Better palliative care for people with a dementia: summary of interdisciplinary workshop highlighting current gaps and recommendations for future research.

BACKGROUND: Dementia is the most common neurological disorder worldwide and is a life-limiting condition, but very often is not recognised as such. People with dementia, and their carers, have been shown to have palliative care needs equal in extent to those of cancer patients. However, many people with advanced dementia are not routinely being assessed to determine their palliative care needs, and it is not clear why this is so. MAIN BODY: An interdisciplinary workshop on "Palliative Care in Neurodegeneration, with a focus on Dementia", was held in Cork, Ireland, in May 2016. The key aim of this workshop was to discuss the evidence base for palliative care for people with dementia, to identify 'gaps' for clinical research, and to make recommendations for interdisciplinary research practice. To lead the discussion throughout the day a multidisciplinary panel of expert speakers were brought together, including both researchers and clinicians from across Ireland and the UK. Targeted invitations were sent to attendees ensuring all key stakeholders were present to contribute to discussions. In total, 49 experts representing 17 different academic and practice settings, attended. Key topics for discussion were pre-selected based on previously identified research priorities (e.g. James Lind Alliance) and stakeholder input. Key discussion topics included: i. Advance Care Planning for people with Dementia; ii. Personhood in End-of-life Dementia care; iii. Topics in the care of advanced dementia at home. These topics were used as a starting point, and the ethos of the workshop was that the attendees could stimulate discussion and debate in any relevant area, not just the key topics, summarised under iv. Other priorities. CONCLUSIONS: The care experienced by people with dementia and their families has the potential to be improved; palliative care frameworks may have much to offer in this endeavour. However, a solid evidence base is required to translate palliative care into practice in the context of dementia. This paper presents suggested research priorities as a starting point to build this evidence base. An interdisciplinary approach to research and priority setting is essential to develop actionable knowledge in this area.

Phenomenological and biological correlates of improved cognitive function in hospitalized elderly medical inpatients.

Deterioration of cognitive ability is a recognized outcome following acute illness in older patients. Levels of circulating cytokines and APOE genotype have both been linked with acute illness-related cognitive decline. In this observational longitudinal study, consecutive admissions to an elderly medical unit of patients aged ≥70 years were assessed within 3 days and re-assessed twice weekly with a range of scales assessing cognitive function, functional status and illness severity. Cytokines and APOE genotype were measured in a subsample. Improvement was defined as either a 20% or three points increase in mini mental state examination (MMSE). From the 142 participants 55 (39%) experienced cognitive improvement, of which 30 (54.5%) had delirium while 25 had non-delirious acute cognitive disorder. Using bivariate statistics, subjects with more severe acute illness, lower insulin-like growth factor-I (IGF-I) levels and more severe delirium were more likely to experience a ≥20% improvement in MMSE scores. When the criterion of cognitive improvement was a 3 point improvement in MMSE, those with more severe delirium, females and older were more likely to be improved. Longitudinal analysis using any criterion of improvement indicated that improvement was significantly (p<.05) predicted by higher levels of IGF-I, lower levels of IL-1 (alpha and beta), lack of APOE epsilon 4 allele, and female gender. In conclusion, cognitive recovery during admission is not exclusively linked to delirium status, but reflects a range of factors. The character and relevance of non-delirious acute cognitive disorder warrants further study.

Antipsychotics in dementia: prevalence and quality of antipsychotic drug prescribing in UK mental health services.

BACKGROUND: Up to a quarter of people in the UK with a diagnosis of dementia are prescribed an antipsychotic in any year. The potential risks of such treatment are becoming clearer, but the benefits remain uncertain. Concern about the frequency and quality of such prescribing was expressed in the National Dementia Strategy for England in 2009. AIMS: To provide an estimate of the prevalence of antipsychotic use for dementia in secondary mental health services in the UK and to collect data relevant to quality improvement initiatives for such prescribing practice. METHOD: In the context of a UK quality improvement programme, relevant clinical audit data were collected for patients with dementia under the care of specialist older people's mental health services. RESULTS: Fifty-four mental health National Health Service (NHS) trusts submitted data on 10 199 patients. Of those patients without comorbid psychotic illness, 1620 (16%) were prescribed an antipsychotic; the common clinical indications for such medication were agitation, psychotic symptoms, aggression and distress. Multivariable regression found younger age, care home or in-patient setting, vascular or Parkinson's disease dementia and greater severity of dementia to be all significantly associated with being prescribed antipsychotic medication. Of the 1001 (62%) patients prescribed treatment for more than 6 months, only three-quarters had a documented review of therapeutic response in the previous 6 months. CONCLUSIONS: The data reveal areas of relatively good current practice, including consideration of alternatives to antipsychotic medication and clear documentation of target symptoms. They also suggest areas for improvement, such as the frequency and quality of review of long-term medication. Strategies to reduce antipsychotic use should take account of the demographic and clinical variables predicting increased likelihood of antipsychotic prescription.

