criteria of the Diagnostic and Sta-tistical Manual of Mental Disorders (DSM) arewidely recognized. In the recently published5th edition of the DSM, DSM-5,9 one of thefive diagnostic criteria requires that there is ev-idence from the patient’s history, physical ex-amination, or laboratory investigations toexplain the presence of delirium in associationwith a medical condition or other etiology(Table 2). In this regard, the level of laboratoryinvestigation in palliative care settings may belimited in the context of goals of care, espe-cially when a possible delirium arises in whatappears to be the last hours or days of life.

The focus of this narrative review was toexplore three principal areas of diagnosticchallenge in the context of advanced illness:1) the nature and relevance of subsyndromaldelirium (SSD); 2) delirium in the context ofcomorbid dementia; and 3) classification ofpsychomotor subtypes of delirium, in partic-ular the hypoactive presentations that arecommonly seen in the palliative care setting.The review also highlights knowledge gapsand pertinent aspects of delirium diagnosisand assessment in palliative care settings todate and proposes future studies in relationto the three areas of focus in the review.

MethodsWe performed a narrative review of pub-

lished articles found by a literature searchthat used the key words ‘‘subsyndromal,’’ ‘‘psy-chomotor subtypes,’’ ‘‘delirium and advanceddementia’’ or ‘‘delirium’’ and ‘‘delirium anddementia’’ combined with ‘‘palliative medi-cine,’’ ‘‘palliative care settings,’’ and ‘‘end-of-life’’ in PubMed and MeSH and limited tothose in English from the years 1997 to 2012inclusive. ‘‘Terminal restlessness’’ and ‘‘termi-nal delirium’’ were not covered, as this topicis covered in a separate article in this section.10

This specific literature is considered in thecontext of what is known regarding deliriumassessment in other populations, so as todevelop specific research questions regardingdelirium diagnosis and classification in pallia-tive care.In addition, we obtained multidisciplinary

input from leading delirium researchers,

Table 1Challenges in Delirium Diagnosis and Classification in Palliative Care Settings

1. Ethical and pragmatic aspects in balancing the burden of investigation (from both patient and caregiver perspectives) withthe need for a thorough delirium assessment and management plan

2. Identifying when delirium pathology is reversible vs. irreversible and in context of a patient’s proximity to death3. Impaired communication and decision-making capacity4. Delirium assessment often occurs in the context of multiple medical morbidities, extreme frailty, cachexia, and fatigue5. Polypharmacy, in particular those medications with psychoactive effects6. Overlap of delirium phenomenology with major differential diagnoses, namely pain, depression, and dementia. High

potential for misdiagnosis of hypoactive delirium as depression7. Lack of clinical agreement regarding the existence of subsyndromal delirium potentially leading to a missed diagnosis

Vol. 48 No. 2 August 2014 201Delirium Diagnostic and Classification Issues

methodologists, primary care and specialist-level clinicians, palliative care experts, andclinical administrators at an international twoday delirium study planning meeting inOttawa, Canada, in June 2012. Our meetingwas designed to promote collaboration andinitiate deliberations toward the developmentof a research framework under the broadheading of ‘‘Studies to Understand DeliriumIn Palliative Settings’’ and hence the acronym,SUNDIPS. Within this broad SUNDIPS pro-gram of research, we targeted two of the majorinvestigational domains for delirium in pallia-tive care settings as subprograms of research:1) epidemiologic issues and issues of deliriumprediction, screening, and diagnosis and 2)experiential or phenomenological aspects ofdelirium in its entire trajectory, including sub-syndromal and full syndromal states. All pre-sentations and interactions during theconference working groups were recordedand transcribed.

ResultsThe literature search yielded 83 research ar-

ticles directly related to the key words. Ofthese, only six articles specifically addressedthe aspects of SSD in palliative care. The

Table 2Diagnostic and Statistical Manual of Mental Disorders

A. A disturbance in attention (i.e., reduced ability to direct, focus,orientation to the environment).

B. The disturbance develops over a short period of time (usually hoattention and awareness, and tends to fluctuate in severity durin

C. An additional disturbance in cognition (e.g., memory deficit, disD. The disturbances in Criteria A and C are not better explained by a

disorder and do not occur in the context of a severely reduced lE. There is evidence from the history, physical examination, or labor

consequences of another medical condition, substance intoxicatimedication), or exposure to a toxin, or is due to multiple etiolo

Reprinted with permission from the Diagnostic and Statistical Manual of Mental DRights Reserved.

concept of SSD is understudied in both pallia-tive care populations and other medical pa-tient groups, and because of the difficulty inconsistently operationalizing its definitionand because of its varying nature, it remainsa contentious diagnosis for some physicians.11

Of the 44 articles exploring the psychomo-tor subtype, there were 11 of specific relevancethat addressed the development and psycho-metric testing of the Delirium Motor SubtypeScale;12,13 documentation of the frequencyand stability of motor subtypes; and the rela-tionship of subtypes with other phenomeno-logical and etiologic aspects, in addition tomedication exposure, treatment, and prog-nosis in a palliative care population.12,14e20

Breitbart et al.21 developed the MemorialDelirium Assessment Scale, which records mo-tor subtype (described in a separate article inthis section22) and which has been used tostudy the frequency of subtypes and their rela-tionship with phenomenology, treatment, andcomorbid dementia.6,23e27

There is a large body of literature on deliriumin the setting of comorbid dementia, addressingvarious aspects, especially the goals of care andfocusingonquality of life, dignity, andcomfort;28

best practice in relation to pain management inpatients with dementia;29 treatment characteris-tics of delirium superimposed on dementia;24

(DSM-5) Diagnostic Criteria for Delirium

sustain, and shift attention) and awareness (reduced

urs to a few days), represents a change from baselineg the course of a day.orientation, language, visuospatial ability, or perception).nother pre-existing, established, or evolving neurocognitiveevel of arousal, such as coma.atory findings that the disturbance is a direct physiologicalon or withdrawal (i.e., due to a drug of abuse or to agies.

isorders, 5th edition, (�2013). American Psychiatric Association. All


and an exploration of the phenomenologicalinterface between delirium and dementia inpalliative care.15 We identified 33 articles of rele-vance in relation to delirium and comorbiddementia.

DiscussionSubsyndromal Delirium

SSD, although still subject to debate amongclinicians and researchers, is an importantconsideration in palliative care as symptomscritical to its identification (altered conscious-ness and inattention) are common inadvanced illness. It is important to acknowl-edge that hypoactive delirium is the most com-mon subtype in palliative care,17,30 and the ‘‘nosubtype’’ or normal psychomotor classificationhas been found to be most common in SSD.17

Hypoactivity, as part of an episode of SSD, hasbeen identified as one of the features thatdistinguish the SSD phenotype from nondeli-rium.31 Given that the hypoactive subtypehas a known association with the under- andmisdiagnosis of delirium,32,33 it is likely thatthe association of hypoactivity or normal psy-chomotor activity with SSD may similarlycontribute to underrecognition of SSD. How-ever, the presence of any delirium symptomwarrants recognition as to how much it relatesto patient and caregiver distress.1

SSD was first described by Lipowski.34 It hasbeen defined by both categorical (i.e., thepresence of any core delirium symptomswithout the presence of all the diagnosticcriteria) and dimensional (i.e., severity scoreson rating scales that are below the diagnosticthreshold) methods. SSD is increasingly recog-nized as prognostically important; its outcomesare consistently identified as being intermedi-ate between the full syndrome of delirium(FSD) and no delirium.31,35e39 As a syndrome,delirium is phenomenologically diverse, symp-toms are relatively nonspecific, and thedilemma is whether there are key symptomsthat are critical for diagnosis, or indeed if therange and contextual pattern are more usefulindicators of a delirium diagnosis than thepresence of individual symptoms.

