Mixed Bag #6: Mark Oldham on Delirium

“Mixed Bag” is a series on Psychiatry at the Margins where I ask an expert to select 5 items to explore a particular topic: a book, a concept, a person, an article, and a surprise item (at the expert’s discretion). For each item they have to explain why they selected it and what it signifies. — Awais Aftab

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Mark Oldham, MD is a consultation-liaison (C-L) psychiatrist and an assistant professor of psychiatry at University of Rochester Medical Center. He completed a fellowship in C-L at Yale, and at URMC he is currently supported by a K23 career development award from the National Institute on Aging to develop expertise on the relationship between sleep-wake disturbance and postoperative cognition—both delirium and Alzheimer disease and related dementias. Clinically, Oldham is the medical director of a proactive psychiatric consult service and leads a multidisciplinary team involved in improving and harmonizing delirium management efforts across the institution. He serves as Deputy Editor of the Journal of the Academy of Consultation-Liaison Psychiatry and Treasurer of the American Delirium Society.  

Oldham’s academic passion is delirium, but he takes an unconventional approach. He challenges the assumption that delirium is a single condition; rather, he sees delirium as a convergent clinical syndrome that represents a variety of different conditions involving disrupted neurophysiology. He aims to spur the field to a more robust understanding of “delirium disorder.” You can find him on twitter: @MarkOldhamMD

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Oldham: I’ve long been mesmerized by the question “What is mental health?” and its converse “What is mental illness?” and not simply to substantiate my professional identity. Quite the opposite: I wanted to become a psychiatrist before I knew what medicine was. I felt a calling to help people who suffered with distressing mental experiences, and, of the options, I found psychiatry the most compelling to me for its appeal not only to the mind and the brain but also the entire body, from the perspective of physician. I readily admit this was a pie-in-the-sky observation because, at the time, I had no clue what “medicine” was and no exposure to physicians other than rare visits to my own PCP. I knew simply that to become a psychiatrist I first had to become a doctor. So I did, and I’ve not questioned or regretted the decision for a moment. It was in medical school, then, that I came to two personal insights: (1) how much I appreciated medicine and (2) how intertwined medical conditions and mental health were. I was also introduced to consultation-liaison (C-L) psychiatry in medical school, and I was instantly hooked.

I quickly came to realize, in the words of Drs. Trzepacz and Lee, “Delirium is the sine qua non of psychiatric disorders in the general hospital.”¹ Delirium and various other secondary psychiatric syndromes are incontestable proofs of concept, not only that brain dysfunction leads to disturbances in the mind but that systemic factors—conditions that chiefly involve any number of organs outside the nervous system—can have distal effects on the brain and, hence, the mind. These mental experiences range widely, mimicking aspects of nearly every “mental illness” imaginable, taking as generous a view of “mental illness” as one might. It is at this level that I find questions along the lines of “Do mental illnesses exist?” bizarre, seemingly borne of certain presuppositions rather than faithfully engaging with people in clear distress. In delirium, the mind is unquestionably ill, along with other parts of the body. With this as prelude, I arrive at my list of 5 items…

Book — Delirium: Acute Brain Failure in Man (1980) by Zbigniew J. Lipowski

Oldham: Written by Lipowski in 1980², this book, his first of two monographs on the condition, reads surprisingly modern. For instance, in the Preface, “[Delirium] is most frequent among people aged sixty years and older, and their number is steadily growing. In these elderly persons, delirium constitutes a ubiquitous and thus clinically important sign of cerebral functional decompensation caused by physical illness. Any medical or surgical ward, or emergency department of a general hospital, provides a setting in which delirium is seen daily and is frequently misdiagnosed, or even overlooked, by the medical staff….Apart from its ubiquity and clinical importance, delirium poses questions for every student of brain-behavior relationships, consciousness, sleep-wakefulness cycle, hallucinations, and organizations of the mind.”

Much of our modern scholarship on delirium as well as our current understanding of it traces itself back to this tome, including the now-commonplace distinction among its hyperactive, hypoactive, and mixed psychomotor presentations. His encyclopedic discussions of the “organic causes of delirium” are hardly surpassed today.

