Elucidating the pathophysiology of delirium and the interrelationship of delirium and dementia.

Delirium, defined as an acute decline of attention and cognitive function, represents a common and potentially devastating problem for hospitalized older persons. With occurrence rates from 14% to 56% and hospital mortality rates from 25% to 33% (1), delirium often initiates a cascade of events culminating in loss of independence, increased morbidity and mortality, and increased health care costs (2). We estimate, on the basis of our previous work (1,3) and extrapolations from Medicare data (4), that each year delirium complicates hospital stays for at least 20% of the 12.5 million persons aged 65 years and older who are hospitalized each year, with an increased hospital cost of $2,500 per patient attributable to delirium. This accounts for over $6.9 billion (2004 U.S. dollars) in Medicare expenditures for hospitalization attributable to delirium each year. Substantial additional direct health care costs accrue after hospital discharge because of the need for institutionalization, emergency room visits, rehospitalization, physician or clinic visits, rehabilitation services, and formal home health care, estimated at $48,785 per patient attributable to delirium, or over $100 billion per year extrapolated nationally (5). Several recent lines of evidence have converged to highlight the interrelationship of delirium and dementia. First, delirium persists much longer than previously believed, with symptoms commonly present for months to years in many studies (6–11). The entities of persistent delirium (6–11) and reversible dementia (12) blur the distinctions between these two conditions. Second, epidemiologic studies have documented long-term cognitive decline following delirium (13). Third, dementia is the leading risk factor for delirium identified in previous studies (14,15). At least two thirds of cases of delirium occur in patients with underlying dementia or cognitive impairment, suggesting that the underlying vulnerability of the brain in dementia predisposes affected patients to the development of delirium when exposed to precipitating factors or insults such as medical illnesses, infections, medications, and medical procedures. Fourth, neuroimaging studies have documented regions of hypoperfusion in patients with delirium, suggesting that delirium may incite a derangement in brain vascular function that may lead to dementia in some cases (16,17). Fifth, dementia with Lewy bodies, which shares clinical features with delirium (e.g., visual hallucination, fluctuating symptoms) along with marked cholinergic deficiency, may reflect an overlap syndrome. Finally, previous studies have postulated shared underlying mechanisms, as both delirium and dementia have been shown to be associated with decreased cerebral oxidative metabolism, cholinergic deficiency, and inflammation (18). To date, the pathophysiology of delirium remains poorly understood, and its underlying mechanisms are largely unknown. Understanding the pathophysiology of delirium will be critical to advancing the field and to developing optimal preventive and treatment strategies. Key issues are whether and in whom delirium leads to permanent cognitive sequelae and, if so, how does this occur? Clarification of this area may offer the unique opportunity to provide early intervention to prevent permanent neurologic damage, and to mitigate the potential downward spiral to dementia. However, studying the interface of delirium and dementia presents extreme challenges in study design and conduction, as well as in the informed consent process. To begin an exploration of this area, we convened the “Aging Brain Center Scientific Symposium: The Interface of Delirium and Dementia” on April 10, 2006. The symposium focused on studies examining the pathophysiology of delirium and the interrelationship of delirium and dementia. From the presentations at this symposium, five articles were developed as a special series for this journal. The goal of this special series of articles is to elucidate the underlying processes that lead to delirium. In addition, we generated hypotheses and new criteria that may help to identify individuals at high risk for adverse outcomes from delirium, such as those persons in whom the instability of cognitive homeostasis may have already exhausted all cognitive reserves. Finally, through this special series, we also hope to initiate a discovery process that will enable us to determine whether delirium itself leads to long-term cognitive sequelae and dementia, to explore whether delirium worsens the cognitive trajectory of an existing dementia, and to probe the pathways leading to these sequelae.