General Hospital Psychiatry 74 (2022) 32–38

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General Hospital Psychiatry

journal homepage: www.elsevier.com/locate/genhospsych

Review article

Delirium disorder: Unity in diversity

Mark A. Oldham
University of Rochester Medical Center, Department of Psychiatry, 300 Crittenden Blvd, Box PSYCH, Rochester, NY 14642, United States of America

A R T I C L E I N F O A B S T R A C T

Keywords: Objective: The first objective of this review is to explore the factors that have led to and maintain the division
Delirium between delirium and acute encephalopathy. The second is to explore the value of harmonizing them through the
Toxic-metabolic encephalopathy model of delirium disorder.
Acute confusional state
Method: This narrative review outlines major distinctions between delirium and acute encephalopathy. It also
Nomenclature
compares them with the model of delirium disorder, which seeks not only to integrate them but also to offer a
broader palette of treatment targets.
Results: Delirium implies an underlying acute encephalopathy, whereas acute encephalopathy presents as a
spectrum from subsyndromal delirium to coma. Key factors that differentiate these two models include tradition,
nuances of the models themselves, linguistic connotations, evoked responses from clinicians, implications of
preventability and responsibility, cultural perceptions of non-pharmacological vs pharmacological interventions
and economic incentives. A validated set of pathophysiological subtypes may ultimately help link the delirium-
spectrum phenotype with various acute encephalopathies.
Conclusions: Developing a coherent clinical and scientific approach to this set of conditions demands that we first
develop a coherent understanding of the conditions themselves and how they relate to one another. Such an
approach must embrace the tension between a convergent phenotype and its diverse biological underpinnings.

1. Delirium and acute encephalopathy
Modern clinical approaches to the acute neurocognitive syndromes
of delirium and acute encephalopathy remain underdeveloped. The
standard of care for delirium emphasizes multicomponent non-
pharmacological strategies to target cognitive vulnerability and treat­
ing the underlying cause(s). The standard of care for acute encepha­
lopathy is disease-specific management. Although these two clinical
approaches offer complementary perspectives, they are inadequate even
when combined. The most assertive non-pharmacological delirium
bundles fail to prevent most deliria [1] and do little to alter the course of
delirium once it begins [2] or to improve delirium outcomes [3].
Further, the clinical phenotype of delirium often persists for days or
longer even after all known modifiable causes have resolved or been
reversed [4]. Every hospital-based clinician knows the irksome reality of
having little more to administer than a tincture of time.
Delirium and acute encephalopathy are emblematic of longstanding
dualistic approaches to the mind and body: one is defined by a clinical
phenotype and the other is the implied pathobiological substrate [5,6].
Yet, the mind and body are not so easily dissected from one another. The
delirium phenotype must have a pathophysiological basis, and
pathobiology would not be pursued except where a clinical phenotype
alerts us to its presence. The complements of a clinical phenotype and
neurobiology want for a meaningful synthesis, if for no other reason
than because mind-to-body and body-to-mind causal pathways must be
acknowledged [7]. Consider the incompleteness of each model in
isolation.
The accepted model of delirium posits a clinical phenotype: ac­
cording to DSM-5, this includes an acute change in mentation charac­
terized by disruption in attention, awareness and at least one additional
cognitive domain [8]. The unifying mental state of delirium, then, un­
derstandably presumes a common final pathway [9–17]. However, a
shared final common pathway does not necessarily imply that all
delirium shares the same upstream pathophysiology as well, nor does it
imply that all delirium may be described by a single physiological theory
such as cholinergic deficiency or neuroinflammation. Biomarker studies
of delirium, where the index criterion for inclusion is the mental status
phenotype of delirium, reveal striking heterogeneity to date [18–20].
Whereas this may mean that the field has failed to identify an as-yet
elusive unifying biomarker, one might suggest a more plausible inter­
pretation is a plurality of physiologically discrete deliria. This is in stark
contradistinction to the illusion of physiological homogeneity fostered

E-mail address: mark_oldham@urmc.rochester.edu.

