IL-6 Inhibition Reduces Neuronal Injury in a Murine Model of Ventilator-induced Lung Injury.

Mechanical ventilation is a known risk factor for delirium, a cognitive impairment characterized by dysfunction of the frontal cortex and hippocampus. Although IL-6 is upregulated in mechanical ventilation-induced lung injury (VILI) and may contribute to delirium, it is not known whether the inhibition of systemic IL-6 mitigates delirium-relevant neuropathology. To histologically define neuropathological effects of IL-6 inhibition in an experimental VILI model, VILI was simulated in anesthetized adult mice using a 35 cc/kg tidal volume mechanical ventilation model. There were two control groups, as follow: 1) spontaneously breathing or 2) anesthetized and mechanically ventilated with 10 cc/kg tidal volume to distinguish effects of anesthesia from VILI. Two hours before inducing VILI, mice were treated with either anti-IL-6 antibody, anti-IL-6 receptor antibody, or saline. Neuronal injury, stress, and inflammation were assessed using immunohistochemistry. CC3 (cleaved caspase-3), a neuronal apoptosis marker, was significantly increased in the frontal (P < 0.001) and hippocampal (P < 0.0001) brain regions and accompanied by significant increases in c-Fos and heat shock protein-90 in the frontal cortices of VILI mice compared with control mice (P < 0.001). These findings were not related to cerebral hypoxia, and there was no evidence of irreversible neuronal death. Frontal and hippocampal neuronal CC3 were significantly reduced with anti-IL-6 antibody (P < 0.01 and P < 0.0001, respectively) and anti-IL-6 receptor antibody (P < 0.05 and P < 0.0001, respectively) compared with saline VILI mice. In summary, VILI induces potentially reversible neuronal injury and inflammation in the frontal cortex and hippocampus, which is mitigated with systemic IL-6 inhibition. These data suggest a potentially novel neuroprotective role of systemic IL-6 inhibition that justifies further investigation.

Older Adults in the Cardiac Intensive Care Unit: Factoring Geriatric Syndromes in the Management, Prognosis, and Process of Care: A Scientific Statement From the American Heart Association.

Longevity is increasing, and more adults are living to the stage of life when age-related biological factors determine a higher likelihood of cardiovascular disease in a distinctive context of concurrent geriatric conditions. Older adults with cardiovascular disease are frequently admitted to cardiac intensive care units (CICUs), where care is commensurate with high age-related cardiovascular disease risks but where the associated geriatric conditions (including multimorbidity, polypharmacy, cognitive decline and delirium, and frailty) may be inadvertently exacerbated and destabilized. The CICU environment of procedures, new medications, sensory overload, sleep deprivation, prolonged bed rest, malnourishment, and sleep is usually inherently disruptive to older patients regardless of the excellence of cardiovascular disease care. Given these fundamental and broad challenges of patient aging, CICU management priorities and associated decision-making are particularly complex and in need of enhancements. In this American Heart Association statement, we examine age-related risks and describe some of the distinctive dynamics pertinent to older adults and emerging opportunities to enhance CICU care. Relevant assessment tools are discussed, as well as the need for additional clinical research to best advance CICU care for the already dominating and still expanding population of older adults.

Interleukin-6 mediates delirium-like phenotypes in a murine model of urinary tract infection.

