Elsevier

Brain, Behavior, and Immunity

Volume 28, February 2013, Pages 1-13
Brain, Behavior, and Immunity

Invited Review
At the extreme end of the psychoneuroimmunological spectrum: Delirium as a maladaptive sickness behaviour response

https://doi.org/10.1016/j.bbi.2012.07.012Get rights and content

Abstract

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

Highlight

► We propose that parallels between exaggerated sickness behavior in vulnerable animals and delirium in older humans may provide insights into delirium pathophysiology.

Introduction

Delirium is a common and severe neuropsychiatric syndrome characterised by acute deterioration and fluctuations in mental status mainly precipitated by acute illness, trauma, surgery, or the side effects of drugs. The core DSM-IV diagnostic criteria are: (a) a disturbance of consciousness (that is, reduced clarity of awareness of the environment, with reduced ability to focus, sustain, or shift attention), (b) a change in cognition (e.g. memory impairment) or a perceptual disturbance, and (c) onset of hours to days, and tendency to fluctuate. Delirium is one of the most common acute medical conditions. The overall prevalence in medical inpatients is greater than 10%; in older patients this rises to greater than 20% and in intensive care units and post-operative hip fracture patients the prevalence is greater than 50%. In a typical 1000-bedded hospital, around 120 people will have delirium at any given time. There are currently no licensed treatments.

Although by definition delirium has an acute onset and always involves attentional deficits, it is otherwise heterogeneous, with the variable presence of multiple other neuropsychiatric features. Prominent among these is disturbance in level of consciousness, which ranges from barely responsive to highly agitated. A reduced level of consciousness is termed hypoactive delirium, whereas agitation and increased motor activity is termed hyperactive delirium. Many patients fluctuate between these motoric subtypes. Other neuropsychiatric manifestations include impairments in memory, perception and other cognitive domains, psychosis, and disturbance of the sleep-wake cycle (Fong et al., 2009, MacLullich and Hall, 2011).

The time-course of delirium is highly variable. Delirium has conventionally been described as a transient disorder, and indeed it does resolve in the majority of cases. Some patients may experience only a few hours of the syndrome, while others may have more prolonged episodes lasting days or weeks. Recent research has found that around 20% still exhibit symptoms three or even six months after onset; this is termed ‘persistent delirium’ (Meagher et al., 2012). Notwithstanding the resolution of most delirium, these episodes have serious long term consequences: it is now known that delirium predicts multiple adverse outcomes, including increased length of stay, morbidity, institutionalisation, and mortality during admission and one year after discharge (Witlox et al., 2010). Moreover, in cognitively normal patients, an episode of delirium is associated with a higher risk of dementia in the years following the episode (MacLullich et al., 2009, Davis et al., 2012). Delirium is also often highly distressing for patients and carers (Fong et al., 2009, MacLullich and Hall, 2011) and may result in post-traumatic stress disorder (Davydow et al., 2008).

Delirium Case History.

An 82-year-old man with a history of mild dementia, ischaemic heart disease and osteoarthritis who lived with his wife was taken to the emergency department with confusion and agitation, and productive cough and fever for 2 days. He had resisted being brought to the hospital initially but had then become drowsy and had to be lifted onto the ambulance trolley. Upon arrival he became agitated, saying that he didn’t want to be ‘locked up’, and he tried to get off the trolley to leave the hospital. With reassurance from his wife he became calmer. A few minutes later he was drowsy again. On examination he was able to say his name on request but did not respond meaningfully to other questions and only intermittently obeyed simple commands such as ‘lift up your arms’. The pulse was raised at 98 and the blood pressure was 108/64. Oxygen saturations were normal and the temperature was elevated at 37.8 °C. Chest examination revealed signs of pneumonia but chest X-ray was not possible because the patient could not tolerate the procedure. Blood tests showed a raised white cell count and evidence of mild acute kidney injury. The patient was treated with antibiotics and intravenous fluids and within one day was less agitated. His vital signs all become normal. He became more compliant with treatment and had no further episodes of agitation. However, he remained drowsy and at times was too sleepy even to exchange a few words. When awake his speech was intermittently coherent but he was unable to sustain meaningful communication for more than a few seconds at a time. He was disorientated and unable to count backwards from 20 down to 1. His wife stated that his mental status was much worse than normal. After three more days he was more consistently awake but remained unable to sustain normal conversation. He was also unsteady when walking and required assistance to do this safely. Seven days after admission he was transferred to a rehabilitation facility, and after a further two weeks his mental and physical status had improved sufficiently such that he was discharged home. However, when visited by the general practitioner two weeks later his wife reported that though he was improving he was still sometimes disorientated, and also considerably more passive and apathetic than he had been before his illness.