https://doi.org/10.1016/j.genhosppsych.2021.11.007
Received 9 August 2021; Received in revised form 28 November 2021; Accepted 29 November 2021
Available online 3 December 2021
0163-8343/© 2021 Elsevier Inc. All rights reserved.
M.A. Oldham General Hospital Psychiatry 74 (2022) 32–38

by the notion of a unitary construct of delirium. Indeed, similarities do Table 1

not imply sameness. Factors distinguishing delirium, acute encephalopathy and delirium disorder.
The model of acute encephalopathy varies in etiology-specific details Delirium Acute Delirium disorder
(e.g., hepatic, uremic, or sepsis-associated), but each type shares the core encephalopathy
features of a distinct set of pathobiological processes and an implied Tradition/early Engel & Romano Plum & Posner Oldham,
clinical phenotype ranging from subtle mental disturbances to coma [5]. theorists Lipowski Victor & Adams Flaherty,
Acute encephalopathy describes the “underlying” pathobiology, yet the Maldonado
question of what “overlies” this process—the sine qua non and herald of Conceptualization “Lumper” (top- “Splitter” (bottom- Unity in diversity
down) up)
the condition, what brings a patient to clinical attention—is acknowl­ Prototypical Psychiatry Neurology Multidisciplinary
edged in the literature almost exclusively by implication. That is, the specialty
clinical spectrum of phenotypes that qualify for a diagnosis of acute Specialty Geriatrics, Medicine and Proposed as
encephalopathy, either in terms of which neuropsychological domains preference anesthesiology, neurocritical care broadly inclusive
critical care
must be disrupted or a severity threshold criterion, lack clinical oper­
medicine
ationalization [21,22]. Prioritizes Mind (mental Body Mind–body
Despite the tremendous impact that acute neurocognitive syndromes state) (neurobiology) system
have on patients, their families, and healthcare systems [23], current Linguistic Psychologized Medicalized Systems theory
conceptual models are incomplete, and this may be a critical reason why connotation
Evoked response Stigmatization Intellectualization Practicability
therapeutics have failed to advance over the past several decades. Nature of Preventability Eventuality Some
Assuming the models of delirium and acute encephalopathy do refer to a occurrence preventability
common set of overlapping clinical syndromes, we should expect a Responsibility Implies failure Not responsible Some
comprehensive model that accommodates both perspectives [6]. responsibility
Non- Emphasized Insufficient Emphasized but
The relationship between delirium and acute encephalopathy lies at
pharmacological insufficient
the heart of understanding this set of conditions. One can construct a perspective
Venn diagram of acute encephalopathy based on a recent position Pharmacological Discouraged Subtly encouraged Deserves
statement approved by 10 medical societies (Fig. 1) [5]. The pathobi­ perspective exploration
ology of acute encephalopathy presents as one of three distinct, non- Reimbursement Relatively Incented Ideally
disincented harmonized
overlapping clinical phenotypes: subsyndromal delirium (i.e., meeting
some but not all delirium criteria), delirium, or coma (n.b., presentations
lying on boundaries between these states may be clinically equivocal, familiarity, which deepens over time with clinical experience. We speak
especially on a single evaluation, though the presence of equivocal cases the language we were taught, what we have come to know, and,
does not undermine the categories themselves [24]). One may also perpetuating the cycle, what we then teach others.
conceptualize the joinder of subsyndromal delirium and delirium as a
broader delirium-spectrum phenotype [6]. Among the most important 3. Traditions and specialties
observations of this diagram is that delirium-spectrum phenotypes
imply acute encephalopathy. There is no delirium sans acute Delirium derives from the tradition of Engel, Romano, and Lipowski
encephalopathy. [25–27], whereas acute encephalopathy follows from the designations
The acute neurocognitive syndromes of delirium and acute enceph­ of Plum and Posner [28] and subsequently Victor and Adams [29]. The
alopathy have been siloed from one another in clinical and research former prioritizes mental status (mind/psyche) and reflects a psychiatric
settings for decades, but they ought to be unified. This narrative review ethos, as exemplified by its inclusion in the Diagnostic and Statistical
has two aims. The first is to discuss the factors that contribute to and Manual of Mental Disorders since DSM-III [30]. The latter prioritizes
maintain such divergent conceptual models. The second aim is to neuropathophysiology (body/soma) and reflects a neurobiological
explore the potential of a harmonized model that embraces the tension mindset. The longstanding conceptual rift between psychiatric and
between delirium and acute encephalopathy to provide a conceptual neurological perspectives is perhaps expressed nowhere else more
basis for clinical and research advance. poignantly than in their disparate approaches to this common set of
acute neurocognitive syndromes.
2. Holding the party line In practice, psychiatric consultations are typically requested in acute
medical settings for assistance managing the dangerous or distressing
A litany of factors contributes to the divide between these terms symptoms of delirium (what might be thought of as the “behavioral and
(Table 1). The most intuitive of these factors must be the routine psychological symptoms of delirium,” akin to those that accompany
exposure to one term or the other. Received terminology fosters dementia [31]) whereas neurological consultations generally pertain to