BACKGROUND: Urinary tract infection (UTI) is frequently implicated as a precipitant of delirium, which refers to an acute confusional state that is associated with high mortality, increased length of stay, and long-term cognitive decline. The pathogenesis of delirium is thought to involve cytokine-mediated neuronal dysfunction of the frontal cortex and hippocampus. We hypothesized that systemic IL-6 inhibition would mitigate delirium-like phenotypes in a mouse model of UTI. METHODS: C57/BL6 mice were randomized to either: (1) non-UTI control, (2) UTI, and (3) UTI + anti-IL-6 antibody. UTI was induced by transurethral inoculation of 1 × 108 Escherichia coli. Frontal cortex and hippocampus-mediated behaviors were evaluated using functional testing and corresponding structural changes were evaluated via quantification of neuronal cleaved caspase-3 (CC3) by immunohistochemistry and western blot. IL-6 in the brain and plasma were evaluated using immunohistochemistry, ELISA, and RT-PCR. RESULTS: Compared to non-UTI control mice, mice with UTI demonstrated significantly greater impairments in frontal and hippocampus-mediated behaviors, specifically increased thigmotaxis in Open Field (p < 0.05) and reduced spontaneous alternations in Y-maze (p < 0.01), while treatment of UTI mice with systemic anti-IL-6 fully reversed these functional impairments. These behavioral impairments correlated with frontal and hippocampal neuronal CC3 changes, with significantly increased frontal and hippocampal CC3 in UTI mice compared to non-UTI controls (p < 0.0001), and full reversal of UTI-induced CC3 neuronal changes following treatment with systemic anti-IL-6 antibody (p < 0.0001). Plasma IL-6 was significantly elevated in UTI mice compared to non-UTI controls (p < 0.01) and there were positive and significant correlations between plasma IL-6 and frontal CC3 (r2 = 0.5087/p = 0.0028) and frontal IL-6 and CC3 (r2 = 0.2653, p < 0.0001). CONCLUSIONS: These data provide evidence for a role for IL-6 in mediating delirium-like phenotypes in a mouse model of UTI. These findings provide pre-clinical justification for clinical investigations of IL-6 inhibitors to treat UTI-induced delirium.

Objectively measured sleep fragmentation is associated with incident delirium in older hospitalized patients: Analysis of data collected from an randomized controlled trial.

Delirium may lead to poor outcomes in hospitalized older adults, and sleep deprivation may contribute to its pathogenesis. Thus, we sought to measure sleep duration and fragmentation using wrist-worn actigraphy in older, hospitalized patients with and without delirium, and to determine if actigraphy-based parameters could be used to predict delirium prior to clinical recognition. We conducted a secondary analysis of data from a recent, randomized clinical trial aimed at preventing inpatient delirium. Participants (n = 70) were aged ≥ 65 years admitted to an internal medicine service. Delirium was defined by the Confusion Assessment Method, or altered mental status identified by a clinician. Sleep measurements were actigraphy-based, and included total sleep time, median sleep bout duration and other measures of sleep fragmentation. We found that total sleep duration was similar between patients with (n = 17) and without (n = 53) delirium (mean 384.9 ± SD 162.7 versus mean 456.6 ± SD 135.8 min; p = .081). Mean sleep bout times were shorter in delirious versus never-delirious patients (median 6.1 [interquartile range 4.3-8.9] versus 7.9 [interquartile range 5.7-11.3] min, p = .048). Patients with delirium had more short sleep bouts (< 10 min) and fewer longer sleep bouts (> 30 min) compared with those without delirium. Increased sleep fragmentation was present prior to the clinical recognition of delirium. Overall, delirium was associated with increased sleep fragmentation detected by actigraphy, and sleep fragmentation might be useful as a biomarker for delirium prediction in the future.

Serotonin-Its Synthesis and Roles in the Healthy and the Critically Ill.

Serotonin (5-hydroxytryptamine, 5-HT) plays two important roles in humans-one central and the other peripheral-depending on the location of the 5-HT pools of on either side of the blood-brain barrier. In the central nervous system it acts as a neurotransmitter, controlling such brain functions as autonomic neural activity, stress response, body temperature, sleep, mood and appetite. This role is very important in intensive care, as in critically ill patients multiple serotoninergic agents like opioids, antiemetics and antidepressants are frequently used. High serotonin levels lead to altered mental status, deliria, rigidity and myoclonus, together recognized as serotonin syndrome. In its role as a peripheral hormone, serotonin is unique in controlling the functions of several organs. In the gastrointestinal tract it is important for regulating motor and secretory functions. Apart from intestinal motility, energy metabolism is regulated by both central and peripheral serotonin signaling. It also has fundamental effects on hemostasis, vascular tone, heart rate, respiratory drive, cell growth and immunity. Serotonin regulates almost all immune cells in response to inflammation, following the activation of platelets.