Efficacy of memantine for agitation in Alzheimer's dementia: a randomised double-blind placebo controlled trial.

BACKGROUND: Agitation in Alzheimer's disease (AD) is common and associated with poor patient life-quality and carer distress. The best evidence-based pharmacological treatments are antipsychotics which have limited benefits with increased morbidity and mortality. There are no memantine trials in clinically significant agitation but post-hoc analyses in other populations found reduced agitation. We tested the primary hypothesis, memantine is superior to placebo for clinically significant agitation, in patients with moderate-to-severe AD. METHODS AND FINDINGS: We recruited 153 participants with AD and clinically significant agitation from care-homes or hospitals for a double-blind randomised-controlled trial and 149 people started the trial of memantine versus placebo. The primary outcome was 6 weeks mixed model autoregressive analysis of Cohen-Mansfield Agitation Inventory (CMAI). Secondary outcomes were: 12 weeks CMAI; 6 and 12 weeks Neuropsychiatric symptoms (NPI), Clinical Global Impression Change (CGI-C), Standardised Mini Mental State Examination, Severe Impairment Battery. Using a mixed effects model we found no significant differences in the primary outcome, 6 weeks CMAI, between memantine and placebo (memantine lower -3.0; -8.3 to 2.2, p = 0.26); or 12 weeks CMAI; or CGI-C or adverse events at 6 or 12 weeks. NPI mean difference favoured memantine at weeks 6 (-6.9; -12.2 to -1.6; p = 0.012) and 12 (-9.6; -15.0 to -4.3 p = 0.0005). Memantine was significantly better than placebo for cognition. The main study limitation is that it still remains to be determined whether memantine has a role in milder agitation in AD. CONCLUSIONS: Memantine did not improve significant agitation in people with in moderate-to-severe AD. Future studies are urgently needed to test other pharmacological candidates in this group and memantine for neuropsychiatric symptoms. TRIAL REGISTRATION: ClinicalTrials.gov NCT00371059. TRIAL REGISTRATION: International Standard Randomised Controlled Trial 24953404.

Delirium and the functional recovery of older medical inpatients after acute illness: the significance of biological factors.

Previous studies have not clarified the relationship of delirium to functional capacity during acute illness. We have investigated this relationship, incorporating the potential roles of APOE genotype and circulating cytokines in a longitudinal study of acutely admitted patients aged 70+ years. In all participants was measured the: Barthel Index (BI), mini-mental state examination (MMSE), confusion assessment method (CAM), delirium rating scale (DRS), APACHE II, APOE genotype. In a sub-sample: serum interferon-γ (IFN-γ), interleukin-1 (Levels of IL-1α, IL-1ß and IL-1 receptor antagonist activity IL-1RA), interleukin-6 (IL-6), leukemia inhibitory factor (LIF), tumor necrosis factor-α (TNF-α) and insulin-like growth factor-I (IGF-I). Of 164 participants, mean age 84.6 ± 6.57 years (± S.D.), 67.1% were women. On first assessment, mean BI was 14.13 ± 4.46 and delirium prevalence was 25.6%. At discharge, the mean BI of survivors (n=150) was 15.61 ± 4.22. By discharge, survivors who had recovered from prevalent delirium had significant improvement in BI (n=38, p=0.005), but non-recovers did not (n=14, p=0.512). On, multivariate analysis, BI was significantly affected by MMSE, APOE, IL-1α, IL-6, LIF and TNF-α levels (p<0.05) but not by delirium. Delirium in acutely admitted patients is associated with functional decline only in those who do not recover. Biological factors, rather that delirium itself, may be responsible for this.

