Alasdair M. J. MacLullich

Delirium and long-term cognitive impairment

Delirium is a severe, acute neuropsychiatric syndrome that is highly prevalent in acute hospital populations. Delirium has noticeable effects on length of hospitalization, cost of care, mortality and morbidity. In addition to these well-established adverse consequences, there is increasing evidence linking delirium and a higher risk of long-term cognitive impairment (LTCI), including dementia. A prior review (Jackson, Gordon, Hart, Hopkins, & Ely, 2004), in which nine studies (total N = 1,885, years 1989–2003) were considered, concluded that there was evidence for an association between delirium and LTCI. Here we provide a review of studies published since Jacksons review. We included nine reports, with a total of 2,025 patients. The studies show diverse sample sizes, methodologies, designs and patient populations. However, taken together, the results of these new studies broadly confirm that there is a link between delirium and LTCI. We go on to discuss putative mechanisms and explanations. These include (1) delirium as a marker of chronic progressive pathology, but unrelated to any progression, (2) delirium as a consequence of acute brain damage which is also responsible for a ‘single hit’ or triggering of active processes causing LTCI, (3) delirium itself as a cause of LTCI, and (4) drug treatment of delirium or other conditions as a cause of LTCI. We conclude with suggestions for future research.

At the extreme end of the psychoneuroimmunological spectrum: delirium as a maladaptive sickness behaviour response.

Delirium is a common and severe neuropsychiatric syndrome characterised by acute deterioration and fluctuations in mental status. It is precipitated mainly by acute illness, trauma, surgery, or drugs. Delirium affects around one in eight hospital inpatients and is associated with multiple adverse consequences, including new institutionalisation, worsening of existing dementia, and death. Patients with delirium show attentional and other cognitive deficits, altered alertness (mostly reduced, but some patients develop agitation and hyperactivity), altered sleep-wake cycle and psychoses. The pathways from the various aetiologies to the heterogeneous clinical presentations are hardly studied and are poorly understood. One of the key questions, which research is only now beginning to address, is how the factors determining susceptibility interact with the stimuli that trigger delirium. Inflammatory signals arising during systemic infection evoke sickness behaviour, a coordinated set of adaptive changes initiated by the host to respond to, and to counteract, infection. It is now clear that the same systemic inflammatory signals can have severe deleterious effects on brain function when occuring in old age or in the presence of neurodegenerative disease. Multiple animal studies now show that even mild acute systemic inflammation can induce exaggerated sickness behaviour responses and cognitive dysfunction in aged animals or those with prior degenerative pathology when compared to young and/or healthy controls. These findings appear highly promising in understanding aspects of delirium. In this review our aim is to describe and assess the parallels between exaggerated sickness behaviour in vulnerable animals and delirium in older humans. We discuss inflammatory and stress-related triggers of delirium in the context of new animal models that allow us to dissect some aspects of the mechanisms underpinning these episodes. We discuss some differences between the sickness behaviour syndrome model and delirium in the context of the complexity in the latter due to other factors such as prior pathology, psychological stress and drug effects. We conclude that, with appropriate caveats, the study of sickness behaviour in the vulnerable brain offers a promising route to uncover the mechanisms of this common and serious unmet medical need.

Cognitive assessment of older people

#### Summary pointsnnCognitive assessment involves examination of higher cortical functions, particularly memory, attention, orientation, language, executive function (planning activities), and praxis (sequencing of activities). This article will focus on cognitive assessment of older people (those aged over about 65 years) in the context of possible dementia, delirium, and depression. These are common and serious clinical syndromes affecting older people, and accurate cognitive assessment is an essential component for diagnosis. Dementia affects 20% of people aged over 80 years,1 and delirium may affect 30-50% of older people in hospitals and an estimated 16% in long term care facilities.2 The annual incidence of major depression in the general older population is about 15% a year and doubles after age 70.3nnWe have used personal archives of references and our own experience. We also examined the guidelines on dementia, delirium, and depression published by the National Institute for Health and Clinical Excellence (NICE) and a systematic review of cognitive assessment instruments.nn#### Case scenario: part 1nnA woman aged 89 years attends your clinic accompanied by her daughter. The daughter explains that her mother has not been herself over the past few months, that she is …