Neuroleptic strategies for terminal agitation in patients with cancer and delirium at an acute palliative care unit: a single-centre, double-blind, parallel-group, randomised trial.

BACKGROUND: The role of neuroleptics for terminal agitated delirium is controversial. We assessed the effect of three neuroleptic strategies on refractory agitation in patients with cancer with terminal delirium. METHODS: In this single-centre, double-blind, parallel-group, randomised trial, patients with advanced cancer, aged at least 18 years, admitted to the palliative and supportive care unit at the University of Texas MD Anderson Cancer Center (Houston, TX, USA), with refractory agitation, despite low-dose haloperidol, were randomly assigned to receive intravenous haloperidol dose escalation at 2 mg every 4 h, neuroleptic rotation with chlorpromazine at 25 mg every 4 h, or combined haloperidol at 1 mg and chlorpromazine at 12·5 mg every 4 h, until death or discharge. Rescue doses identical to the scheduled doses were administered at inception, and then hourly as needed. Permuted block randomisation (block size six; 1:1:1) was done, stratified by baseline Richmond Agitation Sedation Scale (RASS) scores. Research staff, clinicians, patients, and caregivers were masked to group assignment. The primary outcome was change in RASS score from time 0 to 24 h. Comparisons among group were done by modified intention-to-treat analysis. This completed study is registered with ClinicalTrials.gov, NCT03021486. FINDINGS: Between July 5, 2017, and July 1, 2019, 998 patients were screened for eligibility, with 68 being enrolled and randomly assigned to treatment; 45 received the masked study interventions (escalation n=15, rotation n=16, combination n=14). RASS score decreased significantly within 30 min and remained low at 24 h in the escalation group (n=10, mean RASS score change between 0 h and 24 h -3·6 [95% CI -5·0 to -2·2]), rotation group (n=11, -3·3 [-4·4 to -2·2]), and combination group (n=10, -3·0 [-4·6 to -1·4]), with no difference among groups (p=0·71). The most common serious toxicity was hypotension (escalation n=6 [40%], rotation n=5 [31%], combination n=3 [21%]); there were no treatment-related deaths. INTERPRETATION: Our data provide preliminary evidence that the three strategies of neuroleptics might reduce agitation in patients with terminal agitation. These findings are in the context of the single-centre design, small sample size, and lack of a placebo-only group. FUNDING: National Institute of Nursing Research.

Current Pharmacotherapy Does Not Improve Severity of Hypoactive Delirium in Patients with Advanced Cancer: Pharmacological Audit Study of Safety and Efficacy in Real World (Phase-R).

BACKGROUND: Pharmacotherapy is generally recommended to treat patients with delirium. We sought to describe the current practice, effectiveness, and adverse effects of pharmacotherapy for hypoactive delirium in patients with advanced cancer, and to explore predictors of the deterioration of delirium symptoms after starting pharmacotherapy. SUBJECTS, MATERIALS, AND METHODS: We included data of patients with advanced cancer who were diagnosed with hypoactive delirium and received pharmacotherapy for treatment of delirium. This was a pharmacovigilance study characterized by prospective registries and systematic data-recording using internet technology, conducted among 38 palliative care teams and/or units. The severity of delirium and other outcomes were assessed using established measures at days 0 (T0), 3 (T1), and 7 (T2). RESULTS: Available data were obtained from 218 patients. The most frequently used agent was haloperidol (37%). A total of 67 and 42 patients (31% and 19%) had died or discontinued pharmacotherapy by T1 and T2, respectively. Delirium symptoms deteriorated between T0 and T1, but this trend did not reach statistical significance. The most prevalent adverse event was sedation (9%). Delirium severity worsened after starting pharmacotherapy in 121 patients (56%) at T1. In patients whose death was expected within a few days and those with delirium caused by organ failure, symptoms of delirium were significantly more likely to deteriorate after starting pharmacotherapy. CONCLUSION: Current pharmacotherapy for hypoactive delirium in patients with advanced cancer is not recommended, especially in those whose death is expected within a few days and in those with delirium caused by organ failure. IMPLICATIONS FOR PRACTICE: Delirium is common among patients with advanced cancer, and hypoactive delirium is the dominant motor subtype in the palliative care setting. Pharmacotherapy is recommended and regularly used to treat delirium. This article describes the effectiveness and adverse effects of pharmacotherapy for hypoactive delirium in patients with advanced cancer. The findings of this study do not support the use of pharmacotherapy for treatment of hypoactive delirium in the palliative care setting. Pharmacotherapy should especially be avoided in patients whose death is expected within a few days and in those with delirium caused by organ failure.