Perhaps, the most pressing issue is theabsence of a clear definition of SSD, thus lead-ing to a lack of consensus regarding how to

consistently diagnose it in clinical practiceand research studies.40 In the DSM 4th edition(DSM-IV),41 SSD was not specifically catego-rized but included under the vague umbrellaterm ‘‘other cognitive disorders not otherwisespecified.’’ In the DSM-5,9 SSD is now moreclearly listed in the neurocognitive disorders(NCDs) section as ‘‘attenuated delirium syn-drome.’’ However, it still does not have cleardescriptive criteria enabling clinicians tomake a clear diagnosis. Without diagnosticprecision and because of variation in clinicalpopulations studied, there is wide variation inthe estimated prevalence of SSD, with studiesindicating a range from 7% to 50%.36,42e44

Studies to date have defined SSD on the basisof varying criteria: the presence of one ormore symptoms of delirium (inattention,altered level of consciousness, disorientation,and perceptual disturbances);45 the presenceof one or more Confusion Assessment Method(CAM)46 delirium symptoms (acute onsetand fluctuation, inattention, disorganizedthinking, and altered level of consciousness);36

a subdiagnostic score on the Delirium RatingScale Revised-98 (DRS-R98);11,47 and coredomain symptoms of delirium, identifiedthrough cluster analysis of DRS-R98 itemsand demonstrating a phenotype similar todelirium but a severity that is intermediate be-tween FSD and nondelirium.31

Clinically, SSD may reflect a variety ofdelirium-relevant presentations. It can occurduring either evolving or resolving delirium.It also may occur as part of a persistent deficitstate after an episode of FSD, sometimespersisting or interspersed with FSD during re-covery. Moreover, the inherently fluctuatingnature of delirium symptoms is such thatperiods of less prominent symptoms (butmeeting SSD criteria) can occur during anepisode of delirium. Alternatively, SSD maysimply reflect less severe episodes or deliriumthat is less symptomatically intense such thatstudies indicate that SSD can be readily placedon a spectrum of phenomenological severity11

and prognostic severity; outcomes for SSD areintermediate between those who have deliriumand those who do not.35 More detailed longi-tudinal studies of the course of symptoms inpatients experiencing delirium are needed toclarify how SSD relates to emerging and/orresolving delirium episodes.


Study data from the intensive care unitsetting suggest that some SSD cases are oftenaccounted for by altered consciousnesswithout other symptoms of delirium.36 Thesepatients with altered consciousness (butwithout FSD) have outcome profiles that aresimilar to FSD, but this does not necessarilyimply that these disorders are pathophysiolog-ically linked. This raises fundamental issues asto where the concept of delirium as an entitybegins and ends. It is still unknown if deliriumcan be considered as a particular type of distur-bance of consciousness that has wide impacton brain function but yet is distinct from othercauses of altered consciousness. In short, notall patients with altered consciousness willmeet the criteria for delirium, but many expe-rience the similarly poor outcomes that areassociated with delirium.

The diagnosis of SSD is particularly relevantin palliative care because symptoms critical todiagnosis, namely altered consciousness andinattention, are very common in this setting,and the unquestionable attribution of thesenonspecific symptoms to SSD in the absenceof FSD is a moot point. Inattention is a manda-tory feature of FSD, but it is not clear whetherit also should be considered as an essentialcomponent in the definition of SSD. As such,dimensional approaches to diagnosis (rangeof symptoms but at lower severity) may bemore discerning as they are less prone to theinfluence of the presence of single symptoms.

Meagher et al.,11 reporting on the featuresof subsyndromal and persistent delirium in alongitudinal study of 100 palliative care inpa-tients with DSM-IV delirium, used the DRS-R98 score range of 8e15 to delineate thosewho were subsyndromal in severity. The studyfound 27 participants in this score range atbaseline and 41% during the 323 follow-up as-sessments over the six week study period.Similar to prior studies, all symptoms (cogni-tive, perceptual, psychomotor, and attention)were found to occur in SSD and FSD in thiscohort and exhibited minimal fluctuation;the difference was that less severe symptomswere seen in SSD.31,48

The association of hypoactive presentationswith FSD and possibly also SSD may eitherreflect specific pathophysiological mechanismsin their pathogenesis or the pathologic mani-festation of the underlying disease, such as

motor compromise in a cachectic cancer pa-tient. Although such associations are hypothet-ical, the hypoactivity feature probably shouldbe viewed in context, especially in palliativecare settings, in which hypoactive presenta-tions predominate. In everyday clinical prac-tice, hypoactive delirium is frequently notdetected or misdiagnosed as dementia ordepression.49 Similarly, a study of general hos-pital patients suggests that SSD is not aconcept that is appreciated in real-world careand SSD is rarely labeled as delirium or anyof its synonyms by medical or nursing staff.50

In addition to its impact on ongoing careand outcomes, it is relevant that the presenceof any delirium symptoms can cause patientand caregiver distress, and identification ofSSD is crucial to ensure clinicians acknowledgethat the symptoms exist, can provide a mean-ingful explanation of the reason for thesesymptoms and a plan of management, andcontinue to regularly assess symptomatology.

The impact of SSD on outcomes needs to beexplored in the palliative population, but it islikely to infer morbidity and mortality, asseen in acute care populations.35 Importantly,recent studies of pharmacologic interventions,including both typical and atypical antipsy-chotics, have demonstrated significant reduc-tions in the incidence of SSD in critical carepatients51 and a lower transition rate fromSSD to FSD,52 thus highlighting how the timelyand consistent detection of SSD may providean opportunity for effective early intervention.O’Hanlon et al.53 have described a schema formanaging delirium-relevant presentations ineveryday care that incorporates computer-assisted technologies to assist in reliable detec-tion and consistent decision making aroundmanagement; differing levels of deliriumsymptomatology are linked to evidence-basedinterventions. Further studies are required toclarify the impact of antipsychotic administra-tion and other interventions on the clinicalcourse of SSD in general, and also in the palli-ative population.

Comorbid Delirium and Dementia inPalliative Care

Dementia is recognized as a potent predis-posing risk factor for the development ofdelirium.54,55 Delirium in the palliative caresetting may occur either in association with


advanced dementia as the principal life-threatening illness or in the context ofanother principal life-threatening illnesssuch as cancer, and comorbid dementia(spanning all levels from early to late) alsomay be present. The comorbid associationof delirium and dementia in palliative carehighlights issues in relation to the pathophys-iological overlap between the two; theacknowledgment of dementia, especiallyadvanced dementia, as a life-threateningillness within the palliative care remit; clinicalmanifestation, recognition, and assessmentstrategies; and the unmasking of dementiawith the treatment of delirium. Over the lastdecade, the development of a mouse modelfor the study of inflammation (as a deliriogen-ic precipitant) superimposed on pre-existingneurodegeneration (ME7 mouse model ofprion disease) and the plethora of literatureon brain dysfunction in acute illness and de-mentia have greatly helped to advance ourknowledge of the delirium-dementiainterface.56e62

Delirium and Dementia: Overlapping Pathophysi-ology. In addition to the overlap of some clin-ical features between delirium and dementia,there is some sharing of the putative patho-physiological mechanisms that are part of thepathogenesis of both disorders. Most promi-nent among these shared mechanisms arethe phenomena of reduced cerebral cholin-ergic neurotransmission, systemic inflamma-tion, and neuroinflammation, which in turnalso are possibly interrelated.57e59,63 In pallia-tive care settings, many patients have a cancerdiagnosis, and the contribution of known sys-temic inflammation in association with can-cer64 warrants consideration.65

