CSF biomarkers in delirium: a systematic review.

OBJECTIVE: In recent years, there has been a blossoming of studies examining cerebrospinal fluid (CSF) as a method of studying the pathophysiology of delirium. We systematically reviewed the literature for CSF studies in delirium and provide here a summary of the implications for our understanding of delirium pathophysiology. We also summarise the methods used for CSF analysis and discuss challenges and implications for future studies. METHODS: In this systematic review, we screened MEDLINE, EMBASE, PsycINFO, Web of Science, PubMed and the Cochrane Library for articles on CSF biomarkers in delirium, published on 3 September 2016. Studies were required to use Diagnostic and Statistical Manual of Mental Disorders or International Classification of Diseases criteria for delirium or a validated tool. We excluded case reports. There were no other restrictions on study type. RESULTS: We identified 3280 articles from our initial search, and 22 articles were included in this review. All studies were prospective, including over 400 patients with delirium and 700 controls. More than 70 different biomarkers were studied. Studies could not be compared with each other for meta-analysis because of their heterogeneity and varied widely in their risk of bias and quality assessments. CONCLUSIONS: The 22 studies identified in this review reveal a small but growing literature, in which many of the important hypotheses in delirium pathogenesis have been examined, but from which few firm conclusions can currently be drawn. Nevertheless, the overall interpretation of the literature supports the vulnerable brain concept, that is, that biomarker evidence of, for example, Alzheimer's disease pathology and/or neuroinflammation, is associated with delirium.

Cerebrospinal fluid levels of neopterin are elevated in delirium after hip fracture.

BACKGROUND: The inflammatory cell product neopterin is elevated in serum before and during delirium. This suggests a role for disordered cell-mediated immunity or oxidative stress. Cerebrospinal fluid (CSF) neopterin levels reflect brain neopterin levels more closely than serum levels. Here we hypothesized that CSF neopterin levels would be higher in delirium. METHODS: In this prospective cohort study, 139 elderly patients with acute hip fracture were recruited in Oslo and Edinburgh. Delirium was diagnosed with the confusion assessment method performed daily pre-operatively and on the first 5 days post-operatively. Paired CSF and blood samples were collected at the onset of spinal anaesthesia. Neopterin levels were measured using high-performance liquid chromatography. RESULTS: Sixty-four (46 %) of 139 hip fracture patients developed delirium perioperatively. CSF neopterin levels were higher in delirium compared to controls (median 29.6 vs 24.7 nmol/mL, p = 0.003), with highest levels in patients who developed delirium post-operatively. Serum neopterin levels were also higher in delirium (median 37.0 vs 27.1 nmol/mL, p = 0.003). CSF neopterin remained significantly associated with delirium after controlling for relevant risk factors. Higher neopterin levels were associated with poorer outcomes (death or new institutionalization) 1 year after surgery (p = 0.02 for CSF and p = 0.03 for serum). CONCLUSIONS: This study is the first to examine neopterin in CSF from patients with delirium. Our findings suggest potential roles for activation of cell-mediated immune responses or oxidative stress in the delirium process. High levels of serum or CSF neopterin in hip fracture patients may also be useful in predicting poor outcomes.

Associations Between Delirium and Preoperative Cerebrospinal Fluid C-Reactive Protein, Interleukin-6, and Interleukin-6 Receptor in Individuals with Acute Hip Fracture.

OBJECTIVES: To examine whether delirium in individuals with hip fracture is associated with high C-reactive protein (CRP), interleukin-6 (IL-6), and soluble IL-6 receptor (sIL-6R) levels in the cerebrospinal fluid (CSF). DESIGN: Prospective cohort study. SETTING: Two university hospitals in Oslo, Norway, and Edinburgh, United Kingdom. PARTICIPANTS: Individuals admitted with acute hip fracture (N = 151). MEASUREMENTS: Participants were assessed for delirium pre- and postoperatively using the Confusion Assessment Method. Prefracture cognitive impairment was detected using the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Serum was collected preoperatively and CSF just before the onset of spinal anesthesia. Cytokine levels in serum and CSF samples were determined using an enzyme-linked immunosorbent assay. Student t-tests or Mann-Whitney U-tests were used for between-group comparisons. Spearman rho was used for correlations. RESULTS: Sixty participants had prior cognitive impairment (IQCODE score ≥3.44). Delirium was diagnosed in 46 participants (77%) with prior cognitive impairment and 25 (29%) without. In participants without prior cognitive impairment, CSF CRP levels were higher in participants with delirium (median 0.05 µg/mL, interquartile range (IQR) 0.02-0.12 µg/mL) than in those without delirium (median 0.01 µg/mL, IQR 0.00-0.06 µg/mL) (P = .01); there were no differences in participants with prior cognitive impairment. In secondary analyses, in participants with prior cognitive impairment, the concentration of CSF sIL-6R was higher in those participants who developed delirium than in the other subgroups, but this difference was not statistically significant. Serum levels of CRP, IL-6, and sIL-6R were not different according to delirium in participants with or without prefracture cognitive impairment. CONCLUSION: High CSF levels of CRP and sIL-6R may be associated with delirium. Different pathophysiological mechanisms may operate in different subgroups, notably in relation to the presence of prior cognitive impairment.