Fig. 1. Venn diagram of acute encephalopathy.

Acute encephalopathy presents as one of three distinct mental states [5], though cross-sectional evaluations may be equivocal. In such instances, serial evaluations
may be necessary for diagnostic clarification. Additionally, mental status may vary across the spectrum of mental status phenotypes of acute encephalopathy and
from clear sensorium to delirium-spectrum (e.g., sundowning). The word “disorder” in each derives from the proposed model of delirium disorder (see section:
Delirium disorder and the mind–brain system).

33
M.A. Oldham
diagnostic clarification [32]. Despite the mind-brain silos often typified
by psychiatry and neurology, the line dividing mind and brain has
proven to be like a blurry scratch in the sand weathered by time and re-
drawn at will. Nevertheless, this shared set of acute neurocognitive
conditions deserves a multidisciplinary approach because the diseases
that cause them, as a rule, have systemic involvement.
Likewise, these two approaches may be broadly conceptualized as
the competing tendencies either to lump or to split this set of conditions:
delirium focused on lumping them based on a shared phenotype and
acute encephalopathy splitting them based on specific cause [23,33,34].
As case in point, compared to the scores of systematic reviews and meta-
analyses for delirium [35,36], which generally treat delirium as a ho­
mogeneous biological construct, essentially no similar systematic re­
views combine all the acute encephalopathies, with very few reviews
combining several types of acute encephalopathy to determine aggre­
gate risk factors, biomarkers, clinical associations, or outcomes [37,38].
4. The psychology of language
The psychology of these two terms and of the concepts they represent
also conspire against mutual comprehensibility. Delirium speaks to a
psychologized audience. It can conjure images of agitation, hallucina­
tions, and emotional intensity—especially as in the term delirium tre­
mens. The mental health considerations introduced by the word
delirium may also contribute to the stigma attached to it. Such associ­
ations with behavioral and psychological disruption can also evoke
strong emotion in clinicians, almost as though the distress of the
bewildered patient is communicated to those around them.
By contrast, acute encephalopathy is far less accessible both
linguistically and emotionally, at times perhaps even by design. It is
fashioned in the abstruse Greek tradition of medicalese, which engen­
ders intellectualization over confusion. Its absence of a clearly defined
clinical phenotype is fitting as well: it ensures the conceptual box is large
enough to fit all the messiness of confusional states and our own
confusion in response to them inside. A clinician’s sterile somatic
approach to acute encephalopathy comports with general hospital
practice: biological illnesses receive biological interventions.
Certain elements of each psychology deserve adoption. A chief merit
in delirium lies in the awareness of the patient’s lived experience: it
draws attention to distress, danger, and dysfunction. Although there is
no DSM-5 criterion for delirium diagnosis denoting “clinically signifi­
cant distress or impairment,” these are invariant due to the global
neurocognitive disruption required for syndromal diagnosis [8]. The
construct of delirium humanizes the patient, complete with a deep well
of emotions and personality. Acute encephalopathy, on the other hand,
invites necessary biological considerations. It demands that we not lose
sight of disease processes, routine medical practice, and the potential
effectiveness of warranted biological interventions.
Empathy has been described as having three major subtypes:
emotional, cognitive, and compassionate [39]. Delirium can bias toward
emotional empathy: this allows the clinician to intuit the patient’s
emotional state but risks the contagion of negative emotions, leading to
clinician withdrawal or even clinical avoidance. Acute encephalopathy
creates space for cognitive empathy, which can facilitate “helping be­
haviors” but may also predispose to emotional distance or dehuman­
ization. Emotional and cognitive empathy are adaptive but biased;
however, a blend of both perspectives may well serve the greatest
foundation for compassionate empathy, which involves charitable re­
sponses guided by a combination of both legitimate concern and clinical
awareness.
5. The law of unintended consequences
Some delirium is preventable [2,40], and advocates of this message
encourage robust delirium prevention efforts. However, the message is
only partly correct, and when taught as the rule it can be misleading.
