Accepted Manuscript Delirium Diagnostic and Classification Challenges in Palliative Care: Subsyndromal Delirium, Comorbid Delirium-Dementia and Psychomotor Subtypes Maeve M. Leonard , MB, MRCPsych, MD Meera Agar , MBBS, FRACP Juliet A. Spiller , MBChB, MRCPEd Brid Davis , BSc, MSc Mas M. Mohamad , MB, BMed Sci, MRCPI, MRCPsych David J. Meagher , MD, PhD, MRCPsych Peter G. Lawlor , MB, FRCPI, MMedSc PII:

S0885-3924(14)00286-3

DOI:

10.1016/j.jpainsymman.2014.03.012

Reference:

JPS 8686

To appear in:

Journal of Pain and Symptom Management

Received Date: 20 January 2014 Revised Date:

17 March 2014

Accepted Date: 2 April 2014

Please cite this article as: Leonard MM, Agar M, Spiller JA, Davis B, Mohamad MM, Meagher DJ, Lawlor PG, Delirium Diagnostic and Classification Challenges in Palliative Care: Subsyndromal Delirium, Comorbid Delirium-Dementia and Psychomotor Subtypes, Journal of Pain and Symptom Management (2014), doi: 10.1016/j.jpainsymman.2014.03.012. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Special Article

14-00027R1

Delirium Diagnostic and Classification Challenges in Palliative Care: Subsyndromal

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Delirium, Comorbid Delirium-Dementia and Psychomotor Subtypes

Maeve M. Leonard, MB, MRCPsych, MD, Meera Agar, MBBS, FRACP, Juliet A. Spiller, MBChB, MRCPEd, Brid Davis, BSc, MSc, Mas M. Mohamad, MB, BMed Sci, MRCPI,

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MRCPsych, David J. Meagher, MD, PhD, MRCPsych, and Peter G. Lawlor, MB, FRCPI,

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Graduate 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, and South West Sydney Clinical School (M.A.), University of New South Wales and Department of Palliative Care (M.A.), Braeside Hospital,

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HammondCare, Sydney, New South Wales, Australia; Palliative Medicine (J.A.S.), Marie Curie Hospice, Edinburgh and West Lothian Palliative Care Service, Edinburgh, United Kingdom; and Bruyère Research Institute (P.G.L.), Bruyère Continuing Care, Ottawa; Division of Palliative

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Care (P.G.L.), Department of Medicine, Epidemiology and Community Medicine, University of

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Ottawa, Ottawa; and The Ottawa Hospital Research Institute (P.G.L.), Ottawa, Ontario, Canada

Address correspondence to: Peter G. Lawlor, MB, FRCPI, MMedSc Bruyère Continuing Care 43 Bruyère Street, Ottawa, ON K1N 5C8, Canada E-mail: [email protected]

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Abstract Context. Delirium often presents difficult diagnostic and classification challenges in palliative care settings.

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Objectives. To review three major areas of diagnostic and classification challenges in relation to delirium in palliative care: subsyndromal delirium (SSD); delirium in the context of

and research priorities in relation to these three areas of focus.

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comorbid dementia; and classification of psychomotor subtypes, and to identify knowledge gaps

Methods. We combined multidisciplinary input from delirium researchers and

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knowledge users at an international delirium study planning meeting and relevant PubMed literature searches as the knowledge synthesis strategy in this review. Results. We identified six (SSD), 33 (dementia), and 44 (psychomotor subtypes) papers of relevance in relation to the focus of our review. Recent literature data highlight the frequency

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and impact of SSD; the relevance of comorbid dementia; and the propensity for a hypoactive presentation of delirium in the palliative population. The differential diagnoses to consider are wide and include pain, fatigue, mood disturbance, psychoactive medication effects and other

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causes for altered consciousness.

Conclusion. Challenges in the diagnosis and classification of delirium in people with

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advanced disease are compounded by the generalized disturbance of central nervous system function that occurs in the seriously ill, often with comorbid illness, including dementia. Further research is needed to delineate the pathophysiological and clinical associations of these presentations and thus inform therapeutic strategies. The expanding aged population and growing focus on dementia care in palliative care highlight the need to conduct this research.

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Key Words: delirium, palliative care, subsyndromal, diagnosis, assessment, dementia, psychomotor, classification and hospice Running title: Delirium Diagnostic and Classification Issues

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Accepted for publication: April 2, 2014.

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Introduction Delirium is a common and distressing medical syndrome for people with advanced lifelimiting illness, whether viewed from the perspective of the patient, their loved ones or the health

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professionals caring for them.1-6 There are many challenges in achieving a precise diagnosis in patients with possible delirium in palliative care clinical settings (Table 1). These challenges reflect difficulties in the assessment process; issues of conceptual overlap in relation to both the

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neurocognitive status of patients with pre-existing or evolving dementia and overlap between delirium and depression; the impact of extreme frailty and cachexia; and use of potent

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psychoactive medications, often in association with polypharmacy.7,8 The relatively high frequency of hypoactive presentations of delirium in palliative care, whether as part of a mixed or purely hypoactive psychomotor subtype of delirium may present diagnostic challenges and increase the risk of the disorder not being detected.4 The diagnostic criteria of the Diagnostic and

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Statistical Manual of Mental Disorders (DSM) are widely recognized. In the recently published fifth edition of the DSM, DSM-5,9 one of the five diagnostic criteria requires that there is evidence from the patient’s history, physical examination, or laboratory investigations to explain

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the presence of delirium in association with a medical condition or other etiology (Table 2). In this regard, the level of laboratory investigation in palliative care settings may be limited in the

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context of goals of care, especially when a possible delirium arises in what appears to be the last hours or days of life.