Many researchers have queried the basis ofthe clinical observation that a relatively severeinfection is required to precipitate an episodeof delirium in a younger nondemented pa-tient, whereas a relatively minor infection inan older patient with dementia may triggeran episode of delirium.55,63,65,66 The neuronalaging hypothesis of delirium holds that in thecase of pre-existing dementia or even in theolder brain, neuropathologic changes, result-ing in ‘‘overactivated microglia,’’ render suchpatients more vulnerable to the effects ofsystemic inflammation.67 Microglial activity

in the central nervous system is normally in-hibited by acetylcholine.68 In the event ofcholinergic deficiency, as occurs in older age,dementia, or possibly in association with med-ications that have an anticholinergic effect,69

there is the potential for microglial activity togo unchecked or microglia become ‘‘overacti-vated.’’63 This may explain the predisposingvulnerability to delirium in the patient withpre-existing or evolving dementia, wheresystemic inflammation may cross the blood-brain barrier, for example, in the case of infec-tion. It also may explain the persistence ofsome delirium symptoms in association withpersistent neuroinflammation and secondaryneurodegeneration, even after the apparentlysuccessful treatment of infection. Thustogether, these hypotheses may possiblyexplain the risk of delirium occurrence andthe propensity for at least its partial persistencein the presence of dementia.58

Advanced Dementia in the Context of PalliativeCare. Historically, palliative care serviceshave focused mainly on cancer-related illness,in which there is a high prevalence of morepersistent or enduring cognitive problems,often with multifactorial etiology, includingthose resulting from intracranial malignancy.The global prevalence of dementia is pre-dicted to increase to more than 81 million by2040,70 yet there is often a lack of awarenessof dementia itself as a terminal conditionand a lack of clarity regarding how, when,and by whom palliative care should be deliv-ered.71,72 The complexities of caring for thosewith dementia have been highlighted bySmall,73 who emphasizes the fine balance ofactive investigation and intervention asopposed to focusing on ensuring optimallevels of comfort and analgesia, especially inmore advanced illness. Moreover, this chal-lenge frequently arises in the context of wherethe person with dementia has lost decision-making capacity.74 However, there is anemerging international trend for greaterinvolvement and optimal provision of pallia-tive care services in dementia care, as there ismuch overlap in the holistic care needs ofpalliative care and dementia populations.75

Mitchell et al.76 reported that families’ evalua-tion of hospice care for older patients is gener-ally high, irrespective of the decedents’


diagnosis of dementia, cancer, or chronicdisease.

The frequency of dementia in palliative caresettings has been steadily increasing, fromapproximately 1% in 1995 to 6.8% in 2001,with recent U.S. estimates indicating thatalmost 13% of palliative care patients have aprimary diagnosis of dementia.77,78 A longitudi-nal study of the phenomenological profile of100 consecutive adults, almost exclusively withan underlying diagnosis of cancer, admittedto a palliative care inpatient unit reported arate of 27% for either dementia or other causesof persistent cognitive impairment of at leastsix month duration.15 The severity of the co-morbid dementia was not documented.

Clinical Manifestation and Trajectory of ComorbidDelirium and Dementia. Similar to patients inpalliative care, those in the advanced stagesof dementia are especially prone to delirium.There is also a similar preponderance of rela-tively hypoactive presentations, which are asso-ciated with inherent challenges in diagnosingdelirium, in both the dementia and palliativecare populations.49,79,80 Furthermore, hypoac-tivity is also a feature of frailty, a syndromewhich often coexists with dementia, and alsowith advanced disease, such as cancer.81 Frailtyreflects a reduced ability to compensate tostressors and likely also confers a degree ofvulnerability toward the development ofdelirium.82 The type of presentation of comor-bid delirium and dementia is likely to be influ-enced by the severity of the dementia and alsothe type of dementia, for example, dementiawith Lewy bodies has strong association withperceptual disturbance.83 However, the influ-ence of these parameters (severity and typeof dementia) has not been reported in studiesto date.84 In Alzheimer’s disease, studies havedemonstrated an association between systemicinflammation, as reflected by raised serumproinflammatory cytokines, and an increasein cognitive decline independent of delirium61

and neuropsychiatric symptoms of sicknessbehavior (especially the three core symptomsof apathy, depression, and anxiety) both in as-sociation with and independent of delirium.62

These findings are consistent with the premisethat the occurrence of delirium in a youngerand healthier patient may require a greater de-gree of systemic inflammation, whereas only a

mild degree of inflammation may trigger anepisode of delirium in an older patient withdementia.63,66

Delirium can impact the symptom burdenexperienced in dementia at the end of life.Worsening of confusion, often due todelirium, has been identified as the most com-mon problem in people with dementia in theirlast year,85 and dementia co-occurs in as manyas two-thirds of delirium cases in elderly popu-lations.86 Nurses have particular difficultyidentifying delirium when it coexists with de-mentia compared with dementia or deliriumalone,32,87 and the so-called behavioral andpsychological symptoms of dementia (BPSDs)have much phenomenological overlap withthe neuropsychiatric profile that is typical ofdelirious states; some observers have suggestedthat many cases of BPSD encapsulate unrecog-nized delirium.88 In addition, evidence ismounting for the existence of persistent cogni-tive impairment after a delirium episode,89,90

and growing evidence indicates that the occur-rence of delirium can accelerate the cognitivedecline in Alzheimer’s disease.54,91 These ob-servations suggest that palliative care cliniciansneed to be vigilant in determining when symp-toms being manifested are the result of thenatural history of the dementia or indeedmay be a preventable deterioration. This iscompounded by the differing prognostic tra-jectories of dementia vs. those of terminalcancer-related illness; dementia, even in itsadvanced state, is less predictable and oftenmore gradual in progression.77 In the DSM-5,the term NCDs now encompasses the syn-dromes of dementia and delirium. The majorNCDs include Alzheimer’s disease and thosewith other associations: vascular, Lewy bodies,Parkinson’s disease, frontotemporal, traumaticbrain injury, HIV infection, substance/medication-induced, Huntington’s disease,and prion disease.9 The DSM-5 generic diag-nostic criteria for a major NCD such as Alz-heimer’s dementia are presented in Table 3.

Clinically, comorbid delirium in the pres-ence of pre-existing dementia may pose a diag-nostic conundrum because of overlappingfeatures that complicate diagnosis. A compar-ison of features of delirium and dementia,based on onset, course, duration, precipitantidentification, reversibility, mode of presenta-tion in the terminal or dying phase, level of

Table 3Diagnostic and Statistical Manual of Mental Disorders (DSM-5) Diagnostic Criteria for Major Neurocognitive

Disorder

A. Evidence of significant cognitive decline from a previous level of performance in one or more cognitive domains (complexattention, executive function, learning and memory, language, perceptual-motor, or social cognition) based on1. Concern of the individual, a knowledgeable informant, or the clinician that there has been a significant decline in

cognitive function; and2. A substantial impairment in cognitive performance, preferably documented by standardized neuropsychological testing or,

in its absence, another quantified clinical assessment.B. The cognitive deficits interfere with independence in everyday activities (i.e., at a minimum, requiring assistance with

complex instrumental activities of daily living such as paying bills and managing medications).C. The cognitive deficits do not occur exclusively in the context of a delirium.D. The cognitive deficits are not better explained by another mental disorder (e.g., major depressive disorder, schizophrenia).

Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, 5th edition, (�2013). American Psychiatric Association. AllRights Reserved.


association with frailty or cachexia, and othercognitive and behavioral manifestations, ispresented in Table 4. In the palliative setting,making this differentiation is key to ensureoptimal management of symptoms and theirrelated distress. Both syndromes include wide-spread and generalized disturbance of brainfunction, but the context of delirium, whichis relatively acute and tends to include sub-stantial fluctuation in symptoms over the day,is highly characteristic. Moreover, deliriumcan be distinguished from dementia by thepattern of cognitive impairments that includesdisproportionate disturbance of attentionand perceptual performance.15,92 Studies,including work conducted in a palliative caresetting,14 also indicate that delirium symptomstend to overshadow dementia symptoms whenthey co-occur, such that the clinical rule ofthumb is that when the symptoms of deliriumare present, it should be the presumed diag-nosis in the first instance.93e96

Table 4Comparison of Features of Delirium a

Feature Delirium

Onset Hours to daysCourse FluctuatingIdentifiable precipitant(s) FrequentlyReversibility Potentially reversible in some casesPresentation in dying phase Occurs in most patientsAssociated frailty or cachexia CommonLevel of consciousness Impaired/cloudedAttention Deficit is a diagnostic criterionOther cognitive deficits Potentially detectable on cognitivePerceptual disturbance CommonDelusional activity CommonSleep-wake cycle disturbance Very commonSpeech problems Slurred/incoherentPsychomotor behavior Hypo- or hyperactive or mixedInvoluntary movements Asterixis and myoclonus sometime

Assessment of Comorbid Delirium and Dementia.The identification of a prodromal phase ofdelirium in patients with underlying dementiacould potentially help predict the develop-ment of delirium and possibly inform targetedinterventions to prevent delirium.97 Whencompared with nondelirious controls (70% ofthem with dementia), patients with deliriumsuperimposed on dementia were more likelyto have new-onset perceptual disturbances,disorganized thinking, and worsening ofMini-Mental State Examination scores in thetwo weeks preceding their diagnosis ofdelirium.97 Theoretically, the high level of 24hour contact between patients and nursesmight suggest that nurses are ideally placedto recognize the emergence of delirium. How-ever, delirium recognition by nurses in generalis poor, especially in patients with pre-existingdementia and those with hypoactivedelirium.98 Furthermore, a case vignette studysuggested that even nurses with a high level of

nd Dementia in Palliative Care

Dementia

Months to yearsSlowly progressive in most casesNot usuallyRarely reversibleDelirium usually developsCommon in late stagesClear until late in diseasePreserved in early stages

screening Potentially detectable on cognitive screeningInfrequentInfrequentInfrequentPossible dysphasiaNormal in early stages

s Tremor, notably in Parkinson’s disease


geropsychiatric nursing knowledge had diffi-culty recognizing delirium superimposed ondementia compared with recognizing featuresof dementia or delirium alone.87

Perhaps, the most important assessment is todetermine baseline function; for patients withdelirium, it is particularly helpful to know theirlevel of cognitive functioning before the onsetof syndromal delirium and even the prodromalphase of delirium. The availability of suchcognitive data hinges on the degree to whichthe culture of systematic cognitive assessmentexists and is supported in a particular institu-tion. The feasibility of a computerized deci-sional support system to assist nurses with thediagnosis of delirium superimposed on demen-tia has been demonstrated in a small pilot studyand appears to be worthy of further evalua-tion.99 The merits of cognitive screening alonevs. cognitive screening with the added input ofnursing observations have been evaluated inlong-term care residents.100 Prevalence detec-tion of delirium superimposed on dementiaincreased from 14% to 24.7% with the inclu-sion of nurses’ observations in addition tocognitive testing by research assistants. In palli-ative care, the issue of assessment burden mustbe borne in mind.22 Intuitively, observationaltools such as the Nursing Delirium ScreeningScale (NuDESC)101 or the Delirium Observa-tional Screening Scale102 are attractive becauseof their brevity and their observational, andthus nonburdensome, nature. However, thereare limited data on the use of the observationaland cognitive screening tools specifically inrelation to delirium superimposed on demen-tia, especially in palliative care settings.103 AChinese version of the NuDESC demonstrated96% sensitivity and 79% specificity for deliriumscreening in a sample of 100 patients, of whom34% had a diagnosis of dementia.104 The samestudy showed that the CAM had a sensitivityand specificity of 76% and 100%, respectively.The average completion time for the CAMand NuDESC in this study was 10 minutesand one minute, respectively. Adding psycho-motor changes to the four-item CAM diag-nostic algorithm improved its diagnosticspecificity in relation to International Classifica-tion of Diseases, 10th revision, criteria fordelirium and improved sensitivity whensequentially applied in CAM-negative individ-uals.105 A systematic review of tools to detect

delirium superimposed on dementia identifiednine studies as meeting the inclusion criteria.84

It concluded that three tools had demon-strated preliminary evidence in detectingdelirium superimposed on dementia: theCAM, CAM-ICU, and the electroencephalo-gram (EEG). Although an EEG may help toconfirm the diagnosis of delirium in acutemedical settings,106 its utility across the fullspectrum of palliative care settings may belimited. Although the search for specific bio-markers and genomic profiles for deliriumhas yielded some positive results,107 there iscurrently no clearly defined clinical role fortheir use in diagnosing comorbid dementiaand delirium. The advent of newer technologysuch as eye tracking has undergone prelimi-nary investigation and appears worthy offurther evaluation.108 An important area ofassessment that warrants further explorationand study is the process or mechanism bywhich caregiver information is captured. Forexample, a family report version of the CAM,the FAM-CAM, has shown promise in anexploratory study.109 Also, better detection ofspecific dementia or major NCD subtype symp-toms may assist in the diagnosis of deliriumsuperimposed on dementia.84

Reversibility of Delirium in Comorbid Delirium andDementia. Pre-existing cognitive impairmentin palliative care patients is associated withless reversible delirium.110 This is in keepingwith more general findings relating to the rela-tive treatability of delirium when it occurs withcomorbid dementia; both pharmacologicaland other evidence suggest that therapeuticeffectiveness is less when delirium is associatedwith comorbid delirium.53 However, evidencenotably indicates that delirium respondsmore consistently to antipsychotics than dobehavioral and psychological symptoms of de-mentia,80 further emphasizing the importanceof reliable and accurate distinction of theseconditions. In advanced dementia, a similarclinical dilemma exists: balancing the desirefor care that is not unduly demanding or inva-sive (or requires transfer to acute care fromresidential aged care) while also recognizingthe potential reversibility of delirium. In clin-ical practice, the relatively successful treatmentand reversal of an episode of delirium mayunmask a hitherto unrecognized dementia.


Furthermore, it must be recognized that recur-rent or persistent episodes of delirium alsomay be associated with the development andclinical emergence of dementia.

Undoubtedly, palliative care practitioners canbenefit from the growing research activity thatis currently exploring the delirium-dementiainterface, but in addition, there is a need forstudies that are specific to delirium when it oc-curs in the context of advanced dementia.

Psychomotor Subtypes of Delirium inPalliative Care

Delirium, although thought of as a unitary syn-dromearising fromamultitudeofpotential caus-ative factors, has substantive heterogeneity inpresentation, such that specific clinical variantsor subtypes also are recognized. Of the varietyof possible characteristics that could be used todistinguish clinical subtypes, the most intenselystudied are subtypes defined according to thepsychomotor profile.49 The psychomotor sub-typehas been studied in relation to phenomeno-logical characteristics, etiology, treatmentexperiences, and outcomes, including mortalityrates; but lack of consistency in motor subtypedefinitions has hampered research in this area.This work has allowed for motor subtypes to berecognized as hyperactive, hypoactive, or mixedpresentations within the delirium diagnosticcriteria in DSM-5.9 Although different motor ac-tivity profiles have been linked to delirium sincethe descriptions provided by the ancient Greeksof ‘‘phrenitis’’ and ‘‘lethargus’’ to describe hyper-active andhypoactive presentations, respectively,Lipowski34,111 was the first commentator ofmod-ern times to suggest the use of motor subtypes.