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General Hospital Psychiatry 74 (2022) 32–38
Only a minority of delirium is preventable—primarily in patients with
reduced cognitive reserve. Whereas delirium prevention should be
prioritized, most delirium will occur regardless of our best efforts, both
because a significant proportion of delirium is already present upon
arrival to clinical care (“prevalent delirium”) and because the neuro­
physiological effects of severe or critical illness are often not responsive
to current prevention bundles (thus, leading to “incident delirium”). A
real, unintended consequence of this message is that where delirium is
present, providers may be loath to identify or acknowledge it because it
could be interpreted as personal failure or poor medical practice.
On the other hand, the preventability of acute encephalopathy is
seldom considered per se; in fact, when it occurs in the hospital it is often
cordoned off as “hospital delirium,” especially when it is thought to be
attributable to iatrogenic causes. Consequently, clinicians who think in
terms of acute encephalopathy may presume impunity of practice
regarding acute neurocognitive syndromes. Such a mindset may even
embolden inappropriate practices, be it in terms of medication decisions
or lack of prevention efforts such as avoiding deliriogenic agents, early
ambulation, ensuring adequate oral intake, or tending to sensory deficits
(e.g., hearing aids or eyeglasses).
Whereas it may be impossible to identify which patients have been
spared from delirium by prevention efforts, such efforts will spare a
sizeable proportion. In the end, the axiom that delirium is preventable
needs to be modified so that it neither indiscriminately blames clinicians
when delirium occurs nor grants providers an exemption from
comprehensive efforts to prevent delirium.
6. Pharmacology and its discontents
Delirium guidelines routinely identify multicomponent non-
pharmacological interventions as first line for delirium (e.g., ambula­
tion, pain management, deprescribing) [41]. Such interventions have
been shown to prevent more than a third of delirium cases in cognitively
vulnerable populations [1]; however, studies have yet to show that they
improve delirium once it occurs. Although the individual interventions
subsumed in this category are heterogeneous, they all aim to promote
various aspects of physiology that support healthy cognition [23].
Non-pharmacological care bundles are especially well-described for
patients in geriatric and critical care settings, two settings in which the
term delirium is preferred [40,42]. The delirium preventive effect of
non-pharmacological approaches among older adults appears to be by
enhancing cognitive resilience and preventing iatrogenic insults
whereas delirium ICU bundles are likely to exert their effect principally
by limiting iatrogenic causes such as deliriogenic sedatives. Two other
settings, those in which the term acute encephalopathy is preferred, are
internal medicine and neurology [5]. In these settings, non-
pharmacological measures often meet with perfunctory implementa­
tion, if at all. Whereas most clinicians in these latter two settings are
generally aware of non-pharmacological approaches for delirium man­
agement, these approaches are seldom implemented, at times even
perceived as extraneous, despite evidence of their beneficial effects in
both settings.
Pharmacological approaches to delirium prevention or treatment are
often controversial. Those who tend to use the term delirium point to
systematic reviews that fail to find efficacy of antipsychotics for delirium
prevention or treatment [35,36], though the two small studies of que­
tiapine were notably positive [43,44]. However, those who think in
terms of acute encephalopathy are far more likely to consider medica­
tions as potentially meaningful interventions. Examples include lactu­
lose and rifaximin for hepatic encephalopathy, corticosteroids for
steroid-responsive encephalopathy associated with autoimmune
thyroiditis (historically, Hashimoto encephalopathy), physostigmine for
anticholinergic encephalopathy, or levocarnitine for valproate-induced
hyperammonemic encephalopathy. The idea that neuro­
pathophysiology may warrant pharmacological intervention is at the
very least suggested if not implied by the concept of acute
M.A. Oldham
encephalopathy. Whereas each patient population and underlying type
of delirium pathophysiology is likely to entail unique considerations,
there is a growing body of literature on pharmacological approaches to
delirium prevention including, for instance, dexmedetomidine [45] and
sleep-promoting agents [46–48].
