Review Article
Unravelling the pathophysiology of delirium: A focus on the role of aberrant stress responses

https://doi.org/10.1016/j.jpsychores.2008.05.019Get rights and content

Abstract

Delirium is a common and serious acute neuropsychiatric syndrome with core features of inattention and cognitive impairment, and associated features including changes in arousal, altered sleep–wake cycle, and other changes in mental status. The main risk factors are old age, cognitive impairment, and other comorbidities. Though delirium has consistent core clinical features, it has a very wide range of precipitating factors, including acute illness, surgery, trauma, and drugs. The molecular mechanisms by which these precipitating factors lead to delirium are largely obscure. In this article, we attempt to narrow down some specific causal pathways. We propose a basic classification for the etiological factors: (a) direct brain insults and (b) aberrant stress responses. Direct brain insults are largely indiscriminate and include general and regional energy deprivation (e.g., hypoxia, hypoglycaemia, stroke), metabolic abnormalities (e.g., hyponatraemia, hypercalcaemia), and the effects of drugs. Aberrant stress responses are conceptually and mechanistically distinct in that they constitute adverse effects of stress–response pathways, which, in health, are adaptive. Ageing and central nervous system disease, two major predisposing factors for delirium, are associated with alterations in the magnitude or duration of stress and sickness behavior responses and increased vulnerability to the effects of these responses. We discuss in detail two stress response systems that are likely to be involved in the pathophysiology of delirium: inflammation and the sickness behavior response, and activity of the limbic–hypothalamic–pituitary–adrenal axis. We conclude by discussing the implications for future research and the development of new therapies for delirium.

Introduction

Delirium is a syndrome of acutely altered mental status that has the core elements of inattention and fluctuating course and multiple associated features including altered arousal, disorganized thinking, perceptual disturbances, psychosis, and sleep–wake cycle disturbance [1], [2]. Delirium occurs in patients of all ages, but the highest incidence is in older people with a background of chronic central nervous system (CNS) disease. It affects 20–30% of acutely admitted older general hospital inpatients and is associated with adverse outcomes, including functional decline, permanent decrements in cognition, and mortality [2]. In the last two decades, there has been a large rise in published studies of delirium, mainly focusing on clinical manifestations, risk factors, and outcomes, and prevention and treatment of delirium by specific programmes of enhanced clinical care and drug treatment [1], [3], [4], [5], [6], [7], [8], [9], [10]. These studies have led to a greatly increased knowledge of many fundamental features of delirium. However, there has been comparatively little work on the pathophysiology of delirium, which remains poorly understood. Published reviews give comprehensive overviews of the literature on delirium pathophysiology [11], [12], and here, we do not aim to provide such broad coverage. Rather, we take an exploratory approach. Our focus is on two areas of stress biology that appear highly relevant to delirium: the inflammatory response and the activity of the limbic–hypothalamic–pituitary–adrenal (LHPA) axis. We go on to discuss how direct brain insults and aberrant stress responses might lead to delirium and conclude by discussing the implications for future research and the development of new therapies.

Section snippets

Aetiologies of delirium

There is a great diversity of precipitating factors of delirium [11], [12]. Some of these factors manifestly result in brain injury and dysfunction, for example, haemorrhage or prolonged hypoglycaemia. However, the mechanisms of delirium in other clinical scenarios, such as that caused by mild urinary tract infection or psychological stress, are unclear. Understanding the physiological and molecular pathways from these diverse factors to the core features of delirium, such as inattention, is a

Conclusions and discussion

A fundamental goal in delirium research is characterising the physiological and molecular pathways that lead from the wide range of precipitants to the relatively stereotyped syndrome (at least with respect to the core features) of delirium. In this article, we have suggested that the precipitants of delirium can usefully be divided into two conceptually distinct classes: (a) direct brain insults and (b) aberrant stress responses. The rationale for this classification is that these categories

Acknowledgments

A.M. was supported by an MRC Clinician Scientist Fellowship. The UK Medical Research Council and the University of Edinburgh provide core funding for the MRC Centre for Cognitive Ageing and Cognitive Epidemiology, which supported this research. C.C. was supported by a Wellcome Trust Career Development Fellowship.

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