Section snippets

Pathogenesis of delirium: direct brain insults versus aberrant stress responses

The precipitants of delirium are legion. So numerous and diverse are they that to conceptualise delirium as a homogeneous pathological entity with a single molecular pathway is untenable. Frequent causes include peripheral and systemic infections, changes in medication, surgery, trauma, pain, psychological stress, acute CNS pathology caused by stroke or head trauma, and metabolic derangements such as hypoglycemia, hypoxia, hyponatremia and liver failure (usually termed acute hepatic

Sickness behaviour syndrome in health

Peripheral infection can lead to changes in mood, energy, motivation and, consequently, behaviour. These changes were generally seen as direct side-effects of infection until Hart proposed the idea of a coordinated sickness behaviour response (Hart, 1988). This constitutes a reorganisation of priorities by the infected individual, suppressing energy expenditure in activities such as locomotor activity, feeding and social interaction to minimise the risk of predation, to isolate the sick

CNS responses in severe systemic inflammation

Severe infections leading to systemic inflammation and shock generally induce more pronounced behavioural changes, including delirium and even unconsciousness. The CNS changes associated with severe sepsis is often known as septic encephalopathy. This can occur in all age groups and even in the absence of prior illness. The evidence would suggest that these extreme changes in behaviour do not fall within the spectrum of adaptive SBS: humans studies show that severe systemic infections are

Systemic inflammation produces exaggerated CNS inflammation in the susceptible individual

It is now clear that the aged and those with chronic neurodegenerative disease can suffer a more profound CNS inflammation in response to relatively minor systemic inflammation than young healthy controls. Normally this degree of systemic inflammation would only induce adaptive CNS changes. Why is there exaggerated CNS inflammation in certain groups? The basis for this may be explained, at least partly, by the phenomenon of microglial priming. This was first described in an animal model of

Cognitive consequences during exaggerated sickness behaviour and clinical delirium

Although the microglial priming hypothesis has been adopted by researchers in the delirium field (van Gool et al., 2010), clear empirical evidence to support it in clinical populations has not yet been furnished. However, the psychoneuroimmunologists have addressed the hypothesis that systemic LPS stimulation would cause significant cognitive and behavioural impairments in the brains of animals made susceptible by old age or prior neurodegenerative disease. The first of these studies showed

Exaggerated sickness or prior vulnerability?

In classical SBS, as induced by moderate systemic inflammation, affective and motivational changes predominate and cognition is not severely impaired. As discussed above, in the presence of a vulnerable brain, mild or moderate systemic inflammation induces significant cognitive deficits in addition to classical SBS. If the acute cognitive deficits induced by a systemic inflammatory insult superimposed on aging or neurodegenerative disease were a simple case of an exaggerated sickness behaviour

Prior pathology as a predisposing factor

In clinical populations, there are now multiple studies showing associations between plasma levels of pro-inflammatory cytokines and chemokines and delirium (Khan et al., 2011). These studies broadly confirm the hypothesis that systemic inflammation increases the likelihood of delirium and that greater severity of systemic inflammation makes delirium more likely. An important caveat is that, apart from old age, prior cognitive impairment is the major risk factor for delirium, and such

Does aetiology influence the phenotype of delirium or sickness behaviour?

Association studies lead to speculation that particular inflammatory cytokines have a key role in inducing delirium. Whether particular inflammatory mediators contribute to particular presentations of delirium has not been studied in any detail. In a cohort with Alzheimer’s disease systemic inflammatory events were found to exacerbate the rate of cognitive decline in these patients in the absence of detectable delirium (Holmes et al., 2009). These patients showed symptoms of sickness behaviour

Hyperactive versus hypoactive delirium

Another issue in evaluating the hypothesis of delirium as exaggerated sickness behaviour is the observation that systemic inflammation tends to induce a marked hypoactive state in animals and therefore may be incompatible with hyperactive delirium. Though a high proportion of delirious patients exhibit the hypoactive subtype, up to 20% of patients with delirium are classed as ‘hyperactive’. It is currently unknown if certain aetiologies favour certain subtypes nor if hyperactive delirium has a

The hypothalamic-pituitary-axis (HPA) and delirium

An important pathway that may be activated in both hypo- and hyperactive states is the HPA axis. It is well established that systemic LPS or IL-1β challenge induces HPA axis activation and one recent study in healthy volunteers showed dose-dependent and large increases in plasma cortisol following LPS injection (Grigoleit et al., 2011). Indeed some studies of sickness behaviour and cognitive function have shown efficacy the glucocorticoid antagonists mifepristone (RU486) in reversing

The stress response and delirium: mechanisms

That delirium is mostly precipitated by stress, defined broadly as any form of acute threat to homeostasis, is unarguable. The evidence suggesting that there are associations between activation of stress-responsive systems such as the HPA axis and the immune system and delirium is consistent with this axiom. However, the pathways from stress stimuli to delirium are not yet defined. Given that inattention is the core cognitive feature of delirium, understanding how stress might disrupt attention

Conclusion and future perspective

In this review we have proposed that mapping SBS in vulnerable rodents (aged or with prior neurodegeneration) onto delirium in humans is both plausible and supported by clinical and basic research studies. However, the relationship is not simple: there are key differences between SBS in vulnerable rodents and delirium in humans with respect to aetiologies, varying levels of co-morbidity, varying phenomenology (including hyperactivity), and obviously differences between the rodent and human

Acknowledgments

CC is supported by a Senior Fellowship from the Wellcome Trust. AM is a member of The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative. Funding from the BBSRC, EPSRC, ESRC and MRC is gratefully acknowledged.

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