Central nervous system localisation of chronic lymphocytic leukaemia, description of two very distinct cases and a review of the literature.

Central nervous system (CNS) localisation of chronic lymphocytic leukaemia (CLL) can induce various neurological symptoms. Unfamiliarity with this manifestation causes diagnostic delay. We present two cases of leptomeningeal CLL. These cases and our literature review emphasise that CNS localisation of CLL should be considered in patients with any neurological symptom, irrespectively of the stage and systemic activity of CLL.

Advance Directives, Hospitalization, and Survival Among Advanced Cancer Patients with Delirium Presenting to the Emergency Department: A Prospective Study.

BACKGROUND: To improve the management of advanced cancer patients with delirium in an emergency department (ED) setting, we compared outcomes between patients with delirium positively diagnosed by both the Confusion Assessment Method (CAM) and Memorial Delirium Assessment Scale (MDAS), or group A (n = 22); by the MDAS only, or group B (n = 22); and by neither CAM nor MDAS, or group C (n = 199). MATERIALS AND METHODS: In an oncologic ED, we assessed 243 randomly selected advanced cancer patients for delirium using the CAM and the MDAS and for presence of advance directives. Outcomes extracted from patients' medical records included hospital and intensive care unit admission rate and overall survival (OS). RESULTS: Hospitalization rates were 82%, 77%, and 49% for groups A, B, and C, respectively (p = .0013). Intensive care unit rates were 18%, 14%, and 2% for groups A, B, and C, respectively (p = .0004). Percentages with advance directives were 52%, 27%, and 43% for groups A, B, and C, respectively (p = .2247). Median OS was 1.23 months (95% confidence interval [CI] 0.46-3.55) for group A, 4.70 months (95% CI 0.89-7.85) for group B, and 10.45 months (95% CI 7.46-14.82) for group C. Overall survival did not differ significantly between groups A and B (p = .6392), but OS in group C exceeded those of the other groups (p < .0001 each). CONCLUSION: Delirium assessed by either CAM or MDAS was associated with worse survival and more hospitalization in patients with advanced cancer in an oncologic ED. Many advanced cancer patients with delirium in ED lack advance directives. Delirium should be assessed regularly and should trigger discussion of goals of care and advance directives. IMPLICATIONS FOR PRACTICE: Delirium is a devastating condition among advanced cancer patients. Early diagnosis in the emergency department (ED) should improve management of this life-threatening condition. However, delirium is frequently missed by ED clinicians, and the outcome of patients with delirium is unknown. This study finds that delirium assessed by the Confusion Assessment Method or the Memorial Delirium Assessment Scale is associated with poor survival and more hospitalization among advanced cancer patients visiting the ED of a major cancer center, many of whom lack advance directives. Therefore, delirium in ED patients with cancer should trigger discussion about advance directives.

Delirium and dementia with Lewy bodies: distinct diagnoses or part of the same spectrum?