A hybrid model of delirium and acute encephalopathy would posit
that non-pharmacological modalities deserve widespread implementa­
tion with the goal of targeting physiologically plausible mechanisms,
focusing preferentially on those patients at elevated cognitive risk and
considering the range of physiologically distinct deliria that exist. Spe­
cific populations may respond preferentially to certain non-
pharmacological interventions and not to others: the amount of time,
cost and clinical effort required to implement some of these in­
terventions requires that they be implemented in as tailored a fashion as
possible. It bears consideration that most non-pharmacological “in­
terventions” simply constitute humanistic care (e.g., failing to ensure a
patient can see and hear is substandard care in any setting), and many
patients will not receive delirium-prevention benefit from even the most
assertive of non-pharmacological approaches to care.
The question of pharmacology, though, remains fraught. It is curious
that some should have blanket concerns about medication management
of delirium, along with its behavioral and psychological symptoms,
especially given that medications are commonplace to manage the very
medical conditions that lead to delirium. Further, it is inconsistent to
suggest that somatic symptoms (e.g., nausea or pain) might merit
medication but psychological symptoms (e.g., distress or perceptual
disturbances) not. Future systematic reviews for delirium prevention
and treatment need to take a far more granular approach, differentiating
specific antipsychotics (which as a class have dramatically different
patterns of receptor binding affinity), specific physiologically defined
types of delirium, and specific behavioral and psychological symptoms.
Unless proven otherwise, it is scientifically unjustified to lump all
pharmacological agents, physiological types of delirium, and outcomes
together and then, based on the results from this apples-and-oranges
approach, conclude inefficacy.
7. Billing codes and reimbursement
The Medicare Severity Diagnosis Related Groups (MS-DRG) reim­
bursement disparity between delirium and acute encephalopathy is
striking. Specification is encouraged for both delirium and acute en­
cephalopathy, but at each level of specification acute encephalopathy is
designated as a higher complexity of illness. In many instances, a single
“major complication or comorbidity” (MCC) can result in $4000+ more
in reimbursement than a “complication or comorbidity” (CC) per
episode of care (Table 2). Whereas delirium implies an underlying acute
encephalopathy, it is never economically favorable in a US hospital to
code delirium over either metabolic or toxic encephalopathy. Coding
either metabolic or toxic encephalopathy—both designated “MCC”—is
currently necessary to capture the clinical complexity of this hospital
population accurately so that hospital outcomes are adjusted
accordingly.
Theoretically, elevating encephalopathy reimbursement over
delirium prioritizes management of neuropathophysiology. However, in
practice, acknowledging the presence of a non-descript toxic or meta­
bolic disturbance does not lead to better treatment; rather, it signals the
end of clinical reasoning as there are no defined “treatments” or clinical
pathways for toxic/metabolic encephalopathy per se. By contrast, clin­
ical pathways have been developed for delirium. Consequently, this
financial incentive for acute encephalopathy is paradoxically liable to
compromise care.
This reimbursement disparity frequently leads to less precise clinical
formulation as well. For instance, metabolic encephalopathy (MCC) is
less specific than a diagnosis of delirium due to acute kidney failure (CC)
because the latter specifies both a delirium-threshold level of neuro­
cognitive impairment (as opposed to the spectrum of states possible in
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General Hospital Psychiatry 74 (2022) 32–38
Table 2
Related diagnoses within 2020 centers for medicare and medicaid services,
medicare severity-diagnosis related groups (MS-DRGs).
Diagnosis Complexity
designation
Toxic encephalopathy (G92) MCC
Metabolic encephalopathy (G93.41) MCC
Coma (R40)b MCC
Unspecified (G93.40) or other (G93.49) encephalopathy CC
Delirium due to known physiological condition (F05) CC
Substance [x] use disorder [y] with intoxication delirium (F1x. CC
y21)
x: 0 (alcohol), 1 (opioid), 2 (cannabis), 3 (sedative, hypnotic,
or anxiolytic), 4 (cocaine), 5 (other stimulant), 6
(hallucinogen), 8 (inhalant), 9 (other psychoactive
substance
ya: 1 (abuse), 2 (dependence), 9 (unspecified)