The focus of this narrative review was to explore three principal areas of diagnostic challenge in the context of advanced illness: 1) the nature and relevance of subsyndromal delirium (SSD); 2) delirium in the context of comorbid dementia; and 3) classification of psychomotor subtypes of delirium, in particular the hypoactive presentations that are commonly

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seen in the palliative care setting. The review also highlights knowledge gaps and pertinent aspects of delirium diagnosis and assessment in palliative care settings to date, and proposes future studies in relation to the three areas of focus in the review.

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Methods

We performed a narrative review of published papers found by a literature search that used the key words “subsyndromal,” “psychomotor subtypes,” “delirium and advanced

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dementia” or “delirium” and “delirium and dementia” combined with “palliative medicine,” “palliative care settings,” and “end-of-life” in PubMed, MeSH, and limited to those in English

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from the years 1997 to 2012 inclusive. “Terminal restlessness” and “terminal delirium” were not covered, as this topic is covered in a separate paper (Bush et al.) in this section. This specific literature is considered in the context of what is known regarding delirium assessment in other populations, so as to develop specific research questions regarding delirium diagnosis and

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classification in palliative care.

In addition, we obtained multidisciplinary input from leading delirium researchers, methodologists, primary care and specialist-level clinicians, palliative care experts and clinical

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administrators at an international two-day delirium study planning meeting in Ottawa, Canada in June 2012. Our meeting was designed to promote collaboration and initiate deliberations towards

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the development of a research framework under the broad heading of “Studies to Understand Delirium In Palliative Settings” and hence the acronym, SUNDIPS. Within this broad SUNDIPS program of research, we targeted two of the major investigational domains for delirium in palliative care settings as subprograms of research: 1) epidemiological issues and issues of delirium prediction, screening and diagnosis; and 2) experiential or phenomenological aspects of delirium in its entire trajectory, including subsyndromal and full syndromal states. All

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presentations and interactions during the conference working groups were recorded and transcribed. Results

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The literature search yielded 83 research papers directly related to the key words. Of these, only six papers specifically addressed the aspects of SSD in palliative care. The concept of SSD is understudied in both palliative care populations and other medical patient groups, and

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because of the difficulty in consistently operationalizing its definition and because of its varying nature, it remains a contentious diagnosis for some physicians.10

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Of the 44 papers exploring psychomotor subtype, there were 11 of specific relevance that addressed the development and psychometric testing of the Delirium Motor Subtype Scale;11,12 documentation of the frequency and stability of motor subtypes; and the relationship of subtypes with other phenomenological and etiological aspects, in addition to medication exposure,

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treatment and prognosis in a palliative care population.11,13-19 Breitbart et al. developed the Memorial Delirium Assessment Scale, which records motor subtype20 (described in a separate paper in this section21), and which has been used to study the frequency of subtypes and their

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relationship with phenomenology, treatment and comorbid dementia.22-27 There is a large body of literature on delirium in the setting of comorbid dementia,

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addressing various aspects, especially the goals of care and focusing on quality of life, dignity and comfort;28 best practice in relation to pain management in patients with dementia;29 treatment characteristics of delirium superimposed on dementia;23 and an exploration of the phenomenological interface between delirium and dementia in palliative care.14 We identified 33 papers of relevance in relation to delirium and comorbid dementia. Discussion

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Subsyndromal Delirium SSD, although still subject to debate among clinicians and researchers, is an important consideration in palliative care, as symptoms critical to its identification (altered consciousness,

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inattention) are common in advanced illness. It is important to acknowledge that hypoactive delirium is the most common subtype in palliative care,16,30 and the “no subtype” or normal psychomotor classification has been found to be most common in SSD.16 Hypoactivity, as part of

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an episode of SSD, has been identified as one of the features that distinguishes the SSD

phenotype from non-delirium.31 Given that the hypoactive subtype has a known association

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with the under- and misdiagnosis of delirium,32,33 it is likely that the association of hypoactivity or normal psychomotor activity with SSD may similarly contribute to underrecognition of SSD. However, the presence of any delirium symptom warrants recognition as to how much it relates to patient and caregiver distress.34

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SSD was first described by Lipowski.35 It has been defined by both categorical (i.e., the presence of any core delirium symptoms without the presence of all of the diagnostic criteria) and dimensional (i.e., severity scores on rating scales that are below the diagnostic threshold)

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methods. SSD is increasingly recognized as prognostically important; its outcomes are consistently identified as being intermediate between the full syndrome of delirium (FSD) and no