Dementia with Lewy bodies (DLB) is recognised as the second most common form of dementia in older people. Delirium is a condition of acute brain dysfunction for which a pre-existing diagnosis of dementia is a risk factor. Conversely delirium is associated with an increased risk of developing dementia. The reasons for this bidirectional relationship are not well understood. Our aim was to review possible similarities in the clinical presentation and pathophysiology between delirium and DLB, and explore possible links between these diagnoses. A systematic search using Medline, Embase and Psychinfo was performed. References were scanned for relevant articles, supplemented by articles identified from reference lists and those known to the authors. 94 articles were selected for inclusion in the review. Delirium and DLB share a number of clinical similarities, including global impairment of cognition, fluctuations in attention and perceptual abnormalities. Delirium is a frequent presenting feature of DLB. In terms of pathophysiological mechanisms, cholinergic dysfunction and genetics may provide a common link. Neuroimaging studies suggest a brain vulnerability in delirium which may also occur in dementia. The basal ganglia, which play a key role in DLB, have also been implicated in delirium. The role of Cerebrospinal fluid (CSF) and serum biomarkers for both diagnoses is an interesting area although some results are conflicting and further work in this area is needed. Delirium and DLB share a number of features and we hypothesise that delirium may, in some cases, represent early or 'prodromal' DLB. Further research is needed to test the novel hypothesis that delirium may be an early marker for future DLB, which would aid early diagnosis of DLB and identify those at high risk.

Risk factors for delirium after on-pump cardiac surgery: a systematic review.

INTRODUCTION: As evidence-based effective treatment protocols for delirium after cardiac surgery are lacking, efforts should be made to identify risk factors for preventive interventions. Moreover, knowledge of these risk factors could increase validity of etiological studies in which adjustments need to be made for confounding variables. This review aims to systematically identify risk factors for delirium after cardiac surgery and to grade the evidence supporting these associations. METHOD: A prior registered systematic review was performed using EMBASE, CINAHL, MEDLINE and Cochrane from 1990 till January 2015 ( http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42014007371 ). All studies evaluating patients for delirium after cardiac surgery with cardiopulmonary bypass (CPB) using either randomization or multivariable data analyses were included. Data was extracted and quality was scored in duplicate. Heterogeneity impaired pooling of the data; instead a semi-quantitative approach was used in which the strength of the evidence was graded based on the number of investigations, the quality of studies, and the consistency of the association reported across studies. RESULTS: In total 1462 unique references were screened and 34 were included in this review, of which 16 (47 %) were graded as high quality. A strong level of evidence for an association with the occurrence of postoperative delirium was found for age, previous psychiatric conditions, cerebrovascular disease, pre-existent cognitive impairment, type of surgery, peri-operative blood product transfusion, administration of risperidone, postoperative atrial fibrillation and mechanical ventilation time. Postoperative oxygen saturation and renal insufficiency were supported by a moderate level of evidence, and there is no evidence that gender, education, CPB duration, pre-existent cardiac disease or heart failure are risk factors. CONCLUSION: Of many potential risk factors for delirium after cardiac surgery, for only 11 there is a strong or moderate level of evidence. These risk factors should be taken in consideration when designing future delirium prevention strategies trials or when controlling for confounding in future etiological studies.

Preoperative brain magnetic resonance imaging and postoperative delirium after off-pump coronary artery bypass grafting: a prospective cohort study.

