Hashimoto's encephalopathy: a rare cause of delirium.

Cognitive impairment is a frequent presentation of patients who come to the hospital. We report a case of a patient who presents with a common symptom, however, with a rare disease. This is an 84-year-old woman with a history of hypertension and atrial fibrillation who was reported to have confusion of 3 weeks. Investigations, including a complete blood count, MRI imaging of the brain, cerebrospinal fluid analysis and paraneoplastic screen, were all negative. Of note, thyroid peroxidase antibody was elevated. She did not have a history of thyroid disease. Following this, an assessment of Hashimoto encephalopathy was made. She was started on steroids and she showed remarkable recovery within 2 months, therefore, confirming the diagnosis. This case report emphasises the need to consider Hashimoto's encephalopathy as a differential for delirium especially when other common aetiologies have been ruled out.

Orthopedic Surgery Triggers Attention Deficits in a Delirium-Like Mouse Model.

Postoperative delirium is a frequent and debilitating complication, especially amongst high risk procedures such as orthopedic surgery, and its pathogenesis remains unclear. Inattention is often reported in the clinical diagnosis of delirium, however limited attempts have been made to study this cognitive domain in preclinical models. Here we implemented the 5-choice serial reaction time task (5-CSRTT) to evaluate attention in a clinically relevant mouse model following orthopedic surgery. The 5-CSRTT showed a time-dependent impairment in the number of responses made by the mice acutely after orthopedic surgery, with maximum impairment at 24 h and returning to pre-surgical performance by day 5. Similarly, the latency to the response was also delayed during this time period but returned to pre-surgical levels within several days. While correct responses decreased following surgery, the accuracy of the response (e.g., selection of the correct nose-poke) remained relatively unchanged. In a separate cohort we evaluated neuroinflammation and blood-brain barrier (BBB) dysfunction using clarified brain tissue with light-sheet microscopy. CLARITY revealed significant changes in microglial morphology and impaired astrocytic-tight junction interactions using high-resolution 3D reconstructions of the neurovascular unit. Deposition of IgG, fibrinogen, and autophagy markers (TFEB and LAMP1) were also altered in the hippocampus 24 h after surgery. Together, these results provide translational evidence for the role of peripheral surgery contributing to delirium-like behavior and disrupted neuroimmunity in adult mice.

Aging and an Immune Challenge Interact to Produce Prolonged, but Not Permanent, Reductions in Hippocampal L-LTP and mBDNF in a Rodent Model with Features of Delirium.

Aging increases the risk of abrupt declines in cognitive function after an event that triggers immune system activation (e.g. surgery, infection, or injury). This phenomenon is poorly understood, but rodent models may provide clues. We have previously shown that aging (24-mo-old) F344xBN rats generally do not show significant physical or cognitive impairments. However, their brains mount an exaggerated inflammatory response to signals triggered by a peripheral immune challenge (an intraperitoneal injection of Escherichia coli or laparotomy). Their hippocampal levels of the proinflammatory cytokine IL-1ß are significantly elevated for at least 8 d, but generally less than 14 d, after infection or surgery. This IL-1ß elevation is mirrored by prolonged deficits in a hippocampus-dependent long-term memory task. In contrast, young (3-mo-old) counterparts exhibit only transient elevations in IL-1ß that drop to near baseline levels within 24 h. We previously demonstrated that theta burst-evoked late-phase long-term potentiation (L-LTP)-a BDNF-dependent form of synaptic plasticity-is impaired in hippocampal area CA1 of aged animals 4 d after infection. Also, levels of mature brain-derived neurotrophic factor (mBDNF)-the protein isoform required for stabilization of L-LTP-are reduced in hippocampal synaptoneurosomes of aged animals at the same time point. In this study, we investigated whether the deficits in L-LTP and mBDNF persist in parallel with the elevation in IL-1ß and impairment in memory. This was the case, consistent with the idea that an exaggerated brain inflammatory response may compromise memory consolidation in part by altering availability of mBDNF to stabilize memory-related synaptic plasticity.

Anesthetic Immunomodulation of the Neuroinflammation in Postoperative Cognitive Dysfunction.

Postoperative delirium and cognitive dysfunction are phenomena that are associated with increases in morbidity, mortality, and resource utilization after surgery. This review scrutinized a number of studies in order to better characterize the biochemical basis for associated cognitive dysfunction and delirium, with particular focus paid to the interactions of the cholinergic system with innate immunity and how the modulation of the immune system contributes to associated neuroinflammation. Despite the clinical impact of postoperative cognitive dysfunction, evidence-based protocols for the prevention and treatment of these disorders are still lacking. Several previous trials have attempted to prevent or treat clinical manifestation by modulation of the cholinergic system with acetylcholinesterase inhibitors, the results of which have been largely ambiguous at best. As the biochemical basis of postoperative cognitive dysfunction becomes more clearly defined, future research into therapeutics based on immune modulation and treatment of neuroinflammation may prove to be very promising.