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delirium.31,36-40 As a syndrome, delirium is phenomenologically diverse, symptoms are relatively non-specific, and the dilemma is whether there are key symptoms that are critical for diagnosis, or indeed if the range and contextual pattern is a more useful indicator of a delirium diagnosis than the presence of individual symptoms. Perhaps the most pressing issue is the absence of a clear definition of SSD, thus leading to a lack of consensus regarding how to consistently diagnose it in clinical practice and in

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research studies.41 In the DSM fourth edition (DSM-IV),43 SSD was not specifically categorized, but included under the vague umbrella term “other cognitive disorders not otherwise specified.” In the DSM-5,9 SSD is now more clearly listed in the neurocognitive disorders section as

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“attenuated delirium syndrome.” However, it still does not have clear descriptive criteria

enabling clinicians to make a clear diagnosis. Without diagnostic precision and because of

variation in clinical populations studied, there is wide variation in the estimated prevalence of

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SSD, with studies indicating a range from 7-50%.37,43-45 Studies to date have defined SSD on the basis of varying criteria: the presence of one or more symptoms of delirium (inattention, altered

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level of consciousness, disorientation and perceptual disturbances);46 the presence of one or more Confusion Assessment Method (CAM)47 delirium symptoms (acute onset and fluctuation, inattention, disorganized thinking, and altered level of consciousness);37 a subdiagnostic score on the Delirium Rating Scale-Revised-98 (DRS-R98);10,48 and core domain symptoms of delirium,

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identified through cluster analysis of DRS-R98 items and demonstrating a phenotype similar to delirium but a severity that is intermediate between FSD and non-delirium.31 Clinically, SSD may reflect a variety of delirium-relevant presentations. It can occur

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during either evolving or resolving delirium. It also may occur as part of a persistent deficit state after an episode of full syndromal delirium, sometimes persisting or interspersed with FSD

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during recovery. Moreover, the inherently fluctuating nature of delirium symptoms is such that periods of less prominent symptoms (but meeting SSD criteria) can occur during an episode of delirium. Alternatively, SSD may simply reflect less severe episodes or delirium that are less symptomatically intense such that studies indicate that SSD can be readily placed on a spectrum of phenomenological severity10 and prognostic severity; outcomes for SSD are intermediate between those who have delirium and those who do not.36 More detailed longitudinal studies of

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the course of symptoms in patients experiencing delirium are needed to clarify how SSD relates to emerging and / or resolving delirium episodes. Study data from the Intensive Care Unit setting suggests that some SSD cases are often

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accounted for by altered consciousness without other symptoms of delirium.37 These patients with altered consciousness (but without FSD) have outcome profiles that are similar to FSD, but this does not necessarily imply that these disorders are pathophysiologically linked. This raises

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fundamental issues as to where the concept of delirium as an entity begins and ends. It is still unknown if delirium can be considered as a particular type of disturbance of consciousness that

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has wide impact upon brain function but yet is distinct from other causes of altered consciousness. In short, not all patients with altered consciousness will meet the criteria for delirium but many experience the similarly poor outcomes that are associated with delirium. The diagnosis of SSD is particularly relevant in palliative care because symptoms critical

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to diagnosis, namely altered consciousness and inattention, are very common in this setting, and the unquestionable attribution of these non-specific symptoms to SSD in the absence of FSD is a moot point. Inattention is a mandatory feature of FSD but it is not clear whether it also should be

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considered as an essential component in the definition of SSD. As such, dimensional approaches to diagnosis (range of symptoms but at lower severity) may be more discerning, as they are less

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prone to the influence of the presence of single symptoms. Meagher et al.,10 reporting on the features of subsyndromal and persistent delirium in a longitudinal study of 100 palliative care inpatients with DSM-IV delirium, used the DRS-R98 score range of 8–15 to delineate those who were subsyndromal in severity. The study found 27 participants in this score range at baseline, and 41% during the 323 follow-up assessments over the six-week study period. Similar to prior studies, all symptoms (cognitive, perceptual,

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psychomotor, and attention) were found to occur in SSD and FSD in this cohort, and exhibited minimal fluctuation; the difference was that less severe symptoms were seen in SSD.31,49 The association of hypoactive presentations with FSD and possibly also SSD may either

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reflect specific pathophysiological mechanisms in their pathogenesis or the pathological

manifestation of the underlying disease, such as motor compromise in a cachectic cancer patient. Although such associations are hypothetical, the hypoactivity feature probably should be viewed

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in context, especially in palliative care settings, where hypoactive presentations predominate. In everyday clinical practice, hypoactive delirium is frequently not detected or misdiagnosed as

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dementia or depression.50 Similarly, a study of general hospital patients suggests SSD is not a concept that is appreciated in real-world care and SSD is rarely labeled as delirium or any of its synonyms by medical or nursing staff.51 In addition to its impact upon ongoing care and outcomes, it is relevant that the presence of any delirium symptoms can cause patient and

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caregiver distress, and identification of SSD is crucial to ensure clinicians acknowledge that the symptoms exist, can provide a meaningful explanation of the reason for these symptoms and a plan of management, and continue to regularly assess symptomatology.