BACKGROUND: Delirium after cardiac surgery is a serious complication, increasing morbidity and mortality. Despite its high expectations, off-pump coronary artery bypass grafting (OPCAB) has largely failed to reduce the incidence of postoperative neurological complications. To further investigate the reasons for this failure, we used perioperative brain magnetic resonance imaging (MRI) to determine the relation between MRI findings and postoperative delirium. METHODS: Altogether, 98 patients undergoing elective OPCAB were enrolled in this prospective observational study. Patients underwent brain MRI and magnetic resonance angiography (MRA) before and after surgery to identify cerebral infarction, white matter lesions, and intracranial artery stenosis. Postoperative delirium in the intensive care unit was measured using the delirium rating scale. The relation between postoperative delirium and MRI findings was examined using logistic regression. RESULTS: Magnetic resonance imaging and MRA was completed in 88 (90%) of the patients. New ischemic lesions were present in seven (7.9%) patients. Delirium rating scale scores of 0, 1-7, and ≥ 8 were found in 25 (31%), 48 (60%), and seven (9%) patients, respectively. Multivariate logistic regression analysis revealed that new ischemic lesions (odds ratio [OR] 11.07, 95% confidence interval [CI]: 1.53 to 80.03; P = 0.017), carotid artery stenosis (OR 7.06, 95% CI: 1.59 to 31.13; P = 0.010), history of myocardial infarction (OR 3.78, 95% CI: 1.05 to 13.65; P = 0.043), and deep subcortical white matter hyperintensity (OR 3.04, 95% CI: 1.14 to 8.12; P = 0.027) were significantly associated with postoperative delirium. CONCLUSIONS: Magnetic resonance imaging findings of new cerebral ischemic lesions, carotid stenosis, and deep subcortical white matter hyperintensity correlated significantly with postoperative delirium in patients who had undergone OPCAB surgery.

Delirium in advanced age and dementia: A prolonged refractory course of delirium and lower functional status.

OBJECTIVE: The factors associated with persistent delirium, in contrast to resolved delirium, have not been studied well. The aim of our present study was to identify the factors associated with delirium resolution as measured by the Memorial Delirium Assessment Scale (MDAS) and functional improvement as measured by the Karnofsky Performance Status (KPS) scale. METHOD: All subjects were recruited from psychiatric referrals at the Memorial Sloan Kettering Cancer Center (MSKCC). The two study instruments were performed at baseline (T1), at 2-3 days (T2), and at 4-7 days (T3). Subjects with persistent delirium were compared to those with resolved delirium in respect to sociodemographic and medical variables. RESULTS: Overall, 26 out of 111 patients had persistent delirium. These patients were older, predominantly male, and had more frequently preexisting comorbid dementia. Among cancer diagnoses and stage of illness, brain cancer and terminal illness contributed to persistent delirium or late response, whereas gastrointestinal cancer was associated with resolved delirium. Among etiologies, infection responded late to delirium management, usually at one week. Furthermore, delirium was more severe in patients with persistent delirium from baseline through one week. At baseline, MDAS scores were 20.1 in persistent delirium compared to 17 to 18.8 in resolved delirium (T2 and T3), and at one week of management (T3), MDAS scores were 15.2 and 4.7 to 7.4, respectively. At one week of management, persistent delirium manifested in more severe impairment in the domains of consciousness, cognition, organization, perception, psychomotor behavior, and sleep-wake cycle. In addition, persistent delirium caused more severe functional impairment. SIGNIFICANCE OF RESULTS: In this delirium sample, advanced age and preexisting dementia, as well as brain cancer, terminal illness, infection, and delirium severity contributed to persistent delirium or late response, indicating a prolonged and refractory course of delirium, in addition to more severe functional impairment through one week of management.

The immunology of delirium.

Delirium is an acute neuropsychiatric syndrome characterized by acute-onset global cognitive deficits, perceptual and behavioural disturbances affecting mainly elderly subjects with underlying medical or surgical conditions. The pathophysiology of delirium is complex and inflammation is a relevant precipitant factor of this syndrome, although it remains unclear how acute systemic inflammation induces the clinical picture of delirium. The central nervous system is able to detect peripheral infection or tissue destruction through circulating immune mediators and neural ascending signs. Activated microglia is responsible for an acute neuroinflammatory reaction underlying the symptoms of sickness. In healthy conditions descending pathways from the paraventricular nucleus, locus coeruleus and dorsal motor nucleus organize a centralized response to influence the immune response at the periphery and restore homeostasis. In the context of ageing and chronic neurodegeneration, adaptive changes to acute insults are characterized by exaggerated production of pro-inflammatory cytokines by primed microglia coupled with dysfunction of brain-to-immune pathways. In animal models, these changes underlie a more severe manifestation of sickness behaviour with working memory deficits suggesting that inattention, a core feature of delirium, can be a clinical correlate of an increased neuroinflammatory reaction. In patients with delirium, higher levels of pro-inflammatory cytokines and cortisol were identified in plasma and cerebrospinal fluid. However, to date it has not been clarified how peripheral inflammatory or endocrine biomarkers can reflect the likelihood or severity of delirium symptoms. In the future, a better understanding of the interaction between the brain and peripheral organs and the exact mechanism by which systemic inflammation can lead to delirium, will allow the development of new therapeutic agents.