I have a few reasons for citing this book as the first of my 5 items on delirium: First is that we would do well to appreciate that our discoveries are contingent on those who came before. We should be a student of history, engage with the ideas and observations of our forbearers, and consider carefully how their ideas have scaffolded our own. Second is that, whereas we have clearly many advances in the broader field of medicine, much of our current practice and understanding of delirium was known many decades ago. Modernity wishes to see itself as enlightened when in reality the incident light is often simply reflected from the past. Third is one of some disappointment: namely, that many of the issues Lipowski explores—from the association of delirium with subsequent dementia or how little attention was paid to delirium in clinical practice—persist today. How much have we learned since this seminal work? I’m afraid we’ve made precious little progress in the past 40+ years in the management of this condition described from antiquity. This brings me to my second item, a concept—one that I hope will prove disruptive and generatively so.

Concept – “Delirium Disorder”

Oldham: At the risk of being cheeky, I submit as my second item the concept that “delirium is not a thing.” By this I mean the DSM-5-TR entity labeled “delirium” is not a single pathophysiologically homogeneous condition. The tremendous biological diversity inherent in delirium and the sheer number of potential “causes” of delirium is disorienting. How can an anticholinergic medication, decompensated cirrhosis, and the post-ictal state all present with the same clinical syndrome and yet all be declared “the same”? I often think of Maldonado’s concept map of delirium,³ which, as I’ve heard it told, began with a map of Post-It notes on a board that conjured a semi-ordered chaos—that is, with an emphasis on the chaos. Apocryphal or not, it’s an evocative image. Yet, his more recent rendition⁴ provides further organization (and color coding), along with a delimited set of “substrates” by which the many tiny capillaries of pathophysiology aggregate into a smaller set of venules—these “substrates”—before they reach the vena cava of “systems disintegration.”

When one reflects on this kind of approach, it becomes clear that the very term “delirium” is being used in elastic ways, to describe both the clinical syndrome evaluated at the bedside as well as the broader diagnosis that implicates a secondary cause. Ambiguity in language opens the door for conflation and confusion. Building on Maldonado’s models, I reserve the term “delirium” to refer to the phenotype one evaluates at the bedside and have proposed the term “delirium disorder” for the diagnosis.⁵

Delirium is a clinical entity that represents the convergent effects of many causes, but it does not necessarily have a unifying pathophysiology. In systems theory, this is known as equifinality, which is an open system in which a diversity of pathways lead to the same outcome. Is it not striking that so many disparate processes can lead to a unified, identifiable syndrome? One might even suspect that such a fault line in neurocognition might suggest that delirium is a ‘pre-programmed’ process for the brain, something that the brain is ‘supposed to do’ in response to global threats, a way to open Windows in safe mode. We will return to this idea with the surprise item in a moment, but for now I would like to stick with the notion of complexity. For this, I propose the following article as my third item, an exposé disguised as a systematic review.

Article – Ormseth et al. Predisposing and Precipitating Factors Associated With Delirium: A Systematic Review (2023)

Oldham: With a few select exceptions, neurologists rarely use the term “delirium,” except when discussing hyperactive states of confusion. Instead, they favor the word “encephalopathy.” Perhaps this is due in no small part to the long arm of Charcot whose clinicopathological studies inaugurated the now-(in)famous division between neurology and psychiatry. Nevertheless, neurological texts contain de rigueur chapters on metabolic encephalopathies, parsing out unique metabolic disturbances that lead to global cerebral dysfunction, yet this approach to different medical conditions has surprisingly little parallel in the delirium literature. Instead of splitting, the delirium literature lumps as it aims to find commonalities among the many conditions that cause delirium, very rarely differentiating among the physiologically diverse causes of delirium. As such, one supposes that at present the term delirium should be understood as “all-cause delirium,” akin to “all-cause dementia.”