Ethical dilemmas: should antipsychotics ever be prescribed for people with dementia?

The use of antipsychotics for the treatment of behavioural and psychological symptoms of dementia (BPSD) is controversial. Antipsychotics cause harm and evidence-based guidelines advise against their use. We argue that antipsychotics may be justified using a palliative model: by reducing severe distress in those whose life expectancy is short.

The association of the dopamine transporter gene and the dopamine receptor 2 gene with delirium, a meta-analysis.

Delirium is the most common neuropsychiatric syndrome in elderly ill patients. Previously, associations between delirium and the dopamine transporter gene (solute carrier family 6, member 3 (SLC6A3)) and dopamine receptor 2 gene (DRD2) were found. The aim of this study was to validate whether markers of the SLC6A3 and DRD2 genes are were associated with delirium in independent populations. Six European populations collected DNA of older delirious patients. Associations were determined per population and results were combined in a meta-analysis. In total 820 medical inpatients, 185 cardiac surgery patients, 134 non-cardiac surgery patients and 502 population-based elderly subjects were included. Mean age was 82 years (SD 7.5 years), 598 (36%) were male, 665 (41%) had pre-existing cognitive impairment, and 558 (34%) experienced delirium. The SLC6A3 rs393795 homozygous AA genotype was more frequent in patients without delirium in all populations. The meta-analysis showed an Odds Ratio (OR) for delirium of 0.4 (95% confidence interval (C.I.) 0.2-0.6, P = 0.0003) for subjects with AA genotype compared to the AG and GG genotypes. SLC6A3 marker rs1042098 showed no association with delirium. In meta-analysis the DRD2 rs6276 homozygous GG genotype showed an OR of 0.8 for delirium (95% C.I. 0.6-1.1, P = 0.24). When subjects were stratified for cognitive status the rs6276 GG genotype showed ORs of 0.6 (95% C.I. 0.4-1.0, P = 0.06) and 0.8 (95% C.I. 0.5-1.5, P = 0.51) for delirium in patients with and without cognitive impairment, respectively. In independent cohorts, a variation in the SLC6A3 gene and possibly the DRD2 gene were found to protect for delirium.

Ethical research in delirium: arguments for including decisionally incapacitated subjects.

Here we describe how more important findings were obtained in a delirium study by using an informal assessment of mental capacity, and, in those who lacked capacity, obtaining consent later when or if capacity returned or a proxy was found. From a total of 233 patients 23 patients lacked capacity as judged by our informal capacity judgment and 210 did not. Of those who lacked capacity, 13 agreed to enter in the study. Six of them regained capacity later. When these 13 participants were excluded from analysis, significant findings were no longer evident. These results show that by the inclusion of subjects who lacked capacity the results of analyses of the condition from whish they suffer are altered. We suggest that this approach to the study of delirium is more ethical than the usual system of strict exclusion of people who lack capacity to give consent and for whom assent is not available.

Cytokines and IGF-I in delirious and non-delirious acutely ill older medical inpatients.

BACKGROUND: therapeutic use of cytokines can induce delirium, and delirium often occurs during infections associated with elevated levels of cytokines. This study examined the association of demographic, clinical and biological factors (IL-1alpha, IL-1beta, IL-1RA, IL-6, TNF-alpha, IFN-gamma, LIF, IGF-I, APOE genotype) with the presence and severity of delirium. METHODS: in an observational prospective longitudinal study, patients aged 70+ were recruited from an elderly medical unit and assessed every 3-4 days (maximum assessments 4). At each time, the scales MMSE, DRS, CAM, APACHEII were administered and blood was withdrawn to estimate the above biological factors. Mixed effects (PQL) and GEE were used to analyse the repeated measurements and investigate the associations at the individual and population average levels. RESULTS: a total of 205 observations on 67 individuals were analysed. Lower levels of IGF-I, and lower levels of circulating IL-1RA, are significantly (P < 0.05) associated with delirium, while the remaining of cytokines, severity of illness and possession of epsilon 4 allele had a non-significant effect. This has been shown by both statistical methods. Similarly lower levels of IGF-I, and high levels of IFN-gamma, are statistically significantly (P < 0.05) associated with higher DRS scores (more severe delirium). CONCLUSIONS: this study finds that (i) low levels of both neuroprotective factors (IGF-I, IL-1RA) are associated with delirium, (ii) high IFN-gamma and low IGF-I have significant effects on delirium severity and (iii) otherwise the pro-inflammatory cytokines studied, APOE genotype and severity of illness do not appear to be associated, in older medically ill patients, with either delirium or severity of it.