Delirium in the ICU: how much do we know? A narrative review.

Delirium in critical ill patients is a complex and common neurological syndrome in the intensive care unit (ICU) that is caused by a range of structural or functional abnormalities. ICU Delirium is associated with reduced compliance, prolonged hospital stays, greater use or delayed withdrawal of sedatives, higher rates and durations of mechanical ventilation, and higher rates of mortality. The aetiology and pathogenesis of ICU delirium are unclear, and the lack of better prediction, prevention, and treatment measures leads to a non-standardized control of delirium. By searching the relevant literature, we aim in this narrative review to describe progress in the pathogenesis, predictive biomarkers, diagnosis, and treatment of ICU delirium.

Prior pathology in the basal forebrain cholinergic system predisposes to inflammation-induced working memory deficits: reconciling inflammatory and cholinergic hypotheses of delirium.

Delirium is a profound, acute confusional state that leads to long-term cognitive decline. Increased anticholinergic medications and prior dementia, in which basal forebrain cholinergic degeneration is a prominent feature, both predict delirium. Thus, cholinergic hypoactivity is thought to be important in cognitive dysfunction during delirium, and acute systemic inflammation is a major trigger for this dysfunction. Here, we hypothesize that decreased cholinergic function confers increased susceptibility to acute inflammation-induced cognitive deficits. We used the murine-p75-saporin immunotoxin (mu-p75-sap) to induce selective lesions of the basal forebrain cholinergic system in mice, mimicking early dementia-associated cholinergic loss, and superimposed systemic inflammation using low-dose bacterial lipopolysaccharide (LPS). Intracerebroventricular injection of mu-p75-sap produced depletion of cholinergic neurons in the basal forebrain and decreased innervation of the hippocampus, but left performance on hippocampal-dependent reference and working memory tasks relatively intact. However, systemic LPS (100 µg/kg) induced acute and transient working memory deficits in lesioned animals without effect in unlesioned controls. CNS inflammatory responses were similar in normal and lesioned animals and the acetylcholinesterase inhibitor, donepezil (1 mg/kg), protected against the acute cognitive deficits in this cholinergic-dependent task. Thus, cholinergic depletion predisposes to development of acute cognitive deficits upon subsequent systemic inflammatory insult. These data provide a useful model for examining interactions between acute systemic inflammation and chronic cholinergic hypofunction in delirium and have implications for the recent trial of rivastigmine in sepsis-associated delirium.

White-matter hyperintensities predict delirium after cardiac surgery.