Much of the subsequent work establishingthe existence, phenomenological characteris-tics, and outcomes and treatment of deliriumand its relationship to psychomotor subtypeshas been conducted in palliative carepatients.12,14,16,17,19,23,25e27,101,112,113 A recentdetailed systematic review of 34 studiesexploring motor subtypes in delirium citedthat almost one-third (n ¼ 11) had been con-ducted in palliative care.49

Meagher et al.13 examined concordancebetween four commonly used subtypingmethods 47,111,114,115 when applied to the samecohort of 100 consecutive palliative care admis-sions described previously and found that only34%were labeled with the same subtype by these

methods.14 The subsequent development of theDelirium Motor Subtype Scale12 in palliativecare, adult, andold-ageConsultation-LiaisonPsy-chiatry Service populations and its abbreviatedfour-item version‘(DMSS-4)13 can allow for rapidand reliable assessment of the motor subtype indelirium, based on disturbances that are rela-tively specific for delirium and that have demon-strated concurrent validity with bioelectronicmeasures.116 TheDMSS has been used in studiesof palliative care populations.11,15e17

The predominance of hypoactive presenta-tions of delirium has important implicationsfor the management of delirium in palliativecare settings, in particular relating to accuratedetection and diagnosis, and subsequent effec-tive management. Hypoactive presentationsare more common in patients with comorbiddementia and with organ failure as an etiologicissue.117 Also important is that palliative carepatients with altered consciousness andcommunication have difficulty participatingin delirium assessment instruments, and theitems related to hypoactive presentations aremore difficult to complete. Hypoactive presen-tations are more frequently missed in palliativecare.33 Psychomotor dysfunction is almost uni-versal in palliative care delirium, with rates ofup to 94% reported for at least some form ofdiscernible motor activity disturbance (eitherhyperactive or hypoactive).118 A recent longi-tudinal study of motor subtypes in palliativecare emphasized how disturbed motor activityis almost invariably present in actual syndro-mal delirium, such that cases of DSM-IVdelirium with ‘‘no subtype’’ frequently scoredin the subsyndromal range of severity whenrated with the DRS-R98.17 This work alsofound that motor profile is relatively consistentacross an episode.11,17 Disturbances of cogni-tion and thought process abnormalities weresimilar across the motor subtypes, but the prin-cipal differences are in respect to noncognitivesymptoms (sleep-wake cycle, delusions, halluci-nations, affective lability). Similarly, Boettgerand Breitbart23 concluded that there wereno differences between hyperactive and hypo-active groups in terms of cognitive and disorga-nized thinking and that prominent differenceswere principally in respect to noncognitivesymptoms. This work demonstrated thatalthough the mixed subtype manifests as themost phenomenologically severe, relatively

Table 5Priority Issues in Delirium Diagnosis and Classification in Palliative Care Settings

1. Further characterization of the spectrum of delirium presentations,49 particularly subsyndromal delirium, and includinglongitudinal acquisition of phenomenological data in the palliative care setting. The specific clinical context of thenoncommunicative or semiconscious patient warrants particular attention.

2. Consensus on consistent diagnostic criteria for subsyndromal delirium.122

3. Robust and standardized approaches to the assessment of differential diagnoses or concomitant symptoms such as pain andmood disturbance in the person with delirium.43,103

4. Evaluation of the role of cognitive screening and observational (behavioral) screening in the diagnosis of delirium,22,103 bothin the presence and absence of dementia.

5. Development of valid, reliable, convenient, and nonburdensome methods to measure psychomotor activity and help toclassify delirium subtypes in palliative populations, for example, validation of the DMSS-4.13

6. Determine the pathophysiological and clinical correlates of psychomotor subtypes, especially the hypoactive subtype inpalliative care settings, thus informing investigational and therapeutic strategies.65

7. Articulation of the clinical indicators and decision-making framework used to determine the reversibility of delirium,103

especially in the context of comorbid delirium and dementia.


hypoactive presentations are the most prog-nostically grave.16,33

Clear consensus on the management of suchpatients is still evolving, in particular in the useof antipsychotic medication. Although somestudies have highlighted that hypoactive pre-sentations may be less responsive to pharmaco-logic interventions, other work suggests thatdespite the more frequent use of antipsy-chotics for hyperactive presentations, muchof the existing evidence suggests similarresponse rates, regardless of the motor sub-type.80 Studies that are designed to specificallyaddress this issue as a primary outcome areneeded.

Studies have clearly demonstrated that bothhypoactive and hyperactive presentations aredistressing to patients, caregivers, and staffbut often for quite different reasons.1,119 Thepresence of delusions is the most significantpredictor of patient distress.

The key differential diagnoses and othersymptoms to consider for hypoactive deliriuminclude depression, cancer-related pain, fa-tigue, and cachexia. The distinction of hypoac-tive delirium from depressive states can beespecially problematic as these two conditionshave considerable phenomenological overlapand the usual somatic disturbances that canbe important indicators of depressive illnessare less distinguishing in patients with termi-nal illness.43,120 These issues have been recog-nized as part of the so-called overlapsyndrome, which is used to denote the co-occurrence of symptoms that typically charac-terize both delirium and depression and whichis linked to a particularly poor prognosticprofile.121

ConclusionsThere are considerable challenges in the ac-

curate assessment of delirium in people withadvanced disease, where generalized distur-bance of central nervous system function oc-curs in the seriously ill, often with comorbidillness including dementia. The differentialdiagnoses are wide, including pain, fatigue,mood disturbance, psychoactive medicationeffects, and other causes for altered conscious-ness. Delirium presentations are very similarfor both reversible and irreversible episodessuch that clinical decision making needs torely on other factors such as prior functionalstatus and the trajectory of the life-limitingillness to decide the optimal approach tointervention. The increasing research activityexploring palliative care delirium has high-lighted the frequency and impact of SSD, co-morbid dementia, and the hypoactivesubtype as the most prevalent clinical presen-tation in the palliative population. Furtherstudies are needed to delineate the pathophys-iological and clinical associations of thesepresentations so as to inform therapeutic stra-tegies. The priority issues identified in our re-view are summarized in Table 5. The case forfuture studies is compelling; delirium isincreasingly recognized as a key health-caretarget, given the increasingly aged populationand the growing focus on dementia care inpalliative care.

Disclosures and AcknowledgmentsThe authors acknowledge input from the

participants (listed in the Foreword to this


Section) at the SUNDIPS Meeting, Ottawa,Canada, in June 2012. This meeting receivedadministrative support from Bruy�ere ResearchInstitute and funding support through a jointresearch grant to Dr. Lawlor from the GillinFamily and Bruy�ere Foundation. Dr. Lawlorholds a research award from the Departmentof Medicine, University of Ottawa. Dr. Meagherreceives funding from the Health ResearchBoard (Ireland) and the All-Ireland Instituteof Hospice and Palliative Care. The authorsdeclare no conflicts of interest.

References1. Breitbart W, Gibson C, Tremblay A. The

delirium experience: delirium recall and delirium-related distress in hospitalized patients with cancer,their spouses/caregivers, and their nurses. Psycho-somatics 2002;43:183e194.

2. Lawlor PG, Gagnon B, Mancini IL, et al. Occur-rence, causes, and outcome of delirium in patientswith advanced cancer: a prospective study. ArchIntern Med 2000;160:786e794.

3. Namba M, Morita T, Imura C, et al. Terminaldelirium: families’ experience. Palliat Med 2007;21:587e594.

4. Leonard M, Agar M, Mason C, Lawlor P.Delirium issues in palliative care settings.J Psychosom Res 2008;65:289e298.

5. Agar M, Draper B, Phillips PA, et al. Making de-cisions about delirium: a qualitative comparison ofdecision making between nurses working in pallia-tive care, aged care, aged care psychiatry, andoncology. Palliat Med 2012;6:887e896.