A comparison of the revised Delirium Rating Scale (DRS-R98) and the Memorial Delirium Assessment Scale (MDAS) in a palliative care cohort with DSM-IV delirium.

OBJECTIVE: Assessment of delirium is performed with a variety of instruments, making comparisons between studies difficult. A conversion rule between commonly used instruments would aid such comparisons. The present study aimed to compare the revised Delirium Rating Scale (DRS-R98) and Memorial Delirium Assessment Scale (MDAS) in a palliative care population and derive conversion rules between the two scales. METHOD: Both instruments were employed to assess 77 consecutive patients with DSM-IV delirium, and the measures were repeated at three-day intervals. Conversion rules were derived from the data at initial assessment and tested on subsequent data. RESULTS: There was substantial overall agreement between the two scales [concordance correlation coefficient (CCC) = 0.70 (CI 95 = 0.60-0.78)] and between most common items (weighted κ ranging from 0.63 to 0.86). Although the two scales overlap considerably, there were some subtle differences with only modest agreement between the attention (weighted κ = 0.42) and thought process (weighted κ = 0.61) items. The conversion rule from total MDAS score to DRS-R98 severity scores demonstrated an almost perfect level of agreement (r = 0.86, CCC = 0.86; CI 95 = 0.79-0.91), similar to the conversion rule from DRS-R98 to MDAS. SIGNIFICANCE OF RESULTS: Overall, the derived conversion rules demonstrated promising accuracy in this palliative care population, but further testing in other populations is certainly needed.

Cerebrospinal fluid markers of neuroinflammation in delirium: a role for interleukin-1ß in delirium after hip fracture.

OBJECTIVE: Exaggerated central nervous system (CNS) inflammatory responses to peripheral stressors may be implicated in delirium. This study hypothesised that the IL-1ß family is involved in delirium, predicting increased levels of interleukin-1ß (IL-1ß) and decreased IL-1 receptor antagonist (IL-1ra) in the cerebrospinal fluid (CSF) of elderly patients with acute hip fracture. We also hypothesised that Glial Fibrillary Acidic Protein (GFAP) and interferon-γ (IFN-γ) would be increased, and insulin-like growth factor 1 (IGF-1) would be decreased. METHODS: Participants with acute hip fracture aged >60 (N=43) were assessed for delirium before and 3-4 days after surgery. CSF samples were taken at induction of spinal anaesthesia. Enzyme-linked immunosorbent assays (ELISA) were used for protein concentrations. RESULTS: Prevalent delirium was diagnosed in eight patients and incident delirium in 17 patients. CSF IL-1ß was higher in patients with incident delirium compared to never delirium (incident delirium 1.74 pg/ml (1.02-1.74) vs. prevalent 0.84 pg/ml (0.49-1.57) vs. never 0.66 pg/ml (0-1.02), Kruskal-Wallis p=0.03). CSF:serum IL-1ß ratios were higher in delirious than non-delirious patients. CSF IL-1ra was higher in prevalent delirium compared to incident delirium (prevalent delirium 70.75 pg/ml (65.63-73.01) vs. incident 31.06 pg/ml (28.12-35.15) vs. never 33.98 pg/ml (28.71-43.28), Kruskal-Wallis p=0.04). GFAP was not increased in delirium. IFN-γ and IGF-1 were below the detection limit in CSF. CONCLUSION: This study provides novel evidence of CNS inflammation involving the IL-1ß family in delirium and suggests a rise in CSF IL-1ß early in delirium pathogenesis. Future larger CSF studies should examine the role of CNS inflammation in delirium and its sequelae.

Anticholinergic activity in cerebrospinal fluid and serum in individuals with hip fracture with and without delirium.