Increased neutrophil-lymphocyte ratio in delirium: a pilot study.

AIM: Delirium is a common and severe complication among older hospitalized patients. The pathophysiology is poorly understood, but it has been suggested that inflammation and oxidative stress may play a role. The aim of this pilot study was to investigate levels of the neutrophil-lymphocyte ratio (NLR) - a marker of systemic inflammation and oxidative stress - in patients with and without delirium. METHODS: This pilot study was performed within a retrospective chart review study that included acutely ill patients, 65 years and older, who were admitted to the ward of geriatrics of the Erasmus University Medical Center. All patients in whom the differential white blood cell (WBC) counts as well as the C-reactive protein (CRP) level were determined within 24 h after admission were included in the present study. Differences in NLR between patients with and without delirium were investigated using univariate analysis of variance, with adjustments for age, sex, comorbidities, CRP level, and total WBC count. RESULTS: Eighty-six patients were included. Thirteen patients were diagnosed with delirium. In adjusted models, higher mean NLR values were found in patients with, than in those without, delirium (9.10 vs 5.18, P=0.003). CONCLUSION: In this pilot study, we found increased NLR levels in patients with delirium. This finding might suggest that an inadequate response of the immune system and oxidative stress may play a role in the pathogenesis of delirium. Further studies are needed to confirm the association between NLR and delirium.

Pathophysiological and behavioral effects of systemic inflammation in aged and diseased rodents with relevance to delirium: A systematic review.

Delirium is a frequent outcome for aged and demented patients that suffer a systemic inflammatory insult. Animal models that reconstruct these etiological processes have potential to provide a better understanding of the pathophysiology of delirium. Therefore, we systematically reviewed animal studies in which systemic inflammation was superimposed on aged or diseased animal models. In total, 77 studies were identified. Aged animals were challenged with a bacterial endotoxin in 29 studies, 25 studies superimposed surgery on aged animals, and in 6 studies a bacterial infection, Escherichia coli (E. coli), was used. Diseased animals were challenged with a bacterial endotoxin in 15 studies, two studies examined effects of the cytokine IL-1ß, and one study used polyinosinic:polycytidilic acid (poly I:C). This systematic review analyzed the impact of systemic inflammation on the production of inflammatory and neurotoxic mediators in peripheral blood, cerebrospinal fluid (CSF), and on the central nervous system (CNS). Moreover, concomitant behavioral and cognitive symptoms were also evaluated. Finally, outcomes of behavioral and cognitive tests from animal studies were compared to features and symptoms present in delirious patients.

Neuroinflammatory challenges compromise neuronal function in the aging brain: Postoperative cognitive delirium and Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease that targets memory and cognition, and is the most common form of dementia among the elderly. Although AD itself has been extensively studied, very little is known about early-stage preclinical events and/or mechanisms that may underlie AD pathogenesis. Since the majority of AD cases are sporadic in nature, advancing age remains the greatest known risk factor for AD. However, additional environmental and epigenetic factors are thought to accompany increasing age to play a significant role in the pathogenesis of AD. Postoperative cognitive delirium (POD) is a behavioral syndrome that primarily occurs in elderly patients following a surgical procedure or injury and is characterized by disruptions in cognition. Individuals that experience POD are at an increased risk for developing dementia and AD compared to normal aging individuals. One way in which cognitive function is affected in cases of POD is through activation of the inflammatory cascade following surgery or injury. There is compelling evidence that immune challenges (surgery and/or injury) associated with POD trigger the release of pro-inflammatory cytokines into both the periphery and central nervous system. Thus, it is possible that cognitive impairments following an inflammatory episode may lead to more severe forms of dementia and AD pathogenesis. Here we will discuss the inflammation associated with POD, and highlight the advantages of using POD as a model to study inflammation-evoked cognitive impairment. We will explore the possibility that advancing age and immune challenges may provide mechanistic evidence correlating early life POD with AD. We will review and propose neural mechanisms by which cognitive impairments occur in cases of POD, and discuss how POD may augment the onset of AD.

Markers of inflammation as risk predictors of lethal outcome in patients diagnosed with delirium.