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The impact of SSD on outcomes needs to be explored in the palliative population, but it is likely to infer morbidity and mortality, as seen in acute care populations.36 Importantly, recent

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studies of pharmacological interventions, including both typical and atypical antipsychotics have demonstrated significant reductions in the incidence of SSD in critical care patients,52 as well as a lower transition rate from SSD to FSD,53 thus highlighting how the timely and consistent detection of SSD may provide an opportunity for effective early intervention. Meagher and colleagues54 have described a schema for managing delirium-relevant presentations in everyday care that incorporates computer-assisted technologies to assist in reliable detection and consistent

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decision making around management; differing levels of delirium symptomatology are linked to evidence-based interventions. Further studies are required to clarify the impact of antipsychotic administration and other interventions upon the clinical course of SSD in general, and also in the

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palliative population. Comorbid Delirium and Dementia in Palliative Care

Dementia is recognized as a potent predisposing risk factor for the development of

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delirium.55,56 Delirium in the palliative care setting may occur either in association with

advanced dementia as the principal life-threatening illness, or it may occur in the context of

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another principal life-threatening illness such as cancer, and comorbid dementia (spanning all levels from early to late) also may be present. The comorbid association of delirium and dementia in palliative care highlights issues in relation to the pathophysiological overlap between the two; the acknowledgement of dementia, especially advanced dementia as a life-threatening

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illness within the palliative care remit; clinical manifestation, recognition, and assessment strategies; and the unmasking of dementia with the treatment of delirium. Over the last decade, the development of a mouse model for the study of inflammation (as a deliriogenic precipitant)

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superimposed on pre-existing neurodegeneration (ME7 mouse model of prion disease), and the plethora of literature on brain dysfunction in acute illness and dementia have greatly helped to

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advance our knowledge of the delirium-dementia interface.57-63 Delirium and Dementia: Overlapping Pathophysiology. In addition to the overlap of some clinical features between delirium and dementia, there is some sharing of the putative pathophysiological mechanisms that are part of the pathogenesis of both disorders. Most prominent among these shared mechanisms are the phenomena of reduced cerebral cholinergic neurotransmission, systemic inflammation and neuroinflammation, which in turn are also

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possibly inter-related.58-60,64 In palliative care settings, many patients have a cancer diagnosis and the contribution of known systemic inflammation in association with cancer65 warrants consideration.66

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Many researchers have queried the basis of the clinical observation that a relatively severe infection is required to precipitate an episode of delirium in a younger non-demented patient, whereas a relatively minor infection in an older patient with dementia may trigger an

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episode of delirium.56,64,66,67 The neuronal aging hypothesis of delirium holds that in the case of pre-existing dementia or even in the older brain, neuropathological changes, resulting in

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“overactivated microglia,” render such patients more vulnerable to the effects of systemic inflammation.68 Microglial activity in the central nervous system is normally inhibited by acetylcholine.69 In the event of cholinergic deficiency, as occurs in older age, dementia, or possibly in association with medications that have an anticholinergic effect,70 there is the

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potential for microglial activity to go unchecked or microglia become “overactivated.”64 This may explain the predisposing vulnerability to delirium in the patient with pre-existing or evolving dementia, where systemic inflammation may cross the blood brain barrier, for example,

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in the case of infection. It also may explain the persistence of some delirium symptoms in association with persistent neuroinflammation and secondary neurodegeneration, even after the

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apparently successful treatment of infection. Thus together, these hypotheses may possibly explain the risk of delirium occurrence, and the propensity for at least its partial persistence in the presence of dementia.59

Advanced Dementia in the Context of Palliative Care. Historically, palliative care services have focused mainly on cancer-related illness, where there is a high prevalence of more persistent or enduring cognitive problems, often with multifactorial etiology, including those

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resulting from intracranial malignancy. The global prevalence of dementia is predicted to increase to over 81 million by 2040,71 yet there is often a lack of awareness of dementia itself as a terminal condition and a lack of clarity regarding how, when, and by whom palliative care

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should be delivered.72,73 The complexities of caring for those with dementia has been highlighted by Small et al.,74 who emphasize the fine balance of active investigation and intervention as opposed to focusing on ensuring optimal levels of comfort and analgesia, especially in more

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advanced illness. Moreover, this challenge frequently arises in the context of where the person with dementia has lost decision-making capacity.75 However, there is an emerging international

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trend for greater involvement and optimal provision of palliative care services in dementia care, as there is much overlap in the holistic care needs of palliative care and dementia populations.76 Mitchell et al.77 reported that families’ evaluation of hospice care for older patients is generally high, irrespective of the decedents’ diagnosis of dementia, cancer or chronic disease.

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The frequency of dementia in palliative care settings has been steadily increasing, from approximately 1% in 1995, to 6.8% in 2001, with recent U.S. estimates indicating that almost 13% of palliative care patients have a primary diagnosis of dementia.78,79 A longitudinal study of

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the phenomenological profile of 100 consecutive adults, almost exclusively with an underlying diagnosis of cancer, admitted to a palliative care inpatient unit reported a rate of 27% for either

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dementia or other causes of persistent cognitive impairment of at least six months duration.14 The severity of the comorbid dementia was not documented. Clinical Manifestation and Trajectory of Comorbid Delirium and Dementia. Similar to patients in palliative care, those in the advanced stages of dementia are especially prone to delirium. There is also a similar preponderance of relatively hypoactive presentations, which are associated with inherent challenges in diagnosing delirium, in both the dementia and palliative

