Of the many clinical symptoms that people may experience, alterations of mental status strike most directly at our personal core. These distressing symptoms affect not only the individuals directly experiencing them, but also those who care for them, both personally and professionally. The importance of altered mental status is yet further magnified by its prevalence, as one of the most common reasons to receive acute medical care. The term altered mental status, however, represents an especially complex constellation of symptoms, a label applied by clinicians that simultaneously consolidates and oversimplifies different patient concerns and clinical syndromes that can be due to disparate causes within and outside of the nervous system.[1] This complexity can provoke nearly as much confusion in clinicians as patients themselves.

Achieving clarity on acute confusion is challenging given our incomplete understanding of the relevant biological pathways, and further hindered by divergent terminology and fragmented literatures.[2] For example, delirium is a disorder of attention and awareness with widely recognized definitions in both the Diagnostic and Statistical Manual (DSM)[3] and the World Health Organization's International Classification of Diseases.[4] But neurologists have not always used the word delirium in the same manner as specialists in other fields,[5] with some splitting presentations phenotypically into more hyperactive “delirium” and more hypoactive “encephalopathy.”[6] Recent efforts have been made to clarify this terminology, for example in a statement endorsed by 10 societies including the American Academy of Neurology and Neurocritical Care Society.[7] This proposed framework unites DSM-defined delirium on a spectrum with some other presentations of altered mental status such as coma, to represent clinical expressions of underlying pathobiological processes, for which the term “encephalopathy” is reserved. It is not yet clear how widely adopted this proposed framework will be, but it admirably endeavors a unifying path forward.

While our field continues to wrestle with the complexities and nuances of defining various states of altered mentation, the consequences of acutely altered mentation generally, and delirium specifically, are staggering. Altered mental status accounts for nearly 1 in 10 of all emergency department visits.[8] Once hospitalized, reductive labeling with “delirium” or “toxic-metabolic encephalopathy” may create a false sense of diagnostic closure and thus hinder the search for underlying, and potentially, treatable pathology. This is particularly true of medically complex patients. For example, in medical intensive care units, nearly one in three patients may be delirious when screened with the validated Confusion Assessment Method for the Intensive Care Unit.[9] However, approximately 1 in 10 of these complex patients will develop a primary neurologic injury occur during their admission (most frequently stroke, seizure, or hypoxic brain injury).[10] Extreme caution, careful examination, and diagnostic humility are needed to prevent all mental status change from being incorrectly reduced to delirium. Even when the diagnosis of delirium is correctly made, minimizing the diagnosis—“they're just delirious”—undervalues the prognostic significance of the condition. Not only do patients with delirium have an increased length of hospital stay, but also they are endangered by increased mortality and dramatically reduced functional recovery and cognitive performance months beyond the hospitalization.[11]

Our goal in this issue of Seminars in Neurology is to share a resolutely interdisciplinary and pragmatic map to the constellation of related concepts of altered mental status, delirium, and encephalopathy. We first provide two complementary systematic approaches to patients with altered mental status, providing conceptual frameworks and practical bedside guidance for these patients: a neurologically informed approach to the recognition and diagnosis of acute changes in mental status, as covered by Lieberman and Berkowitz, and a psychiatrically informed approach by Hamm and Rosenthal. While all patients with altered mental status require careful examination, those at the most extreme end of the altered spectrum with disorders of consciousness represent both unique challenges and opportunities, as highlighted in article by Dhadwal et al. Similarly, those in the intensive care unit, with history of organ transplant, or with cancer also require a unique diagnostic approach—as discussed in articles by Albin et al, Weiss, Pflugrad, and Kandiah, and Rhee et al, respectively. We have been deliberate to include special considerations in the approach to pregnant patients, as presented by Kroopnick and Miller, and children, as explored by Bieber et al—populations that have been classically underrepresented in the literature on this topic.

Given how common delirium is, the latter half of the issue focuses on a more detailed examination of delirium, including its pathophysiology in an article authored by Smith et al. This is followed by a careful examination of its tight interrelationship with dementia by Oh et al. The impacts of social determinants of health have been previously underappreciated; Khanna et al explore this complex interplay and establish a call to action for a nuanced view of delirium that incorporates the social ecological impact on the diagnosis, management, and treatment of delirium. Once identified, clinicians often feel compelled to treat delirium pharmacologically, but as the article by John Devlin explores, there are no Food and Drug Administration–approved therapies and a lack of a strong evidence basis for the use of any specific medication to prevent or treat delirium. Presently, this is both a humbling and motivating circumstance for all prescribers who would care for patients with delirium, and his article explores the future of delirium pharmacologic management. We lastly focus on the nonpharmacologic prevention and treatment of delirium, led in an article by Sophia Ryan, which currently represents the only effective method of delirium management, as confirmed by high-quality, randomized controlled trials. These multimodal, nonpharmacologic strategies represent fundamentally good medical care applicable not only to patients with delirium, but likely also to those with other forms of altered mental status, or even other concerns.

We appreciate each of the authors who have put together thoughtful, comprehensive, and insightful manuscripts that are both practical and inspiring. We are grateful to Dr. David Greer and Dr. Ariane Lewis for their vision and mentorship willingness to allow us to guest edit this issue. Moreover, we are indebted to the patients and families whose experiences, lives, and stories have both informed and transformed our continued clinical care.

Article published online:
12 November 2024

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