Substance [x] use disorder [y] with withdrawal delirium (F1x. CC
y31)
x: 1 (alcohol), 3 (sedative, hypnotic, or anxiolytic), 9 (other
psychoactive substance)
y: 2 (dependence), 9 (unspecified)b
Delirium not otherwise specified (R41.0)c Neither
Altered mental status (R41.82)c Neither
Abbreviations: CC, complication or comorbidity; MCC, major complication or
comorbidity.
a
Recognized patterns of use vary based on the psychoactive substance.
b
Unspecified use pattern applies only to “other psychoactive substance”.
c
Note the stark disparity between symptom codes: coma is designated MCC
whereas delirium not otherwise specified and altered mental status have no
complexity designation.
acute encephalopathy, as in Fig. 1) and implicates a specific etiology.
More importantly, the current US Centers for Medicare and Medicaid
Services incentive structure disparages psychological considerations. A
clinician needs only to acknowledge that a patient’s mental state is
altered (e.g., “confused,” “reduced arousal,” “disoriented” [49]) without
considering its severity, characterizing specific symptoms, assessing for
concerning behaviors, or evaluating a patient’s level of distress.
There is no justifiable reason whatsoever that specified delirium
diagnoses should be considered of lesser complexity than the corre­
sponding codes for acute encephalopathy. The MS-DRG designations for
these two conditions should be aligned. One might propose a harmo­
nized approach to re-design the coding structure to reflect the comple­
mentarity of these two clinical entities. Every code for acute
encephalopathy should require mental status specification (e.g., meta­
bolic encephalopathy with coma, toxic encephalopathy with delirium,
or unspecified encephalopathy with delirium), just as codes for delirium
specify underlying cause (e.g., subsyndromal delirium due to hepatic
encephalopathy, delirium due to Streptococcus pneumoniae pneumonia,
or coma due to opioid intoxication). Assuming physiological subtypes of
delirium become identifiable, these would ideally be specified as well.
An additional billing-related issue specific to Evaluation and Man­
agement (E&M) services rendered by psychiatrists is that delirium
diagnosis, which are F-series codes (i.e., Mental, Behavioral and Neu­
rodevelopmental Disorders) require that the cause (non-F-series codes)
be listed first. For most insurances, this is inconsequential; however,
some mental health carve-out insurances require psychiatrists to use an
F-series code as the primary diagnosis for E&M service reimbursement.
This means that psychiatrists involved in the care of patients with such a
mental health carve-out insurance plan receive no compensation if the
only diagnosable condition is delirium (i.e., prior to the current
delirium, given that a cross-sectional diagnosis of delirium excludes
primary psychiatric diagnoses), which would require a non-F-series code
first. Notably, too, acute encephalopathies are G-series codes (Table 2).
8. Delirium disorder and the mind–brain system
Each model and the distinctions between them are important and
M.A. Oldham
instructive, but even in sum they are incomplete. What the field needs is
a holistic model of acute neurocognitive syndromes—one that unifies
delirium and acute encephalopathy and, while doing so, suggests po­
tential avenues for novel insights. It was along these lines that the
recently described model of delirium disorder was conceived, to
describe a plurality of biologically distinct states whose various patho­
physiological disturbances converge downstream to the final common
pathway of critical brain network disruption, leading to a set of equifinal
delirium-spectrum phenotypes [50,51] (Fig. 2). Within this model,
delirium and acute encephalopathy are understood as necessary
complements.
The model involves four interactive elements.
1. Cognitive resilience: Baseline biopsychosocial factors are necessary
to promote healthy cognitive function (“pro-cognitive factors”), and,
in aggregate, they influence delirium risk. These factors are variably
modifiable: some, such as extent of cerebrovascular disease or car­
diac output, may be largely resistant to acute interventions whereas
others, such as nutritional status and sleep/wake integrity, may be
readily modified. The fact that these include both biological and
psychosocial domains implies a role for both pharmacological and
non-pharmacological interventions to prevent and treat delirium.
2. Delirium: This describes the index features [52] of the delirium
phenotype as operationalized in various nosologies (DSM-5 and ICD-
10) and clinical instruments (family of CAM instruments, 4-AT). The
mental status of delirium represents a convergent syndrome, indi­