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care populations.50,80,81 Furthermore, hypoactivity is also a feature of frailty, a syndrome which often co-exists with dementia, and also with advanced disease, such as cancer.82 Frailty reflects a reduced ability to compensate to stressors, and likely also confers a degree of vulnerability

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towards the development of delirium.83 The type of presentation of comorbid delirium and dementia is likely to be influenced by the severity of the dementia and also the type of dementia, for example, dementia with Lewy bodies has a strong association with perceptual disturbance.84

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However, the influence of these parameters (severity and type of dementia) has not been reported in studies to date.85 In Alzheimer’s disease, studies have demonstrated an association between

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systemic inflammation, as reflected by raised serum proinflammatory cytokines, and an increase in cognitive decline independent of delirium,62 and neuropsychiatric symptoms of sickness behavior (especially the three core symptoms of apathy, depression and anxiety) both in association with and independent of delirium.63 These findings are consistent with the premise

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that the occurrence of delirium in a younger and healthier patient may require a greater degree of systemic inflammation, whereas only a mild degree of inflammation may trigger an episode of delirium in an older patient with dementia.64,67

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Delirium can impact the symptom burden experienced in dementia at the end of life. Worsening of confusion, often because of delirium, has been identified as the most common

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problem in people with dementia in their last year,86 and dementia co-occurs in as many as twothirds of delirium cases in elderly populations.87 Nurses have particular difficulty identifying delirium when it coexists with dementia as compared with dementia or delirium alone,32,88 and the so-called behavioral and psychological symptoms of dementia (BPSD) have much phenomenological overlap with the neuropsychiatric profile that is typical of delirious states; some observers have suggested that many cases of BPSD encapsulate unrecognized delirium.89

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In addition, evidence is mounting for the existence of persistent cognitive impairment following a delirium episode90,91 and gathering evidence indicates that the occurrence of delirium can accelerate the cognitive decline in Alzheimer’s disease.55,92 These observations suggest that

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palliative care clinicians need to be vigilant in determining when symptoms being manifested are the result of the natural history of the dementia, or indeed may be a preventable deterioration. This is compounded by the differing prognostic trajectories of dementia versus those of terminal

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cancer-related illness; dementia, even in its advanced state, is less predictable and often more gradual in progression.78 In the DSM-5, the term neurocognitive disorders (NCDs) now

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encompasses the syndromes of dementia and delirium. The major NCDs include Alzheimer’s disease and those with other associations: vascular, Lewy bodies, Parkinson’s disease, frontotemporal, traumatic brain injury, HIV infection, substance / medication-induced, Huntington’s disease, and prion disease.9 The DSM-5 generic diagnostic criteria for a major

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neurocognitive disorder such as Alzheimer’s dementia are presented in Table 3. Clinically, comorbid delirium in the presence of pre-existing dementia may pose a diagnostic conundrum because of overlapping features that complicate diagnosis. A comparison

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of features of delirium and dementia, based on onset, course, duration, precipitant identification, reversibility, mode of presentation in the terminal or dying phase, level of association with frailty

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or cachexia, and other cognitive and behavioral manifestations, is presented in Table 4. In the palliative setting, making this differentiation is key to ensuring optimal management of symptoms and their related distress. Both syndromes include widespread and generalized disturbance of brain function but the context of delirium, which is relatively acute and tends to include substantial fluctuation in symptoms over the day, is highly characteristic. Moreover, delirium can be distinguished from dementia by the pattern of cognitive impairments that

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includes disproportionate disturbance of attention and perceptual performance.14,93 Studies, including work conducted in a palliative care setting,14 also indicate that delirium symptoms tend to overshadow dementia symptoms when they co-occur, such that the clinical rule of thumb is

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that where the symptoms of delirium are present, it should be the presumed diagnosis in the first instance.94-97

Assessment of Comorbid Delirium and Dementia. The identification of a prodromal

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phase of delirium in patients with underlying dementia could potentially help predict the

development of delirium and possibly inform targeted interventions to prevent delirium.98 When

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compared with no-delirious controls (70% of them with dementia), patients with delirium superimposed on dementia were more likely to have new onset perceptual disturbances, disorganized thinking and worsening of Mini-Mental State Examination scores in the two weeks preceding their diagnosis of delirium.98 Theoretically, the high level of 24-hour contact between

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patients and nurses might suggest that nurses are ideally placed to recognize the emergence of delirium. However, delirium recognition by nurses in general is poor, especially in patients with pre-existing dementia and those with hypoactive delirium.99 Furthermore, a case vignette study

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suggested that even nurses with a high level of geropsychiatric nursing knowledge had difficulty recognizing delirium superimposed on dementia when compared with recognizing features of

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dementia or delirium alone.88

Perhaps the most important assessment is to determine baseline function; for patients with delirium it is particularly helpful to know their level of cognitive functioning prior to the onset of syndromal delirium and even the prodromal phase of delirium. The availability of such cognitive data hinges on the degree to which the culture of systematic cognitive assessment exists and is supported in a particular institution. The feasibility of a computerized decisional

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support system to assist nurses with the diagnosis of delirium superimposed on dementia has been demonstrated in a small pilot study and appears to be worthy of further evaluation.100 The merits of cognitive screening alone versus cognitive screening with the added input of nursing