6. Breitbart W, Alici Y. Evidence-based treatmentof delirium in patients with cancer. J Clin Oncol2012;30:1206e1214.

7. Zimmerman K, Rudolph J, Salow M, Skarf LM.Delirium in palliative care patients: focus on phar-macotherapy. Am J Hosp Palliat Care 2011;28:501e510.

8. Lawlor PG. The panorama of opioid-relatedcognitive dysfunction in patients with cancer: a crit-ical literature appraisal. Cancer 2002;94:1836e1853.

9. American Psychiatric Association. Diagnosticand statistical manual of mental disorders, 5th ed.Washington, DC: American Psychiatric Association,2013.

10. Bush SH, Leonard MM, Agar M, et al. End-of-life delirium: issues regarding recognition, optimalmanagement, and the role of sedation in the dyingphase. J Pain Symptom Manage 2014;48:215e230.

11. Meagher DJ, Adamis D, Trzepacz P,Leonard M. Features of subsyndromal and persis-tent delirium. Br J Psychiatry 2012;200:37e44.

12. Meagher DJ, Moran M, Raju B, et al. A newdata-based motor subtype schema for delirium.J Neuropsychiatry Clin Neurosci 2008;20:185e193.

13. Meagher DJ, Adamis D, Leonard M, et al.Development of an abbreviated version of thedelirium motor subtyping scale, DMSS-4. Int Psycho-geriatr 2014;26:693e702.

14. Meagher DJ, Moran M, Raju B, et al. Motorsymptoms in 100 patients with delirium versus con-trol subjects: comparison of subtyping methods. Psy-chosomatics 2008;49:300e308.

15. Meagher DJ, Leonard M, Donnelly S, et al.A comparison of neuropsychiatric and cognitiveprofiles in delirium, dementia, co-morbiddelirium-dementia and cognitively intact controls.J Neurol Neurosurg Psychiatry 2010;8:876e881.

16. Meagher DJ, Leonard M, Donnelly S, et al.A longitudinal study of motor subtypes in delirium:relationship with other phenomenology, etiology,medication exposure, and prognosis. J PsychosomRes 2011;71:395e403.

17. Meagher DJ, Leonard M, Donnelly S, et al.A longitudinal study of motor subtypes in delirium:frequency and stability during episodes.J Psychosom Res 2012;72:236e241.

18. Leonard M, Godfrey A, Silberhorn M, et al.Motion analysis in delirium: a novel method of clar-ifying motoric subtypes. Neurocase 2007;13:272e277.

19. Leonard M, Donnelly S, Conroy M, Trzepacz P,Meagher DJ. Phenomenological and neuropsycho-logical profile across motor variants of delirium ina palliative-care unit. J Neuropsychiatry Clin Neuro-sci 2011;23:180e188.

20. Leonard M, Adamis D, Saunders J, Trzepacz P,Meagher D. A longitudinal study of delirium phe-nomenology indicates widespread neural dysfunc-tion. Palliat Support Care 2013;4:1e10.

21. Breitbart W, Rosenfeld B, Roth A, et al. Thememorial delirium assessment scale. J Pain Symp-tom Manage 1997;13:128e137.

22. Leonard MM, Nekolaichuk C, Meagher DJ,et al. Practical assessment of delirium in palliativecare. J Pain Symptom Manage 2014;48:176e190.

23. Boetteger S, Breitbart W. Phenomenology ofthe subtypes of delirium: phenomenological differ-ences between hyperactive and hypoactive delirium.Palliat Support Care 2011;9:129e135.

24. Boettger S, Passik S, Breitbart W. Treatmentcharacteristics of delirium superimposed on demen-tia. Int Psychogeriatr 2011;23:1671e1676.

25. Breitbart W, Tremblay A, Gibson C. An opentrial of olanzapine for the treatment of delirium inhospitalized cancer patients. Psychosomatics 2002;43:175e182.

26. Boettger S, Friedlander M, Breitbart W,Passik S. Aripiprazole and haloperidol in the

http://refhub.elsevier.com/S0885-3924(14)00286-3/sref1



































































































treatment of delirium. Aust N Z J Psychiatry 2011;45:477e482.

27. Stagno D, Gibson C, Breitbart W. The deliriumsubtypes: a review of prevalence, phenomenology,pathophysiology, and treatment response. PalliatSupport Care 2004;2:171e179.

28. Ostgathe C, Gaertner J, Voltz R. Cognitive fail-ure in end of life. Curr Opin Support Palliat Care2008;2:187e191.

29. Buffum MD, Hutt E, Chang VT, Craine MH,Snow AL. Cognitive impairment and pain manage-ment: review of issues and challenges. J RehabilRes Dev 2007;44:315e330.

30. Spiller JA, Keen JC. Hypoactive delirium: as-sessing the extent of the problem for inpatientspecialist palliative care. Palliat Med 2006;20:17e23.

31. Trzepacz PT, Franco JG, Meagher DJ, et al.Phenotype of subsyndromal delirium using pooledmulticultural Delirium Rating ScaledRevised-98data. J Psychosom Res 2012;73:10e17.

32. Inouye SK, Foreman MD, Mion LC, Katz KF,Cooney LM Jr. Nurses’ recognition of deliriumand its symptoms: comparison of nurse andresearcher ratings. Arch Intern Med 2001;12:2467e2473.

33. Fang CK, Chen HW, Liu SI, et al. Prevalence,detection and treatment of delirium in terminalcancer inpatients: a prospective survey. Jpn J ClinOncol 2008;38:56e63.

34. Lipowski ZJ. Transient cognitive disorders(delirium, acute confusional states) in the elderly.Am J Psychiatry 1983;140:1426e1436.

35. Marcantonio ER, Kiely DK, Simon SE, et al.Outcomes of older people admitted to postacute fa-cilities with delirium. J Am Geriatr Soc 2005;53:963e969.

36. Ouimet S, Riker R, Bergeron N, et al. Subsyn-dromal delirium in the ICU: evidence for a diseasespectrum. Intensive Care Med 2007;33:1007e1013.

37. Dosa D, Intrator O, McNicoll L, Cang Y,Teno J. Preliminary derivation of a Nursing HomeConfusion Assessment method based on data fromthe Minimum Data Set. J Am Geriatr Soc 2007;55:1099e1105.

38. Cole MG, McCusker J, Ciampi A, Belzile E. The6-and 12-month outcomes of older medical inpa-tients who recover from subsyndromal delirium.J Am Geriatr Soc 2008;56:2093e2099.

39. Martinz-Velilla N, Alonsa-Bouzon C, Cambra K,Ibanez-Beroiz B, Alonso-Renedo J. Outcomes incomplex patients with delirium and subsyndromaldelirium one year after hospital discharge. Int Psy-chogeriatr 2013;25:2087e2088.

40. Cole MG, McCusker J, Voyer P, et al. Symptomsof delirium predict incident delirium in older long-term care residents. Int Psychogeriatr 2013;25:887e894.

41. American Psychiatric Association. Diagnosticand statistical manual of mental disorders, 4th ed.Washington, DC: American Psychiatric Association,1994.

42. Voyer P, Richard S, Doucet L, Carmichael PH.Detecting delirium and subsyndromal delirium us-ing different diagnostic criteria among dementedlong-term care residents. J Am Med Dir Assoc2009;10:181e188.

43. Leonard M, Spiller J, Keen J, et al. Symptomsof depression and delirium assessed serially in palli-ative care inpatients. Psychosomatics 2009;50:506e514.