OBJECTIVES: To examine whether anticholinergic activity (AA) in cerebrospinal fluid (CSF) and serum is associated with risk of delirium in individuals with hip fracture. DESIGN: Prospective cohort study. SETTING: Two university hospitals in Oslo, Norway, and Edinburgh, UK. PARTICIPANTS: Individuals admitted with acute hip fracture (N = 151). MEASUREMENTS: Participants were assessed daily for delirium using the Confusion Assessment Method (preoperatively and postoperative days 1-5 (all) or until discharge (participants with delirium)). Prefracture cognitive function was assessed using the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Serum was collected preoperatively and CSF at the onset of spinal anesthesia. AA in serum (SAA) and CSF samples was determined according to a muscarinic radio receptor bioassay. The association between AA measures and delirium was evaluated using logistic multivariate analyses. RESULTS: Fifty-two (54%) of the participants in Oslo and 20 (39%) in Edinburgh developed delirium. There was no statistically significant difference in AA between participants with and without delirium in Oslo (serum: 7.02 vs 6.08 pmol/mL, P = .54; CSF: 0.39 vs 0.48 pmol/mL, P = .26) or in Edinburgh (serum: 1.35 vs 1.62 pmol/mL, P = .76; CSF: 0.36 vs 0.31 pmol/mL, P = .93). Nor was there any difference in SAA (Oslo, P = .74; Edinburgh, P = .51) or CSF AA (Oslo, P = .21; Edinburgh, P = .93) when participants were subdivided into prevalent, incident, subsyndromal, and never delirium. Stratifying participants according to prefracture cognitive status (IQCODE) gave the same results. CONCLUSION: This is the first study of AA in CSF of individuals with and without delirium. The study does not support the hypothesis that central (CSF) or peripheral (serum) AA is an important mechanism of delirium in individuals with hip fracture.

Abnormal level of arousal as a predictor of delirium and inattention: an exploratory study.

OBJECTIVE: Abnormal level of arousal (LoA) and inattention are key features of delirium. However, the extent to which abnormal LoA alone might predict delirium and inattention is unclear. Here we tested the hypotheses that (1) patients with abnormal LoA have delirium, and (2) abnormal LoA is associated with worse performance on tests of attention. METHODS: Thirty acute hip fracture patients aged 64-97 years underwent assessments of LoA, delirium status, and attentional functioning in the 24 hours before surgery and at 2-4 and 7-10 days after surgery. The Observational Scale of Level of Arousal (OSLA) and the Richmond Agitation-Sedation Scale (RASS) were used to assess LoA. Sustained attention was measured with the Edinburgh Delirium Test Box. Delirium was assessed with the Confusion Assessment Method and the Delirium Rating Scale-Revised-98. RESULTS: Ten patients (33%) were diagnosed with delirium. Abnormal LoA as measured by the OSLA was strongly associated with the presence of delirium. The area under the receiver operating characteristic curve was 0.89 (95% confidence interval: 0.81-0.97), with a sensitivity of 0.87 and a specificity of 0.81. Area under the curve, sensitivity, and specificity for the RASS were 0.81 (95% confidence interval: 0.68-0.94), 0.80, and 0.79, respectively. Abnormal LoA was associated with worse attentional deficits preoperatively and at postoperative days 2-4 (p <0.01). CONCLUSION: These exploratory findings suggest that abnormal LoA is a strong indicator of delirium. Also, abnormal LoA is strongly associated with inattention as measured by an objective cognitive test. These findings suggest that acute-onset abnormal LoA could be used as a trigger for delirium assessment in routine clinical practice. Future work will help to clarify further the interrelationships among abnormal LoA, inattention, and delirium.

New horizons in the pathogenesis, assessment and management of delirium.

UNLABELLED: Delirium is one of the foremost unmet medical needs in healthcare. It affects one in eight hospitalised patients and is associated with multiple adverse outcomes including increased length of stay, new institutionalisation, and considerable patient distress. Recent studies also show that delirium strongly predicts future new-onset dementia, as well as accelerating existing dementia. The importance of delirium is now increasingly being recognised, with a growing research base, new professional international organisations, increased interest from policymakers, and greater prominence of delirium in educational and audit programmes. Nevertheless, the field faces several complex research and clinical challenges. In this article we focus on selected areas of recent progress and/or uncertainty in delirium research and practice. (i) PATHOGENESIS: recent studies in animal models using peripheral inflammatory stimuli have begun to suggest mechanisms underlying the delirium syndrome as well as its link with dementia. A growing body of blood and cerebrospinal fluid studies in humans have implicated inflammatory and stress mediators. (ii) PREVENTION: delirium prevention is effective in the context of research studies, but there are several unresolved issues, including what components should be included, the role of prophylactic drugs, and the overlap with general best care for hospitalised older people. (iii) ASSESSMENT: though there are several instruments for delirium screening and assessment, detection rates remain dismal. There are no clear solutions but routine screening embedded into clinical practice, and the development of new rapid screening instruments, offer potential. (iv) MANAGEMENT: studies are difficult given the heterogeneity of delirium and currently expert and comprehensive clinical care remains the main recommendation. Future studies may address the role of drugs for specific elements of delirium. In summary, though facing many challenges, the field continues to make progress, with several promising lines of enquiry and an expanding base of interest among researchers, clinicians and policymakers.