Associations of delirium with in-hospital and in 6-months mortality in elderly medical inpatients.

BACKGROUND: Studies on the association between mortality and delirium in older hospital inpatients have produced conflicting results. This insconsistency might be explained by case-mix differences in terms of clinical or underlying patho-physiological processes. For example, both albumin and C-reactive protein (CRP) have been reported as predictors of in-hospital mortality and interleukin-6 of longer-term mortality. METHODS: We used data from a longitudinal study of delirium to investigate the delirium-mortality relationship. A cohort of 164 patients, 70+ years were assessed within 3 days of acute hospital admission and hence twice weekly until hospital discharge, for the presence and severity of delirium and a range of clinical and laboratory measures, including initial albumin (n = 149), CRP (n = 76) and cytokine (n = 60) levels. In-hospital and 6-months mortality were determined from clinical records and telephone contact. RESULTS: During hospitalisation 14 (8.5%) patients died, 6 with delirium: mortality was not associated with delirium. At 6 months, 119 of 150 (77.3%) discharged patients were still alive, 21 (14.0%) dead, and 13 (8.7%) uncontactable. In bivariate analysis, 6-months mortality was associated with older age (P = 0.013), lower albumin (P = 0.001), higher CRP (P = 0.014) and higher interleukin-6 levels (P = 0.007), but not with presence or severity of in-hospital delirium. After controlling for other variables significant predictors (P < 0.05) for six-month mortality were initial MMSE, albumin, interferon-lambda and interleukin-6. CONCLUSIONS: The lack of demonstrable association between delirium and mortality may reflect inadequate statistical power in this study due to low numbers. These findings, however, highlight specific patho-physiological factors which may be important in the prognosis after delirium.

APOE and cytokines as biological markers for recovery of prevalent delirium in elderly medical inpatients.

BACKGROUND: Delirium frequently occurs in the context of infection and other inflammatory conditions associated with elevated levels of cytokines. Cytokines used therapeutically can induce symptoms of delirium as an adverse effect. We hypothesized that a causal relationship might exist between delirium and cytokine production during illness. Further, we speculated that the APOE genotype of patients might influence their rate of recovery from delirium given that APOE is associated with amyloid deposition, increased susceptibility to exogenous neurotoxins, and can affect the immune response. METHODS: A cohort of 164 acutely ill patients, 70 years or older, admitted to an elderly medical unit were studied within 3 days of hospital admission and re-assessed twice weekly until their discharge, to identify and follow the clinical course of delirium. The APOE genotype and the level of circulating cytokines were determined for 116 and 60 patients respectively. RESULTS: Prevalent delirium was significantly (p < 0.05) associated with a previous history of dementia, age, illness severity, disability and low levels of circulating IGF-I. Recovery was significantly associated (p < 0.05) with lack of APOE 4 allele and higher initial IFN-gamma. A model incorporating gender, APOE epsilon 4 status and IGF-I levels predicted recovery or not from delirium in 76.5% of cases, with a sensitivity 0.77 and specificity 0.75. CONCLUSIONS: A relationship between delirium with APOE genotype, IFN-gamma, and IGF-I, but not with IL-6, IL-1, TNF-alpha, and LIF was found. A predictive model of recovery was derived from gender, APOE status, and IGF-I levels. This model needs replication with further studies.

A brief review of the history of delirium as a mental disorder.

We review the most important concepts about delirium, from ancient times until the twentieth century. We also focus on the question of how these concepts have dealt with the particular problems posed by prognosis and outcome. Althought different terms have been used, a robust description of delirium has existed since antiquity--at some times as a symptom and at others as a syndrome. It is clear that, throughout the millennia, delirium has been--and still is--a highly lethal syndrome; a poor mental outcome for survivors was often noted. Not until the twentieth century was it thought that delirium was marked by a full recovery among survivors, and this was probably due to the desire for a clear distinction from dementia.