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observations have been evaluated in long-term care residents.101 Prevalence detection of

delirium superimposed on dementia increased from 14% to 24.7% with the inclusion of nurses’ observations in addition to cognitive testing by research assistants. In palliative care, the issue of

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assessment burden must be borne in mind.21 Intuitively, observational tools such as the Nursing Delirium Screening Scale (NuDESC)102 or the Delirium Observational Screening Scale103 are

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attractive because of their brevity and their observational, and thus non-burdensome, nature. However, there are limited data on the use of the observational and cognitive screening tools specifically in relation to delirium superimposed on dementia, especially in palliative care settings.104 A Chinese version of the NuDESC demonstrated a 96% sensitivity and 79%

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specificity for delirium screening in a sample of 100 patients, of whom 34% had a diagnosis of dementia.105 The same study showed that the confusion assessment method (CAM) had a sensitivity and specificity of 76% and 100%, respectively. The average completion time for the

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CAM and NuDESC in this study was 10 minutes and one minute, respectively. Adding psychomotor change to the four-item CAM diagnostic algorithm improved its diagnostic

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specificity in relation to ICD-10 criteria for delirium, and improved sensitivity when sequentially applied in CAM-negative individuals.106 A systematic review of tools to detect delirium superimposed on dementia identified nine studies as meeting the inclusion criteria.85 It concluded that three tools had demonstrated preliminary evidence in detecting delirium superimposed on dementia: the CAM, CAM-ICU, and the electroencephalogram (EEG). Although an EEG may help to confirm the diagnosis of delirium in acute medical settings,107 its utility across the full

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spectrum of palliative care settings may be limited. Although the search for specific biomarkers and genomic profiles for delirium have yielded some positive results,108 there is currently no clearly defined clinical role for their use in diagnosing comorbid dementia and delirium. The

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advent of newer technology such as eye tracking has undergone preliminary investigation and appears worthy of further evaluation.109 An important area of assessment that warrants further exploration and study is the process or mechanism by which caregiver information is captured.

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For example, a family report version of the CAM, the FAM-CAM, has shown promise in an exploratory study.110 Also, better detection of specific dementia or major neurocognitive disorder

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subtype symptoms may assist in the diagnosis of delirium superimposed on dementia.85 Reversibility of Delirium in Comorbid Delirium and Dementia. Pre-existing cognitive impairment in palliative care patients is associated with less reversible delirium.111 This is in keeping with more general findings relating to the relative treatability of delirium when it occurs

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with comorbid dementia; both pharmacological and other evidence suggests that therapeutic effectiveness is less when delirium is associated with comorbid delirium.54 However, evidence notably indicates that delirium responds more consistently to antipsychotics than do behavioral

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and psychological symptoms of dementia,112 further emphasizing the importance of reliable and accurate distinction of these conditions. In advanced dementia, a similar clinical dilemma exists:

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balancing the desire for care that is not unduly demanding or invasive (or requires transfer to acute care from residential aged care) while also recognizing the potential reversibility of delirium. In clinical practice, the relatively successful treatment and reversal of an episode of delirium may unmask a hitherto unrecognized dementia. Further, it must be recognized that recurrent or persistent episodes of delirium also may be associated with the development and clinical emergence of dementia.

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Undoubtedly, palliative care practitioners can benefit from the growing research activity that is currently exploring the delirium-dementia interface, but in addition, there is a need for studies that are specific to delirium when it occurs in the context of advanced dementia.

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Psychomotor Subtypes of Delirium in Palliative Care

Delirium, although thought of as a unitary syndrome arising from a multitude of potential causative factors, has substantive heterogeneity in presentation, such that specific clinical

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variants or subtypes also are recognized. Of the variety of possible characteristics that could be used to distinguish clinical subtypes, the most intensely studied are subtypes defined according

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to psychomotor profile.50 Psychomotor subtype has been studied in relation to phenomenological characteristics, etiology, treatment experiences, and outcomes, including mortality rates; but lack of consistency in motor subtype definitions has hampered research in this area. This work has allowed for motor subtypes to be recognized as hyperactive, hypoactive or mixed presentations

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within the delirium diagnostic criteria in DSM-5.9 Although different motor activity profiles have been linked to delirium since the descriptions provided by the ancient Greeks of “Phrenitis” and “lethargus” to describe hyperactive and hypoactive presentations. respectively, Lipowski

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was the first commentator of modern times to suggest the use of motor subtypes.35,113 Much of the subsequent work establishing the existence, phenomenological

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characteristics and outcomes and treatment of delirium and its relationship to psychomotor subtypes has been conducted in palliative care patients.11,13,15,16,18,22,24,25,27,114-116 A recent detailed systematic review of 34 studies exploring motor subtypes in delirium cited that almost one-third (n=11) had been conducted in palliative care.50 Meagher et al.13 examined concordance between four commonly used subtyping methods 48,113,117,118

when applied to the same cohort of 100 consecutive palliative care admissions

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described above, and found that only 34% were labeled with the same subtype by these methods.13 The subsequent development of the Delirium Motor Subtype Scale11 in palliative care, adult and old-age Consultation-Liaison psychiatry service populations, and its abbreviated