Delirium and cerebrospinal fluid S100B in hip fracture patients: a preliminary study.

OBJECTIVES: Delirium is associated with an increased risk of long-term cognitive decline, suggesting the possibility of concurrent central nervous system (CNS) injury. S100B is a putative biomarker of CNS injury and elevated serum levels in delirium have been reported. Here we hypothesize that delirium is associated with raised concentrations of cerebrospinal fluid (CSF) S100B. METHODS: Forty-five patients with hip fracture aged over 60 and awaiting surgery under spinal anesthesia were assessed for delirium pre- and post-operatively. CSF S100B levels were measured in samples collected at the onset of surgery. RESULTS: Participants with pre-operative delirium (N = 8) had elevated Log10 CSF S100B (mean: -0.156; SD: 0.238) compared with those without delirium (mean: -0.306; SD: 0.162), Student's t-test t = 2.18, df = 43, p = 0.035. CONCLUSIONS: This study provides preliminary evidence of elevated CSF S100B in current delirium, consistent with findings in serum and with other studies showing elevated S100B in the presence of diverse forms of CNS injury.

Delirium detection and monitoring outside the ICU.

Delirium affects many patients in hospital settings but is under-detected and associated with a range of adverse health-care outcomes, including institutionalisation and elevated mortality. Detection is essential because it leads to identification and management of precipitants and assessment and management of distress caused by hallucinations and delusions. Moreover, delirium may affect communication and, thus, assessment of pain. This is important because inadequate analgesia may cause agitation and prolong the delirium. Here, we provide an overview of the main features of delirium. Informal and formal methods of assessment of the features are covered. We describe some of the main rating scales used in delirium screening and severity grading. Incorporating formal and systematic screening and assessment into everyday clinical practice can substantially improve delirium diagnosis and treatment.

A systematic literature review of cerebrospinal fluid biomarkers in delirium.

BACKGROUND: Cerebrospinal fluid (CSF) analysis has great potential to advance understanding of delirium pathophysiology. METHODS: A systematic literature review of CSF studies of DSM or ICD delirium was performed. RESULTS: In 8 studies of 235 patients, delirium was associated with: elevated serotonin metabolites, interleukin-8, cortisol, lactate and protein, and reduced somatostatin, ß-endorphin and neuron-specific enolase. Elevated acetylcholinesterase predicted poor outcome after delirium and higher dopamine metabolites were associated with psychotic features. CONCLUSIONS: No clear conclusions emerged, but the current literature suggests multiple areas for further investigation with more detailed studies.

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 Jackson's 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.

Predictors and correlates of edentulism in the healthy old people in Edinburgh (HOPE) study.

OBJECTIVES: To determine the extent to which correlates of edentulism are explained by an association between tooth loss and cognitive ability. METHODS: Participants in the Healthy Old People in Edinburgh (HOPE) study aged 70 or more at baseline were assessed and health, cognitive, socio-economic and socio-environmental data collected on four consecutive occasions. It was noted whether the participant had any retained teeth and if not, the age when the last tooth was lost. Prior determinants of edentulism were investigated with binary logistic regression models. At the 9-year follow-up, associations with edentulism were examined using general linear models with edentulism as an independent factor. RESULTS: 201 participants were adequately tested, of whom 104 (51.7%) were edentulous. A logistic regression model that considered age, sex, education, social class, deprivation index of residence, objective distance from dentist, participant's estimate of distance from dentist and NART-estimated IQ (NARTIQ) found age (p = 0.032), occupational class (p = 0.019) and NARTIQ (p = 0.027) as significant predictors of edentulism. Cox's proportional hazards modelling found only NARTIQ (p = 0.050) to be correlated. Being edentulous was associated with poorer respiratory function but not hand grip strength (p = 0.23). Edentulous participants had lower self esteem scores (p = 0.020) and poorer dietary assessment scores (p = 0.028). Being edentulous was also associated with significantly lower mean scores on all cognitive testing, although these associations became non-significant after adjustment for NARTIQ and age. CONCLUSIONS: In healthy older people, edentulism is associated with relative impairment of cognitive ability, although this association is explained by the fact that lower original intelligence predisposes to edentulism and poorer performance on cognitive tests in old age. Once original intelligence is adjusted for, tooth loss is not related to cognitive ability. Tooth loss is, however, associated with poorer status across a wide range of health measures: physical health, nutrition, disability and self-esteem. Establishing the degree to which these health outcomes are causally related to edentulism could usefully be factored into cost-benefit analyses of programmes designed to prevent tooth loss.