This brings us to the review in question. I had the pleasure of collaborating with colleagues in neurology at the University of California San Francisco on a comprehensive literature review on the “Predisposing and Precipitating Factors Associated With Delirium.”⁶ What makes this review unique is that it was not restricted to a specific patient population or clinical setting: it was cross-cutting in a way that reveals, in cross-section, the tremendous biological heterogeneity that underlies delirium—again, this idea of “all-cause delirium.” This review makes plain this idea of equifinality and provides an empirical nudge toward embracing a diversified model of delirium [disorder]. The review qua exposé speaks for itself, and what it has to say speaks to the timeless questions of mind and body. And this is, of course, why we need to turn to my fourth item.

Person – Janus

Oldham: Janus (/JAY-nus/) is a mythical figure from ancient Roman times who represented doorways, transitions, and dualities. Immediately apparent when one sees Janus is that this is no ordinary person. Janus has one head but two faces, each facing opposite directions. Anatomical curiosities aside, Janus illustrates something telling about delirium in that it offers a fitting analogy for mind–brain relationships.

Among the core unsettled issues at the heart of “mental illness” is how the mind and body are related to one another. Although commonly understood as the mind–body problem or the hard problem of consciousness, this central relationship — or relationships⁷ — is not something that I would describe as a problem. Setting aside metaphysical questions for the time, it seems to me an essential fact of embodied existence that the mind and brain are related and that they are related in a dynamic fashion. One has to look no further than to delirium to appreciate this: again, delirium offers us a fitting proof of concept.

So let’s bring back our old friend, the brain. It’s hard to fault the broader medical field for having such a difficult time architecting a model of delirium that encompasses mental and encephalic elements. There is clearly a tension here, and the closer we look the more mysterious the nature of this tension becomes. The tension itself is more of an abstract object than anything else. It’s a force, not unlike the strong nuclear force, that pulls toward itself and defies the deepest investigation. This is why we cannot have a model of delirium without embracing the idea embodied by encephalopathy (as I would just as soon dispense with the cumbersome and undefined term) and certainly no model of encephalopathy without embracing delirium. They are two faces on the same head. You might be able to cover one up to make for a more inviting guest, but which one? And, even if we did, we would be doing so only for our own polite convenience.

This is why we cannot have a model of delirium without embracing the idea embodied by encephalopathy and certainly no model of encephalopathy without embracing delirium. They are two faces on the same head.

Such a relationship, as mysterious as it is, should drive us, not deter us. We should wish to look at it, not to look away. It is such a relationship that ought to inspire us to consider the possibilities rather than an either–or approach, even if picking sides is far easier. This is where we might be creative. If we for a moment entertain the epiphenomenal nature of delirium in relation to underlying somatic pathophysiology, then we might begin to see delirium entirely differently. It might even be a valuable, if surprising, herald that tells of tales to come.

Surprise item – cognitive stress test

Oldham: Cardiac stress tests provide critical information about heart health. We want to know how the heart responds to physiological “stress,” be it by walking on a treadmill, riding a stationary bike, or injecting a vasoactive agent such as dipyridamole. The results of a stress test inform clinical decisions regarding the risk of cardiac events associated with surgery, provide an index of cardiac function, and grade the severity of a heart condition. Yes, the heart is being stressed briefly, but it is done so in a controlled fashion and with an outcome that meaningfully informs clinical care—an outcome that one would much rather encounter in a safely controlled experiment than in an ICU setting where variables vastly outweigh controls.

This brings us to our surprise item: a cognitive stress test. It is not a foregone conclusion that a brief episode of delirium is neurotoxic. Like fever or pain, delirium alerts us to something amiss in the body. Granted, delirium itself warrants independent attention for its potential to cause distress and injury, yet it is nevertheless quite valuable in that it tells us something. Work by Colm Cunningham’s group using a mouse model of delirium even suggests that the mechanisms leading to confusion may be different from those that lead to brain injury,⁸ and so by preventing delirium one might even end up paradoxically saving “the canary while poisoning the coalminers.”⁹ Lest someone suggest I’m courting anathema, I’ll quote from the “International drive to illuminate delirium: A developing public health blueprint for action,” whose authors are a veritable Who’s Who list of international delirium authorities: “The research agenda should also explore unmasking the vulnerability to episodes of delirium by developing stress tests to examine what regions or functions of the brain are, or are not, working at capacity to remain above thresholds for preserving function.”¹⁰