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four-item version`(DMSS-4),12 can allow for rapid and reliable assessment of motor subtype in delirium, based upon disturbances that are relatively specific for delirium and that have

demonstrated concurrent validity with bioelectronic measures.119 The DMSS has been used in

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studies of palliative care populations.10,14-16

The predominance of hypoactive presentations of delirium has important implications for

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the management of delirium in palliative care settings, in particular relating to accurate detection and diagnosis, and subsequent effective management. Hypoactive presentations are more common in patients with comorbid dementia and with organ failure as an etiological issue.120 Also important is that palliative care patients with altered consciousness and communication

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have difficulty participating in delirium assessment instruments, and the items related to hypoactive presentations are more difficult to complete. Hypoactive presentations are more frequently missed in palliative care.33 Psychomotor dysfunction is almost universal in palliative

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care delirium, with rates of up to 94% reported for at least some form of discernible motor activity disturbance (either hyperactive or hypoactive).121 A recent longitudinal study of motor

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subtypes in palliative care emphasized how disturbed motor activity is almost invariably present in actual syndromal delirium, such that cases of DSM-IV delirium with “no subtype” frequently scored in the subsyndromal range of severity when rated with the DRS-R98.16 This work also found that motor profile is relatively consistent across an episode.10,16 Disturbances of cognition and thought process abnormalities were similar across the motor subtypes but the principal differences are in respect to non-cognitive symptoms (sleep-wake cycle, delusions,

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hallucinations, affective lability). Similarly, Boettger and Breitbart concluded that there were no differences between hyperactive and hypoactive groups in terms of cognitive and disorganized thinking and that prominent differences were principally in respect to non-cognitive symptoms.22

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This work demonstrated that although the mixed subtype manifests as the most

phenomenologically severe, relatively hypoactive presentations are the most prognostically grave.15,33

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Clear consensus on the management of such patients is still evolving, in particular in the use of antipyschotic medication. Although some studies have highlighted that hypoactive

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presentations may be less responsive to pharmacological interventions, other work suggests that despite the more frequent use of antipsychotics for hyperactive presentations, much of the existing evidence suggests similar response rates, regardless of motor subtype.81 Studies that are designed to specifically address this issue as a primary outcome are needed.

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Studies have clearly demonstrated that both hypoactive and hyperactive presentations are distressing to patients, caregivers and staff, but often for quite different reasons.1,122 The presence of delusions is the most significant predictor of patient distress.

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The key differential diagnoses and other symptoms to consider for hypoactive delirium include depression, cancer-related pain, fatigue and cachexia. The distinction of hypoactive

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delirium from depressive states can be especially problematic as these two conditions have considerable phenomenological overlap and the usual somatic disturbances that can be important indicators of depressive illness are less distinguishing in patients with terminal illness.123,124 These issues have been recognized as part of the so-called “overlap syndrome,” which is used to denote the co-occurrence of symptoms that typically characterize both delirium and depression and which is linked to a particularly poor prognostic profile.125

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Conclusions There are considerable challenges in the accurate assessment of delirium in people with advanced disease, where generalized disturbance of central nervous system function occurs in

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the seriously ill, often with comorbid illness including dementia. The differential diagnoses are wide, including pain, fatigue, mood disturbance, psychoactive medication effects and other causes for altered consciousness. Delirium presentations are very similar for both reversible and

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irreversible episodes such that clinical decision making needs to rely on other factors such as prior functional status and the trajectory of the life-limiting illness to decide the optimal

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approach to intervention. The increasing research activity exploring palliative care delirium has highlighted the frequency and impact of SSD, comorbid dementia, and the hypoactive subtype as the most prevalent clinical presentation in the palliative population. Further studies are needed to delineate the pathophysiological and clinical associations of these presentations so as to inform

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therapeutic strategies. The priority issues identified in our review are summarized in Table 5. The case for future studies is compelling; delirium is increasingly recognized as a key health care target, given the increasingly aged population and the growing focus on dementia care in

Acknowledgements

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palliative care.

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The authors acknowledge input from the participants (listed in the Foreword to this Section) at the SUNDIPS Meeting, Ottawa, Canada in June 2012. This meeting received administrative support from Bruyère Research Institute and funding support through a joint research grant to Dr. Peter Lawlor from the Gillin Family and Bruyère Foundation. Dr. Lawlor holds a research award from the Department of Medicine, University of Ottawa. Dr. David Meagher receives funding from the Health Research Board (Ireland) and the All-Ireland Institute

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119. Godfrey A, Leonard M, Donnelly S, et al. Validating a new clinical subtyping scheme for delirium with electronic motion analysis. Psychiatry Res 2010;178:186-190. 120. Friedlander MM, Brayman Y, Breitbart WS. Delirium in palliative care. Oncology 2004;18:1541-1550.

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121. Meagher JD, Moran M, Raju B, et al. Phenomenology of 100 cases using standardised measures. Br J Psychiatry 2007;190:135-241. 122. O’Malley G, Leonard M, Meagher D, O’Keeffe ST. The delirium experience: a review. J

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Psychosom Res 2008;65:223-228.