Background/Aim: Delirium is an acute or subacute, and most frequently reversible syndrome of higher cortical functions disturbances that is manifested as generalized disorder. If not prevented, it is associated with various adverse outcomes. The aim of this study was to determine the connection between the markers of inflammation and lethal outcome in patients diagnosed with delirium, hospitalized in the psychiatric intensive care unit. Methods: This retrospective study included 120 patients hospitalized in the psychiatric intensive care unit in whom examination of differences in inflammation markers was done. The examinees have been divided into two groups: the case group of 40 patients who died during the hospitalization, and the control group of 80 examinees who were discharged with the diagnosis Post delirium status. The following variables were taken into account: age, gender, clinical diagnosis of infection (pneumonia and urinary tract infection), laboratory parameters (total of white blood cells, granulocytes, monocytes, C-reactive protein − CRP) and type of delirium (withdrawal or organic). Results: The average age of patients was 50.3 ± 13.1 years. The patients who survived delirium, were on the average 10.5 years younger than the deceased (p < 0.001). More than half (57.5%) of the deceased had pneumonia. There was a statistically significant correlation between pneumonia and lethal outcome in the patients with delirium (p < 0.001). The examinees with lethal outcome had significantly higher median CRP levels than the group of examinees who survived (75.6% ± 54.0 vs 30.3 ± 42.5 ng/L, p < 0.001). Conclusion: Aiming to better and more precise diagnostics of this complicated and still unclear neuropsychiatric syndrome it would be useful to consider introduction of more precise diagnostic algorithms in every unit of intensive care. That would significantly reduce the number of delirium diagnosis overlook, decrease complication of clinical features and would also reduce the unfavorable outcome rate, therefore the total cost of treatment.

The impact of lymphopenia on delirium in ICU patients.

BACKGROUND: Immunosuppressed states may predispose patients to development of acute brain injury during times of critical illness. Lymphopenia is a non-specific yet commonly used bedside marker of immunosuppressed states. METHODS: We examined whether lymphopenia would predict development of acute brain dysfunction (delirium and/or coma) in 518 patients enrolled in the Bringing to Light the Risk Factors and Incidence of Neuropsychological Dysfunction in ICU Survivors (BRAIN-ICU) study in medical and surgical ICUs of a tertiary care, university-based medical center. Utilizing proportional odds logistic regression and Cox proportional hazards survival analysis, we assessed the relationship between pre-enrollment lymphocytes and subsequent cognitive outcomes including delirium- and coma-free days (DCFDs) and 30-day mortality. RESULTS: There were no statistically significant associations between lymphocytes and DCFDs (p = 0.17); additionally, the relationship between lymphocytes and mortality was not statistically significant (p = 0.71). Among 259 patients without history of cancer or diabetes, there was no statistically significant association between lymphocytes and DCFDs (p = 0.07). CONCLUSION: lymphopenia, a commonly used bedside marker of immunosuppression, does not appear to be a marker of risk for acute brain injury (delirium/coma) or 30-day mortality in general medical/surgical ICU patients.

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.

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.

High serum interleukin-6 level is associated with increased risk of delirium in elderly patients after noncardiac surgery: a prospective cohort study.

BACKGROUND: The relationship between inflammation and delirium remains to be determined. The purposes of this study were to investigate the association between serum interleukin-6 levels and the occurrence of delirium in elderly patients after major noncardiac surgery. METHODS: A total of 338 elderly patients (60 years of age and over) undergoing major noncardiac surgery were enrolled. Blood samples were obtained before anesthesia and in the first postoperative morning and serum interleukin-6 concentrations were measured. Delirium was assessed twice daily by the confusion assessment method for the Intensive Care Unit during the first three postoperative days. Survival analyses were performed to assess the relationship between the serum IL-6 level and the occurrence of postoperative delirium. RESULTS: Postoperative delirium occurred in 14.8% (50 of 338) of patients. High serum interleukin-6 levelsafter surgery were significantly associated with increased risk of the occurrence of postoperative delirium (hazard ratio 1.514, 95% confidence interval 1.155-1.985, P = 0.003). Other independent predictors of delirium included increasing age, poor preoperative New York Heart Association classification, low preoperative Mini-Mental State Examination score, and high total postoperative Visual Analogue Scale pain score. Patients who developed delirium had a prolonged hospital stay after surgery. CONCLUSIONS: Delirium is a frequent complication in elderly patients after noncardiac surgery. High serum interleukin-6 level after surgery is associated with increased risk of the occurrence of postoperative delirium.

Non-steroidal anti-inflammatory drugs and cognitive function: are prostaglandins at the heart of cognitive impairment in dementia and delirium?

Studies of non-steroidal anti-inflammatory drugs (NSAIDs) in rheumatoid arthritis imply that inflammation is important in the development of Alzheimer's disease (AD). However, these drugs have not alleviated the symptoms of AD in those who have already developed dementia. This suggests that the primary mediator targeted by these drugs, PGE2, is not actively suppressing memory function in AD. Amyloid-ß oligomers appear to be important for the mild cognitive changes seen in AD transgenic mice, yet amyloid immunotherapy has also proven unsuccessful in clinical trials. Collectively, these findings indicate that NSAIDs may target a prodromal process in mice that has already passed in those diagnosed with AD, and that synaptic and neuronal loss are key determinants of cognitive dysfunction in AD. While the role of inflammation has not yet become clear, inflammatory processes definitely have a negative impact on cognitive function during episodes of delirium during dementia. Delirium is an acute and profound impairment of cognitive function frequently occurring in aged and demented patients exposed to systemic inflammatory insults, which is now recognised to contribute to long-term cognitive decline. Recent work in animal models is beginning to shed light on the interactions between systemic inflammation and CNS pathology in these acute exacerbations of dementia. This review will assess the role of prostaglandin synthesis in the memory impairments observed in dementia and delirium and will examine the relative contribution of amyloid, synaptic and neuronal loss. We will also discuss how understanding the role of inflammatory mediators in delirious episodes will have major implications for ameliorating the rate of decline in the demented population.