Who understands delirium

This New York Times article on Pulitzer Prize-winning historian Justin Kaplan’s experience of delirium [1] provided welcome publicity of this enormously impactful but historically neglected syndrome. Nevertheless, the remarkable scarcity of such exposure in the mass media speaks to what is perhaps the most significant obstacle to progress in delirium research and practice: its invisibility. Why has delirium remained so obscure? There would appear to be several reasons. Patients rarely speak of their experiences of delirium, perhaps because of embarrassment or bewilderment; currently, there are no specific charities or patient advocacy groups. Healthcare staff use a wide variety of informal words and phrases to describe delirium. This diagnostic ambivalence and imprecision greatly hinders the implementation of formal methods of improving care. Another likely factor is that delirium is very challenging: it is heterogeneous in its precipitants, symptomatology, severity and course. The mixture of mental status abnormalities and complex medicine means that healthcare professionals require multiple skills to manage delirium. Indeed, these skills may be lacking: a recent survey of UK junior doctors suggested that there are serious deficiencies in knowledge of the diagnostic criteria [2]. However, there have been major advances over the last three or four decades that ought to be more widely disseminated [3]. We know that delirium is common and that it has several adverse consequences, including loss of independence, acceleration of dementia and death [3–5]. The clinical predisposing and precipitating factors are now well documented [3]. Recent work has shown that delirium persists for months in around 20% of cases [6]. The significance of delirium in critically ill patients and in palliative care settings is now far clearer [7–9]. Crucially, it is now established that multi-component prevention strategies are effective, and should be introduced into standard health-care practice [3]. What might be the current priorities for research? Direct brain insults such as oxygen deprivation, hyponatraemia and adverse drug effects are common causes of delirium, and in many such cases, the routes to disruption of cognitive processes are clear. In contrast, the mechanisms by which peripheral illness such as urinary tract infection can cause acute, severe mental deterioration over periods of as little as a few hours are poorly understood. Recent experiments in animal models and humans have found that in older individuals peripheral stimuli can induce adverse inflammatory and stress system responses in the central nervous system, with resultant maladaptive behavioural change including delirium [10–12]. Delirium could thus represent an exaggeration of the sickness behaviour syndrome (a set of normally adaptive behavioural responses to illness including sleepiness, fatigue, anhedonia and impaired concentration), but may also simply be due to the effects of pathologically sustained high cortisol levels [10]. These leads in dissecting the ‘indirect’ causes of delirium may suggest potential new treatments. The role of stress mediators is also relevant to the patient experience of delirium: studies in animal models suggest that chronic unpredictable psychological stress over periods of days can cause marked brain damage [13]. Patients with delirium are often in a comparable position, suffering pain, fear, an unpredictable environment and strangers undertaking invasive activities. All of this is exacerbated by the inability of the patient’s mind to fully comprehend what is happening to them. The implications here are that effective psychological care of patients with delirium may be particularly important, not simply to relieve distress, but to protect the brain. Detection is a pre-requisite for good care, but the problem of achieving acceptable levels of recognition of delirium has not yet been solved. This partly reflects the lack of validated brief screening tools that do not require special training and that discriminate delirium from dementia [14, 15]. Another need is for methods of recording the status of conscious but untestable patients, that is, those too drowsy to undergo cognitive testing or even a brief interview. Such patients are overwhelmingly likely to have a diagnosis of hypoactive delirium, but are often left without any label and resultant management plan. More broadly, further research on the neuropsychology of delirium is essential to the development of better testing instruments for screening and diagnosis in clinical practice and in research. There are many challenges here, not least because of the range of mental status change, from stupor to relatively mild deficits in attention. Subsyndromal delirium, where there are one or more features of delirium but in which full DSM-IV criteria are not met, has recently been shown to have prognostic significance [16]. Despite this, its neuropsychology is all but unexplored. The clinical role of other methods of assessment, such as neuroimaging, plasma biomarkers and lumbar puncture, also remain greatly under-researched. A recent systematic review of the literature on neuroimaging findings in delirium found that though there may be some relationships between white

Cortisol levels and the severity and outcomes of acute stroke: a systematic review

Studies in non-stroke patients have shown an association between dysregulation of the hypothalamic–pituitary–adrenal axis and morbidity and mortality. We conducted a systematic review to evaluate cortisol levels in acute stroke and their associations with outcome. We searched MEDLINE and EMBASE for articles up to April 2013 and PsychINFO for articles up to July 2013, using the keywords “cortisol” and “stroke” and associated terms or synonyms. We included studies published in peer-reviewed journals that recruited 10 or more participants and measured cortisol at least once in the first year following stroke. Data were extracted regarding cortisol levels, including changes over time and their relationship to stroke severity, and outcome. Of 11,240 abstracts, 101 full texts were obtained and 48 fulfilled our inclusion criteria. Cortisol levels were high in the first week after stroke in the majority of studies (26 studies, nxa0=xa01,340). Higher cortisol was associated with dependency (8/11 studies, nxa0=xa0822), delirium (5/6 studies, nxa0=xa0269) depression (3/5 studies nxa0=xa0117) and mortality (8/10 studies, nxa0=xa0856). Five studies adjusted for stroke severity; one found an association between higher cortisol and dependency, and three found an association between higher cortisol and mortality. Cortisol levels are high for at least 7xa0days after stroke. Elevated cortisol after stroke is associated with dependency, morbidity, and mortality; however, there is insufficient evidence to conclude that these relationships are independent of stroke severity.