123. Leonard M, Spiller J, Keen J, et al. Symptoms of delirium assessed serially in palliativecare inpatients. Psychosomatics 2009;50:506-514.

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124. Marchington KL, Carrier L, Lawlor PG. Delirium masquerading as depression. Palliat Support Care 2012;10:59-62.

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125. Givens JL, Jones RN, Inouye SK. The overlap syndrome of depression and delirium in older hospitalized patients. J Am Geriatr Soc 2009;57:1347-1353. 126. Cole MG. Subsyndromal delirium in old age: conceptual and methodological issues. Int

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Psychogeriatr 2013;25:863-866.

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ACCEPTED MANUSCRIPT 1 Table 1. Challenges 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) with the need for a thorough delirium assessment and management plan

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2. Identifying when delirium pathology is reversible versus irreversible and in context of imminent death

3. Impaired communication and decision making capacity

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4. Delirium assessment often occurs in the context of multiple medical morbidities, extreme frailty, cachexia and fatigue

5. Polypharmacy, in particular those medications with psychoactive effects

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6. Overlap of delirium phenomenology with major differential diagnoses, namely pain, depression and dementia. High potential for misdiagnosis of hypoactive delirium as depression

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7. Lack of clinical agreement regarding the existence of subsyndromal delirium potentially leading to a missed diagnosis

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Table 2. Diagnostic and Statistical Manual of Mental Disorders (DSM-5) Diagnostic Criteria for Delirium

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

B. The disturbance develops over a short period of time (usually hours to a few days), represents a change from baseline attention and awareness, and tends to fluctuate in severity during the course of a day.

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C. An additional disturbance in cognition (e.g., memory deficit, disorientation, language, visuospatial ability, or perception).

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D. The disturbances in Criteria A and C are not better explained by another preexisting, established or evolving neurocognitive disorder and do not occur in the context of a severely reduced level of arousal, such as coma. E. There is evidence from the history, physical examination, or laboratory findings that the disturbance is a direct physiological consequences of another medical condition, substance intoxication or withdrawal (i.e., due to a drug of abuse or to a medication), or exposure to a toxin, or is due to multiple etiologies.

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Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (Copyright ©2013). American Psychiatric Association. All Rights Reserved.

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

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A. Evidence of significant cognitive decline from a previous level of performance in one or more cognitive domains (complex attention, executive function, learning and memory, language, perceptual-motor, or social cognition) based on:

1. Concern of the individual, a knowledgeable informant, or the clinician that there has been a significant decline in cognitive function; and

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2. A substantial impairment in cognitive performance, preferably documented by standardized neuropsychological testing or, in its absence, another quantified clinical assessment.

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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).

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Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (Copyright ©2013). American Psychiatric Association. All Rights Reserved.

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Table 4. Comparison of Features of Delirium and Dementia in Palliative Care Dementia

Onset

Hours to days

Months to years

Course

Fluctuating

Slowly progressive in most cases

Identifiable precipitant(s)

Frequently

Not usually

Reversibility

Potentially reversible in some cases

Rarely reversible

Presentation in dying phase

Occurs in most patients

Delirium usually develops

Associated frailty or cachexia

Common

Common in late stages

Level of consciousness

Impaired / clouded

Attention

Deficit is a diagnostic criterion

Other cognitive deficits

Potentially detectable on cognitive

Potentially detectable on

screening

cognitive screening

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Delirium

Clear until late in disease

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Preserved in early stages

Common

Delusional activity

Common

Sleep wake cycle disturbance

Very common

Speech problems

Slurred / incoherent

Possible dysphasia

Psychomotor behaviour

Hypo- or hyperactive, or mixed

Normal in early stages

Involuntary movements

Asterixus and myoclonus

Tremor, notably in Parkinson’s

sometimes

disease

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Perceptual disturbance

Infrequent Infrequent Infrequent

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Table 5. Priority Issues in Delirium Diagnosis and Classification in Palliative Care Settings 1. Further characterization of the spectrum of delirium presentations,50 particularly subsyndromal

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delirium, and including longitudinal acquisition of phenomenological data in the palliative care setting. The specific clinical context of the non-communicative or semiconscious patient warrants particular attention.

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2. Consensus on consistent diagnostic criteria for subsyndromal delirium.126

3. Robust and standardized approaches to the assessment of differential diagnoses or concomitant

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symptoms such as pain and mood disturbance in the person with delirium. 44,104 4. Evaluation of the role of cognitive screening and observational (behavioral) screening in the diagnosis of delirium,21,104 both in the presence and absence of dementia. 5. Development of valid, reliable, convenient and non- burdensome methods to measure

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psychomotor activity and help to classify delirium subtypes in palliative populations e.g. validation of the DMSS-4.12

6. Determine the pathophysiological and clinical correlates of psychomotor subtypes, especially

strategies.66

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the hypoactive subtype in palliative care settings, thus informing investigational and therapeutic

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7. Articulation of the clinical indicators and decision making framework used to determine the reversibility of delirium,104 especially in the context of co-morbid delirium and dementia.

Delirium diagnostic and classification challenges in palliative care: subsyndromal delirium, comorbid delirium-dementia, and psychomotor subtypes.

Delirium often presents difficult diagnostic and classification challenges in palliative care settings...
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