44. Bond SM, Dietrich MS, Shuster JL Jr,Murphy BA. Delirium in patients with head andneck cancer in the outpatient treatment setting.Support Care Cancer 2012;20:1023e1030.

45. Cole M, McCusker J, Dendukuri N, Han L. Theprognostic significance of subsyndromal delirium inelderly medical inpatients. J Am Geriatr Soc 2003;51:754e760.

46. Inouye SK, van Dyck CH, Alessi CA, et al. Clar-ifying confusion: the confusion assessment method.A new method for detection of delirium. AnnIntern Med 1990;113:941e948.

47. Trzepacz PT, Mittal D, Torres R, et al. Valida-tion of the Delirium Rating Scale revised 98 (DRS-R-98). J Neuropsychiatry Clin Neurosci 2001;13:229e242.

48. Franco JG, Trzepacz PT, Meja MA, Ochoa S.Factor analysis of the Colombian translation of theDelirium Rating Scale (DRG), Revised-98. Psychoso-matics 2009;50:255e262.

49. Meagher D. Motor subtypes of delirium: past,present and future. Int Rev Psychiatry 2009;21:59e73.

50. Ryan DJ, O’Regan NA, Caoimh R �O, et al.Delirium in an adult acute hospital population: pre-dictors, prevalence and detection. BMJ Open 2013;3:e001772.

51. Skrobik Y, Ahern S, Leblanc M, et al. Protocol-ized intensive care unit management of analgesia,sedation, and delirium improves analgesia and sub-syndromal delirium rates. Anesth Analg 2010;111:451e463.

52. Hakim SM, Othman AI, Naoum DO. Earlytreatment with risperidone for subsyndromaldelirium after on-pump cardiac surgery in theelderly: a randomized trial. Anesthesiology 2012;116:987e997.

53. O’Hanlon S, O’Regan N, Maclullich AM, et al.Improving delirium care through early interven-tion: from bench to bedside to boardroom.J Neurol Neurosurg Psychiatry 2014;85:207e213.

54. Davis DH, Muniz Terrera G, Keage H, et al.Delirium is a strong risk factor for dementia inthe oldest-old: a population-based cohort study.Brain 2012;135:2809e2816.






















































































































55. Inouye SK, Charpentier PA. Precipitating fac-tors for delirium in hospitalized elderly persons.Predictive model and interrelationship with base-line vulnerability. JAMA 1996;275:852e857.

56. Cunningham C, Campion S, Lunnon K, et al.Systemic inflammation induces acute behavioraland cognitive changes and accelerates neurodegen-erative disease. Biol Psychiatry 2009;65:304e312.

57. Murray C, Sanderson DJ, Barkus C, et al. Sys-temic inflammation induces acute working memorydeficits in the primed brain: relevance for delirium.Neurobiol Aging 2012;33:603e616.e3.

58. Cunningham C. Systemic inflammation anddelirium: important co-factors in the progressionof dementia. Biochem Soc Trans 2011;39:945e953.

59. Field RH, Gossen A, Cunningham C. Prior pa-thology in the basal forebrain cholinergic systempredisposes to inflammation-induced workingmemory deficits: reconciling inflammatory andcholinergic hypotheses of delirium. J Neurosci2012;32:6288e6294.

60. Hughes CG, Brummel NE, Vasilevskis EE,Girard TD, Pandharipande PP. Future directionsof delirium research and management. Best PractRes Clin Anaesthesiol 2012;26:395e405.

61. Holmes C, Cunningham C, Zotova E, et al. Sys-temic inflammation and disease progression in Alz-heimer disease. Neurology 2009;73:768e774.

62. Holmes C, Cunningham C, Zotova E,Culliford D, Perry VH. Proinflammatory cytokines,sickness behavior, and Alzheimer disease.Neurology 2011;77:212e218.

63. van Gool WA, van de Beek D, Eikelenboom P.Systemic infection and delirium: when cytokinesand acetylcholine collide. Lancet 2010;375:773e775.

64. Laird BJ, McMillan DC, Fayers P, et al. The sys-temic inflammatory response and its relationship topain and other symptoms in advanced cancer.Oncologist 2013;18:1050e1055.

65. Lawlor PG, Bush SH. Delirium in patients withcancer: assessment, impact, mechanisms and man-agement. Nat Rev Oncol 2014; In press.

66. Inouye SK, Westendorp RG, Saczynski JS.Delirium in elderly people. Lancet 2014;383:911e922.

67. Maldonado JR. Neuropathogenesis ofdelirium: review of current etiologic theories andcommon pathways. Am J Geriatr Psychiatry 2013;21:1190e1222.

68. Pavlov VA, Parrish WR, Rosas-Ballina M, et al.Brain acetylcholinesterase activity controls systemiccytokine levels through the cholinergic anti-inflammatory pathway. Brain Behav Immun 2009;23:41e45.

69. Fox C, Richardson K, Maidment ID, et al. Anti-cholinergic medication use and cognitive

impairment in the older population: the medicalresearch council cognitive function and ageingstudy. J Am Geriatr Soc 2011;59:1477e1483.

70. Ferri CP, Prince M, Brayne H, et al. Alz-heimer’s Disease International. Global prevalenceof dementia: a Delphi consensus study. Lancet2005;366:2112e2117.

71. Hughes JC, Jolley D, Jordan A, Sampson EL.Palliative care in dementia: issues and evidence.Adv Psychiatr Treat 2007;13:251e260.

72. Ryan T, Gardiner C, Bellamy G, Gott M,Ingleton C. Barriers and facilitators to the receiptof palliative care for people with dementia: the viewsof medical and nursing staff. Palliat Med 2012;26:879e886.

73. Small N. Living well until you die: quality ofcare and quality of life in palliative and dementiacare. Ann N Y Acad Sci 2007;1114:193e203.

74. Meeussen K, Van den Block L, Echteld M, et al.Older people dying with dementia: a nationwidestudy. Int Psychogeriatr 2012;24:1581e1591.

75. Van der Steen JT, Radbruch L, Hertogh CM,et al. White paper defining optimal palliative carein older people with dementia: a Delphi study andrecommendations from the European Associationfor Palliative Care. Palliat Med 2014;28:197e209.

76. Mitchell SL, Kiely DK, Miller SC, et al. Hospicecare for patients with dementia. J Pain SymptomManage 2007;34:7e16.

77. Torke AM, Holtz LR, Hui S, et al. Palliativecare for patients with dementia: a national survey.J Am Geriatr Soc 2010;58:2114e2121.

78. National Hospice and Palliative Care Organiza-tion (NHPCO). Facts and figures: hospice care inAmerica 2013. Available at: http://www.nhpco.org/sites/default/files/public/Statistics_Research/2013_Facts_Figures.pdf. Accessed June 17, 2014.

79. Leonard M, Adamis D, Saunders J, Trzepacz P,Meagher D. A longitudinal study of delirium phe-nomenology indicates widespread dysfunction. Pall-iat Support Care 2013;1e10.

80. Meagher DJ, McLoughlin L, Leonard M, et al.What do we really know about the treatment ofdelirium with antipsychotics? Ten key questions fordelirium pharmacotherapy. Am J Geriatr Psychiatry2013;21:1223e1238.

81. Balducci L. Frailty: a common pathway in ag-ing and cancer. Interdiscip Top Gerontol 2013;38:61e72.

82. Quinlan N, Marcantonio ER, Inouye SK, et al.Vulnerability: the crossroads of frailty and delirium.J Am Geriatr Soc 2011;59:S262eS268.

83. Auning E, Rongve A, Fladby T, et al. Early andpresenting symptoms of dementia with Lewy bodies.Dement Geriatr Cogn Disord 2011;32:202e208.