Coda

Oldham: Drawing these strands together, what is my vision for delirium and the delirium field? It is a future in which our very models become part of the message itself, where we hold tightly to both delirium and its pathobiology, one in each hand. I see delirium as a prototype of mental illness or, as I’ve said above, a proof of concept. It demands that we take seriously the interplay between mind and body. Beneath the clinical syndrome of confusion lies a vast and variegated range of pathophysiologies. Perhaps schizophrenia and depression are equally complex. I don’t know, but it’s not out of the question. Even Bleuler, when coining the term schizophrenia, did so in the plural.¹¹ However, what I would like to believe is that advances in the delirium field might teach us about mental illness in general and also that any such insights and advances in the delirium would advance the care of those with other mental illnesses just the same.

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See previous posts in the “Mixed Bag” series

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1. Trzepacz PT, Lee HB. Have Consultation-Liaison Psychiatrists Abandoned Delirium Research? J Acad Consult Liaison Psychiatry 2022;63(6):519-520. DOI: 10.1016/j.jaclp.2022.11.002

2. Lipowski ZJ. Delirium: Acute Brain Failure in Man. Springfield, IL: Charles C Thomas, 1980.

3. Maldonado JR. Pathoetiological model of delirium: a comprehensive understanding of the neurobiology of delirium and an evidence-based approach to prevention and treatment. Crit Care Clin 2008;24(4):789-856, ix. DOI: 10.1016/j.ccc.2008.06.004.

4. Maldonado JR. Delirium pathophysiology: An updated hypothesis of the etiology of acute brain failure. Int J Geriatr Psychiatry 2018;33(11):1428-1457. DOI: 10.1002/gps.4823.

5. a. Oldham MA, Flaherty JH, Maldonado JR. Refining Delirium: A Transtheoretical Model of Delirium Disorder with Preliminary Neurophysiologic Subtypes. Am J Geriatr Psychiatry 2018;26(9):913-924. DOI: 10.1016/j.jagp.2018.04.002.

b. Oldham MA, Holloway RG. Delirium disorder: Integrating delirium and acute encephalopathy. Neurology 2020;95(4):173-178. DOI: 10.1212/WNL.0000000000009949.

c. Oldham MA. Delirium disorder: Unity in diversity. Gen Hosp Psychiatry 2022;74:32-38. DOI: 10.1016/j.genhosppsych.2021.11.007.

d. Oldham MA, Slooter AJC, Ely EW, Crone C, Maldonado JR, Rosenthal LJ. An Interdisciplinary Reappraisal of Delirium and Proposed Subtypes. J Acad Consult Liaison Psychiatry 2022. DOI: 10.1016/j.jaclp.2022.07.001.

6. Ormseth CH, LaHue SC, Oldham MA, Josephson SA, Whitaker E, Douglas VC. Predisposing and Precipitating Factors Associated With Delirium: A Systematic Review. JAMA Netw Open 2023;6(1):e2249950. DOI: 10.1001/jamanetworkopen.2022.49950.

7. Pernu TK. The Five Marks of the Mental. Front Psychol 2017;8:1084. DOI: 10.3389/fpsyg.2017.01084.

8. Skelly DT, Griffin EW, Murray CL, et al. Acute transient cognitive dysfunction and acute brain injury induced by systemic inflammation occur by dissociable IL-1-dependent mechanisms. Mol Psychiatry 2019;24(10):1533-1548. DOI: 10.1038/s41380-018-0075-8.

9. Oldham MA, Flaherty JH, Maldonado JR. Refining Delirium: A Transtheoretical Model of Delirium Disorder with Preliminary Neurophysiologic Subtypes. Am J Geriatr Psychiatry 2018;26(9):913-924. DOI: 10.1016/j.jagp.2018.04.002.

10. Khachaturian AS, Hayden KM, Devlin JW, et al. International drive to illuminate delirium: A developing public health blueprint for action. Alzheimers Dement 2020;16(5):711-725. DOI: 10.1002/alz.12075.

11. Peralta V, Cuesta MJ. Eugen Bleuler and the schizophrenias: 100 years after. Schizophr Bull 2011;37(6):1118-20. DOI: 10.1093/schbul/sbr126.