OBJECTIVES: Postoperative delirium is a common psychiatric disorder among patients who undergo cardiac surgery. Although several studies have investigated risk factors for delirium after cardiac surgery, the association between delirium and cerebral white-matter hyperintensities (WMH) on magnetic resonance (MR) imaging has not been previously studied. The aim of this study was to identify general risk factors for delirium, as well as to examine the specific relationship between WMH and delirium. DESIGN: Retrospective chart review. SETTING: University hospital. PARTICIPANTS: A total of 130 patients who underwent cardiac surgery. MEASUREMENTS: Variables recorded included patient demographics, comorbidities, mental health, laboratory data, surgical information, and cerebrovascular disease. The presence of WMH was assessed using MR images. Two groups of patients were compared (patients with and without delirium) using both univariate and multiple logistic analyses. RESULTS: Delirium occurred in 18 patients (13.8%) and patients with delirium were significantly older than patients who did not develop delirium. The prevalence of severe WMH (Fazekas score = 3) was significantly higher in patients with delirium. Three independent predictors of delirium were identified: abnormal creatinine (odds ratio [OR]: 4.5; 95% confidence interval [CI]: 1.4-13.9), severe WMH (OR: 3.9; 95% CI: 1.2-12.5), and duration of surgery (OR: 1.4; 95% CI: 1.0-1.8). CONCLUSIONS: The results of this study suggest that white-matter abnormality is one of the most important risk factors for development of delirium after cardiac surgery. These factors can be used for prediction and prevention of delirium following cardiac surgery.

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.

Treatable neurological disorders misdiagnosed as Creutzfeldt-Jakob disease.

OBJECTIVE: Heightened awareness of Creutzfeldt-Jakob disease (CJD) among physicians and the lay public has led to its frequent consideration in the differential diagnosis of patients with rapidly progressive dementia (RPD). Our goal was to determine which treatable disorders are most commonly mistaken for CJD. METHODS: We performed a retrospective clinical and neuropathological review of prion-negative brain autopsy cases referred to the US National Prion Disease Pathology Surveillance Center at Case Western Reserve University from January 2006 through December 2009. RESULTS: Of 1,106 brain autopsies, 352 (32%) were negative for prion disease, 304 of which had adequate tissue for histopathological analysis. Alzheimer disease (n = 154) and vascular dementia (n = 36) were the 2 most frequent diagnoses. Seventy-one patients had potentially treatable diseases. Clinical findings included dementia (42 cases), pyramidal (n = 20), cerebellar (n = 14), or extrapyramidal (n = 12) signs, myoclonus (n = 12), visual disturbance (n = 9), and akinetic mutism (n = 5); a typical electroencephalogram occurred only once. Neuropathological diagnoses included immune-mediated disorders (n = 26), neoplasia (n = 25, most often lymphoma), infections (n = 14), and metabolic disorders (n = 6). INTERPRETATION: In patients with RPD, treatable disorders should be considered and excluded before diagnosing CJD. Misdiagnosed patients often did not fulfill World Health Organization criteria. RPD with positive 14-3-3 cerebrospinal fluid protein should not be regarded as sufficient for the diagnosis of CJD. Adherence to revised criteria for CJD, which include distinctive magnetic resonance imaging features of prion disease, is likely to improve diagnostic accuracy.

Pathophysiology of acute brain dysfunction: what's the cause of all this confusion?

PURPOSE OF REVIEW: To survey the recent medical literature examining the pathophysiology of acute brain dysfunction (delirium and coma) in the ICU. RECENT FINDINGS: Clinical risk factors for brain dysfunction in the ICU continue to be elucidated and prediction models developed. Multiple studies have identified sedatives, especially benzodiazepines, as modifiable risk factors for delirium. Imaging studies examining global brain disorders have demonstrated white matter lesions and brain atrophy to be associated with delirium. Endothelial dysfunction, increased blood-brain barrier permeability, and reduced blood flow have also been implicated in cerebral perfusion abnormalities associated with brain dysfunction. The response of the brain to inflammation, including activation of microglia and neuronal apoptosis, leads to synaptic and neurochemical disturbances. Decreased availability of acetylcholine during critical illness leads to decreased counter-regulatory activity in response to inflammatory disease states, likely causing additional injury and further neurotransmitter imbalances. Dopamine, norepinephrine, and serotonin excess and their respective amino acid precursors have also been associated with brain dysfunction. SUMMARY: The multifactorial pathophysiology of acute brain dysfunction remains incompletely understood. Multiple clinical risk factors have been identified and numerous pathophysiologic pathways have been hypothesized. Future research is required to investigate the roles of these pathways on differing clinical presentations, potential therapeutic options, and patient outcomes.