Dysgraphia in elderly delirious medical inpatients.

BACKGROUND AND AIMS: Dysgraphia is a recognized clinical finding in delirium, but few studies have evaluated handwriting, and results have been inconsistent. In particular, handwritten signatures, which may be a motor automatism, have not been previously evaluated in delirious patients. The aim was to assess abnormalities of signature and spontaneous writing in delirious patients and to investigate their clinical utility in the detection of delirium. METHODS: Secondary analysis of data was collected from a prospective observational study of acutely ill inpatients 70 years or older. Mini-Mental State Examination, Confusion Assessment Method, Delirium Rating Scale, Activities of Daily Living, and APACHE II were administered to each subject, their signatures were evaluated from the consent form, and their handwriting from the spontaneous sentence written as part of the MMSE. RESULTS: The signatures of patients with delirium were significantly more impaired than those without (Chi-square= 14.749, df=1, p<0.0001). The sensitivity of the signature for delirium as defined by CAM was 0.54, with specificity of 0.88. Handwriting abnormalities of omission (p=0.018), illegibility (p=0.034) and spelling (p=0.035) were significantly more common in delirious patients than others (Chi-square with Fisher's Exact tests. This difference was mainly attributable to the fact that a large number of delirious patients were unable to provide any response to the handwriting questions. CONCLUSIONS: An abnormal signature may be an indicator of delirium. People with delirium have handwriting problems, which may be partly caused by cognitive impairment but also by disorders of motor function.

Recovery and outcome of delirium in elderly medical inpatients.

This study investigates the relationships between delirium, cognitive impairment and acute illness severity with adverse clinical outcomes; in-hospital mortality, hospital length of stay, or new entry to a care home. It is a prospective observational study of medical inpatients 70 years or older, with repeated measurements of cognition, delirium status, delirium severity, and severity of physical illness every 3 days until the 18th day and then the 28th day of hospitalization. Of 94 participants, 33 had delirium and 14 recovered during their hospitalization. Predictor variables for recovery were initial Mini Mental State Examination (MMSE) (p=0.003) and severity of delirium at second assessment (p=0.02), for mortality initial MMSE (p=0.002) and for discharge to care home were initial delirium status (p=0.008) and age (p=0.004). Delirious people newly discharged to care homes stayed longer in hospital than those discharged to their previous address (p=0.016). We conclude that delirium is not a transient disorder. The presence of delirium was not related to measures of the severity of physical illness or disability. High mortality was associated with delirium but was specifically associated with cognitive impairment. Prolonged length of stay of delirious people may depend on discharge destination.

The utility of EEG in dementia: a clinical perspective.

BACKGROUND: Despite being simple and cheap, the EEG is not often used in clinical practice. METHODOLOGY: Literature search using PUBMED and Medline. RESULTS: Quantitative EEG can help to identify mild dementia and mild cognitive impairment and can increase diagnostic accuracy when used with other imaging techniques. EEG helps differentiate organic from functional brain disease and predict response to cholinesterase inhibitors and is central in the diagnosis of Creutzfeldt Jacob disease. The accuracy of EEG may be greater than that of CT or MRI scans alone. DISCUSSION: Quantitative EEG may save on specialist interpretation time and enable more routine use of EEG in diagnosis and care. More widespread use of EEG's is indicated. Agreement on the parameters that are best measured on qEEG is still awaited.

The performance of the Clock Drawing Test in elderly medical inpatients: does it have utility in the identification of delirium?

The Clock Drawing Test is an often-used test for the detection of cognitive impairment, but the few studies that have evaluated its utility in delirium have produced rather inconsistent results. In a longitudinal study of delirium in elderly medical inpatients, we have investigated the relationships between the Clock Drawing Test, the presence and severity of delirium, and cognitive impairment. Using mixed linear model analysis we found that cognitive impairment was the major factor associated with low Clock Drawing Test scores (P < .0001): neither the presence nor the severity of delirium had additional significant effect on the Clock Drawing Test. Thus, we conclude that although the Clock Drawing Test is a good detector of cognitive impairment, it is not a suitable tool for detection of delirium in elderly medical inpatients.