84. Morandi A, McCurley J, Vasilevskis EE, et al.Tools to detect delirium superimposed on


























































































http://www.nhpco.org/sites/default/files/public/Statistics_Research/2013_Facts_Figures.pdf
























dementia: a systematic review. J Am Geriatr Soc2012;60:2005e2013.

85. McCarthey M, Addington-Hall J, Altmann D.The experience of dying with dementia: a retrospec-tive study. Int J Geriatr Psychiatry 1997;12:404e409.

86. Fick D, Foreman M. Consequences of not rec-ognising delirium superimposed on dementia inhospitalised elderly individuals. J Gerontol Nurs2000;26:30e40.

87. Fick D, Hodo D, Lawrence F, Inouye SK.Recognizing delirium superimposed on dementia:assessing nurses’ knowledge using case vignettes.J Gerontol Nurs 2007;33:40e49.

88. Meagher DJ, Trzepacz P. Phenomenologicaldistinctions needed in DSM-V: delirium, subsyndro-mal delirium and dementias. J Neuropsychiatry ClinNeurosci 2007;19:468e470.

89. Jackson JC, Gordon SM, Hart RP, Hopkins RP,Ely EW. The association between delirium andcognitive decline: a review of the empirical litera-ture. Neuropsychol Rev 2004;14:87e98.

90. MacLullich AM, Beaglehole A, Hall RJ,Meagher DJ. Delirium and long-term cognitiveimpairment. Int Rev Psychiatry 2009;21:30e42.

91. Fong TG, Jones RN, Shi P, et al. Delirium accel-erates cognitive decline in Alzheimer disease.Neurology 2009;72:1570e1575.

92. Brown LJ, Fordyce C, Zaghdani H, Starr JM,MacLuullich AM. Detecting deficits of sustained vi-sual attention in delirium. J Neurol Neurosurg Psy-chiatry 2011;82:1334e1340.

93. Trzepacz PT, Mulsant BH, Dew MA, et al. Isdelirium different when it occurs in dementia? Astudy using the delirium rating scale.J Neuropsychiatry Clin Neurosci 1998;13:229e242.

94. Laurila JV, Pitkala KH, Strandberg TE,Tilvis RS. Delirium among patients with and withoutdementia: does the diagnosis according to the DSM-IV differ from the previous classifications? Int J Ger-iatr Psychiatry 2004;19:271e277.

95. Voyer P, Cole MG, McCusker J, et al. Preva-lence and symptoms of delirium superimposed ondementia. Clin Nurs Res 2006;15:46e66.

96. Edlund A, Lundstrom M, Sandberg O, et al.Symptom profile of delirium in older people withand without dementia. J Geriatr Psychiatry Neurol2007;20:166e171.

97. Voyer P, McCusker J, Cole MG, et al. Prodromeof delirium among long-term care residents: whatclinical changes can be observed in the two weekspreceding a full-blown episode of delirium? Int Psy-chogeriatr 2012;24:1855e1864.

98. Rice KL, Bennett M, Gomez M, et al. Nurses’recognition of delirium in the hospitalized olderadult. Clin Nurse Spec 2011;25:299e311.

99. Fick DM, Steis MR, Mion LC, Walls JL.Computerized decision support for delirium

superimposed on dementia in older adults.J Gerontol Nurs 2011;37:39e47.

100. McCusker J, Cole MG, Voyer P, et al. Use ofnurse-observed symptoms of delirium in long-termcare: effects on prevalence and outcomes ofdelirium. Int Psychogeriatr 2011;23:602e608.

101. Gaudreau JD, Gagnon P, Harel F, Tremblay A,Roy MA. Fast, systematic, and continuous deliriumassessment in hospitalized patients: the nursingdelirium screening scale. J Pain Symptom Manage2005;29:368e375.

102. Detroyer E, Clement PM, Baeten N, et al.Detection of delirium in palliative care unit pa-tients: a prospective descriptive study of theDelirium Observation Screening Scale administeredby bedside nurses. Palliat Med 2014;28:79e86.

103. Lawlor PG, Davis DHJ, Ansari M, et al. Ananalytical framework for delirium research inpalliative care settings: integrated epidemiologic,clinician-researcher, and knowledge user perspec-tives. J Pain Symptom Manage 2014;48:159e175.

104. Leung J, Leung V, Leung CM, Pan PC. Clinicalutility and validation of two instruments (the Confu-sion Assessment Method Algorithm and the Chi-nese version of Nursing Delirium Screening Scale)to detect delirium in geriatric inpatients. GenHosp Psychiatry 2008;30:171e176.

105. Thomas C, Kreisel SH, Oster P, et al. Diag-nosing delirium in older hospitalized adults with de-mentia: adapting the confusion assessment methodto International Classification of Diseases, tenthrevision, diagnostic criteria. J Am Geriatr Soc2012;60:1471e1477.

106. Thomas C, Hestermann U, Walther S, et al.Prolonged activation EEG differentiates dementiawith and without delirium in frail elderly patients.J Neurol Neurosurg Psychiatry 2008;79:119e125.

107. Khan BA, Zawahiri M, Campbell NL,Boustani MA. Biomarkers for deliriumda review.J Am Geriatr Soc 2011;59:S256eS261.

108. Exton C, Leonard M. Eye tracking technology:a fresh approach in delirium assessment? Int RevPsychiatry 2009;21:8e14.

109. Steis MR, Evans L, Hirschman KB, et al.Screening for delirium using family caregivers:convergent validity of the Family Confusion Assess-ment Method and interviewer-rated ConfusionAssessment Method. J Am Geriatr Soc 2012;60:2121e2126.

110. Leonard M, Raju B, Conroy M, et al. Revers-ibility of delirium in terminally ill patients and pre-dictors of mortality. Palliat Med 2008;22:848e854.

111. Lipowski ZJ. Delirium in the elderly patient.N Engl J Med 1989;320:378e382.

112. Lawlor PG, Nekolaichuk C, Gagnon B, et al.Clinical utility, factor analysis, and further validationof the Memorial Delirium Assessment Scale in




















































































































patients with advanced cancer. Cancer 2000;88:2850e2867.

113. Lam PT, Tse CY, Lee CH. Delirium in a pallia-tive care unit. Prog Palliat Care 2003;11:126e133.

114. Liptzin B, Levkoff SE. An empirical study ofdelirium subtypes. Br J Psychiatry 1992;161:843e845.

115. O’Keeffe ST, Lavan JN. Clinical significance ofdelirium subtypes in older people. Age Ageing1999;28:115e119.

116. Godfrey A, Leonard M, Donnelly S, et al. Vali-dating a new clinical subtyping scheme for deliriumwith electronic motion analysis. Psychiatry Res 2010;178:186e190.

117. Friedlander MM, Brayman Y, Breitbart WS.Delirium in palliative care. Oncology 2004;18:1541e1550.

118. Meagher JD, Moran M, Raju B, et al. Phenom-enology of 100 cases using standardised measures.Br J Psychiatry 2007;190:135e241.

119. O’Malley G, Leonard M, Meagher D,O’Keeffe ST. The delirium experience: a review.J Psychosom Res 2008;65:223e228.

120. Marchington KL, Carrier L, Lawlor PG.Delirium masquerading as depression. Palliat Sup-port Care 2012;10:59e62.

121. Givens JL, Jones RN, Inouye SK. The overlapsyndrome of depression and delirium in older hos-pitalized patients. J Am Geriatr Soc 2009;57:1347e1353.

122. Cole MG. Subsyndromal delirium in old age:conceptual and methodological issues. Int Psycho-geriatr 2013;25:863e866.


































Documents

Delirium Diagnostic and Classification Challenges in Palliative Care: Subsyndromal Delirium, Comorbid Delirium-Dementia, and Psychomotor Subtypes