The neuroinflammatory hypothesis of delirium.

Delirium is a neuropsychiatric syndrome characterized by a sudden and global impairment in consciousness, attention and cognition. It is particularly frequent in elderly subjects with medical or surgical conditions and is associated with short- and long-term adverse outcomes. The pathophysiology of delirium remains poorly understood as it involves complex multi-factorial dynamic interactions between a diversity of risk factors. Several conditions associated with delirium are characterized by activation of the inflammatory cascade with acute release of inflammatory mediators into the bloodstream. There is compelling evidence that acute peripheral inflammatory stimulation induces activation of brain parenchymal cells, expression of proinflammatory cytokines and inflammatory mediators in the central nervous system. These neuroinflammatory changes induce neuronal and synaptic dysfunction and subsequent neurobehavioural and cognitive symptoms. Furthermore, ageing and neurodegenerative disorders exaggerate microglial responses following stimulation by systemic immune stimuli such as peripheral inflammation and/or infection. In this review we explore the neuroinflammatory hypothesis of delirium based on recent evidence derived from animal and human studies.

Systemic infection and delirium: when cytokines and acetylcholine collide.

Systemic infection and drugs with anticholinergic effects are well-recognised and prevalent risk factors for delirium in elderly people. Experimental findings and neuropathological observations suggest that activation of microglia is pivotal for mediation of the behavioural effects of systemic infections. The microglial response is usually regulated tightly, but defensive features could turn neurotoxic once microglial cells escape from cholinergic inhibition. A self-propelling neuroinflammatory reaction might follow, and this cascade could account for the strong association between delirium and long-term cognitive impairment and even dementia. Here, we propose a hypothetical model, suggesting that poor outcome after delirium can be averted in vulnerable elderly people by use of readily available drugs. Agents that either restore cholinergic control of microglia or directly inhibit neuroinflammation warrant testing in clinical trials.

Opsoclonus-myoclonus syndrome in anti-N-methyl-D-aspartate receptor encephalitis.

BACKGROUND: Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis has been recently reported as autoimmune/paraneoplastic encephalitis, affecting mostly young females. OBJECTIVE: To describe opsoclonus-myoclonus syndrome in association with anti-NMDAR antibodies. DESIGN: Case report. SETTING: Geneva University Hospital. Patient A 23-year-old woman with opsoclonus-myoclonus syndrome. RESULTS: Two weeks after an episode of gastroenteritis, the patient developed symptoms of depression associated with psychomotor slowing, progressive gait instability, and opsoclonus-myoclonus. Cerebrospinal fluid examination showed mild lymphocytic pleocytosis and intrathecal IgG synthesis with oligoclonal bands. The patient's condition worsened rapidly to an akinetic mutism, followed by a period of agitation, delirium, and hallucinations. These gradually subsided; however, a frontal behavior and executive dysfunction persisted 5 months after symptom presentation. No tumor was found. Anti-NMDAR antibodies were found in the cerebrospinal fluid. CONCLUSIONS: Opsoclonus-myoclonus may occur in patients with anti-NMDAR encephalitis. Prompt diagnosis of this disorder is important because after tumor removal and immunomodulatory therapies it has a relatively good prognosis.

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.

Delirious behavior in influenza is associated with a reversible splenial lesion.

Delirious behavior is one of the main clinical features in patients with clinically mild encephalitis/encephalopathy with a reversible splenial lesion. On the other hand, it has been reported that more than 10% of patients with influenza in Japan develop delirious behavior. Magnetic resonance imaging (MRI) studies in patients with influenza-associated delirious behavior were examined to determine how often a reversible splenial lesion is associated with this symptom. All patients who presented to Kameda Medical Center between November 2007 and March 2008 with delirious behavior associated with influenza were studied using MRI and EEG. Of the 370 patients with influenza, 11 had delirious behavior, lasting for less than 12h. MRI revealed a reversible splenial lesion with homogeneously reduced diffusion in 5 patients. Transient EEG abnormalities (occipital slow waves during wakefulness) were observed in 4 of the 9 patients examined. A reversible splenial lesion with reduced diffusion should be considered as an underlying condition in patients with delirious behavior associated with influenza.