Development of an abbreviated version of the delirium motor subtyping scale (DMSS-4)

BACKGROUNDnDelirium is a common neuropsychiatric syndrome with considerable heterogeneity in clinical profile. Identification of clinical subtypes can allow for more targeted clinical and research efforts. We sought to develop a brief method for clinical subtyping in clinical and research settings.nnnMETHODSnA multi-site database, including motor symptom assessments conducted in 487 patients from palliative care, adult and old age consultation-liaison psychiatry services was used to document motor activity disturbances as per the Delirium Motor Checklist (DMC). Latent class analysis (LCA) was used to identify the class structure underpinning DMC data and also items for a brief subtyping scale. The concordance of the abbreviated scale was then compared with the original Delirium Motor Subtype Scale (DMSS) in 375 patients having delirium as per the American Psychiatric Associations Diagnostic and Statistical Manual (4th edition) criteria.nnnRESULTSnLatent class analysis identified four classes that corresponded closely with the four recognized motor subtypes of delirium. Further, LCA of items (n = 15) that loaded >60% to the model identified four features that reliably identified the classes/subtypes, and these were combined as a brief motor subtyping scale (DMSS-4). There was good concordance for subtype attribution between the original DMSS and the DMSS-4 (κ = 0.63).nnnCONCLUSIONSnThe DMSS-4 allows for rapid assessment of clinical subtypes in delirium and has high concordance with the longer and well-validated DMSS. More consistent clinical subtyping in delirium can facilitate better delirium management and more focused research effort.

Under-detection of delirium and impact of neurocognitive deficits on in-hospital mortality among acute geriatric and medical wards.

BACKGROUNDnDelirium is a neuropsychiatric disorder, triggered by medical precipitants causes. Study aims were to describe the prevalence and impact on in-hospital mortality of delirium identified through ICD-9 codes as well as evidence of neurocognitive deficits demonstrated in a population of older patients admitted to acute medical wards.nnnMETHODSnThis was a prospective cohort multicenter study of 2521 older patients enrolled in the Registro Politerapie SIMI (REPOSI) during the years 2010 and 2012. The diagnosis of delirium was obtained by ICD-9 codes. Cognitive function was evaluated with the Short Blessed Test (SBT) and single SBT items were used as measures of deficits in attention, orientation and memory. Combination of deficits in SBT items was used as a proxy for delirium. Logistic regression was used to evaluate the association with in-hospital mortality of delirium and combined deficits in SBT items.nnnRESULTSnDelirium was coded in 2.9%, while deficits in attention, orientation, and memory were found in 35.4%, 29.7% and 77.5% of patients. Inattention and either disorientation or memory deficits were found in 14.1%, while combination of the 3 deficits in 19.8%. Delirium, as per ICD-9 codes, was not a predictor of in-hospital mortality. In contrast, objective deficits of inattention, in combination with orientation and memory disorders, were stronger predictors after adjusting for covariates.nnnCONCLUSIONSnThe documentation of delirium is poor in medical wards of Italian acute hospitals. Neurocognitive deficits on objective testing (in a pattern suggestive of undiagnosed delirium) should be used to raise awareness of delirium, given their association with in-hospital mortality.

Months backward test: A review of its use in clinical studies.

AIMnTo review the use of the Months Backwards Test (MBT) in clinical and research contexts.nnnMETHODSnWe conducted a systematic review of reports relating to the MBT based upon a search of PsychINFO and MEDLINE between January 1980 and December 2014. Only reports that specifically described findings pertaining to the MBT were included. Findings were considered in terms of rating procedures, testing performance, psychometric properties, neuropsychological studies and use in clinical populations.nnnRESULTSnWe identified 22 data reports. The MBT is administered and rated in a variety of ways with very little consistency across studies. It has been used to assess various cognitive functions including focused and sustained attention as well as central processing speed. Performance can be assessed in terms of the ability to accurately complete the test without errors (MB accuracy), and time taken to complete the test (MB duration). Completion time in cognitively intact subjects is usually < 20 s with upper limits of 60-90 s typically applied in studies. The majority of cognitively intact adults can complete the test without error such that any errors of omission are strongly suggestive of cognitive dysfunction. Coverage of clinical populations, including those with significant cognitive difficulties is high with the majority of subjects able to engage with MBT procedures. Performance correlates highly with other cognitive tests, especially of attention, including the digit span backwards, trailmaking test B, serial threes and sevens, tests of simple and complex choice reaction time, delayed story recall and standardized list learning measures. Test-retest and inter-rater reliability are high (both > 0.90). Functional magnetic resonance imaging studies comparing the months forward test and MBT indicate greater involvement of more complex networks (bilateral middle and inferior frontal gyri, the posterior parietal cortex and the left anterior cingulate gyrus) for backwards cognitive processing. The MBT has been usefully applied to the study of a variety of clinical presentations, for both cognitive and functional assessment. In addition to the assessment of major neuropsychiatric conditions such as delirium, dementia and Mild Cognitive Impairment, the MBT has been used in the assessment of concussion, profiling of neurocognitive impairments in organic brain disorders and Parkinsons disease, prediction of delirium risk in surgical patients and medication compliance in diabetes. The reported sensitivity for acute neurocognitive disturbance/delirium in hospitalised patients is estimated at 83%-93%. Repeated testing can be used to identify deteriorating cognitive function over time.nnnCONCLUSIONnThe MBT is a simple, versatile tool that is sensitive to significant cognitive impairment. Performance can be assessed according to accuracy and speed of performance. However, greater consistency in administration and rating is needed. We suggest two approaches to assessing performance - a simple (pass/fail) method as well as a ten point scale for rating test performance (467).