cating dysfunction of critical brain networks [9]. It has both index
diagnostic features (per DSM-5: acute change in mentation charac­
terized by disturbances in attention, awareness, and at least one
additional cognitive domain) and a host of associated neuropsychi­
atric features. These “behavioral and psychological symptoms of
delirium” are analogous to “behavioral and psychological symptoms
of dementia” and include symptoms such as impulsivity, emotional
dysregulation, abulia, delusions, hallucinations, agitation, akathisia,
sundowning, or catatonia [53].
3. Neuropathophysiology: Delirium disorder proposes that biologi­
cally discrete “rivulets” of neuropathophysiology converge down­
stream to the “river” of critical network dysfunction. Preliminary
lists of these subtypes have been published previously [23,50] and
await further validation. It also awaits to be shown how these
pathophysiological subtypes interrelate with one another and ulti­
mately lead to downstream effects. Notably, this suggests that
biomarker research should differentiate between markers generic to
the delirium-spectrum phenotype (e.g., functional imaging and EEG
studies), which likely reflect network disintegration [9], from those
that may define specific pathophysiological subtypes—along the
Fig. 2. Delirium disorder.
Contingent causal pathways are illustrated by arrows.
36
General Hospital Psychiatry 74 (2022) 32–38
lines of the recent systems integration failure hypothesis by Maldo­
nado [17].
4. Underlying cause(s): Often categorized into mnemonics (e.g., I
WATCH DEATH, PINCH ME DELRIUM[S], Dr. DRE, END ACUTE
BRAIN FAILURE NOW), the list of individual conditions that pre­
cipitate delirium is extensive. Modifiable precipitants should be
treated assertively, though precipitants should be differentiated from
downstream effects (e.g., hyperammonemia vs downstream
glutamine-related neuronal swelling in hepatic encephalopathy;
blood-borne infection vs dysregulated clotting affecting cerebral
vasculature in sepsis-associated encephalopathy; antibodies target­
ing N-methyl-D-aspartate receptors vs effectuated neuronal excito­
toxicity in anti-NMDA receptor antibody encephalitis). Defining the
hallmark patterns of neurophysiological disruptions for specific
causes of delirium would ideally allow for upstream and downstream
inferences.
The delirium disorder model draws several insights from the model
of delirium. First, it employs delirium’s intuitive approach to case
identification by recognizing the delirium-spectrum phenotype, the sine
qua non of the broader set of acute neurocognitive syndromes (n.b., one
may conceive of coma either as being on the extreme end of this
delirium-spectrum or a categorically distinct state). The operationalized
delirium phenotype has good reliability, validity, and clinical utility
[49]. A defined clinical phenotype allows for systematic screening and
enables prevention efforts because the outcome(s) of interest can be
assessed empirically. This fact also deliberately prioritizes the patient’s
mental state, thereby centralizing the patient’s experiences, psycho­
logical concerns and wishes. Overall, it honors the patient as a person
and facilitates person-centered care.
Delirium disorder also incorporates insights from acute encepha­
lopathy. Foremost, and in line with the model of delirium, acute en­
cephalopathy emphasizes the underlying cause(s) of the acute
neurocognitive disturbance. However, unlike delirium, the unique
models of acute encephalopathy that are specific to etiology (e.g., he­
patic encephalopathy, septic encephalopathy) allow for detailed char­
acterization of not only the proximal precipitants, which are
occasionally identified simply as an academic exercise, but also the
downstream pathophysiology. This type of mechanistic approach is
necessary to eliciting distinct physiological disturbances and defining
novel treatment targets.
The models of delirium and acute encephalopathy must be bridged if
we are to have a coherent approach to this shared set of conditions. Such
an endeavor is necessary to inform gainful research and to facilitate
effective healthcare delivery. Delirium disorder offers such a unified
approach: beyond capitalizing on the insights of both delirium and acute
encephalopathy, it provides a variety of additional benefits in concep­
tualizing acute neurocognitive syndromes and expanding upon their
clinical management.
1. This model univocally differentiates delirium—the phenotype—from
delirium disorder—the diagnostic construct. This is important
because the word delirium is commonly used indiscriminately to
describe three distinct but related ideas: the phenotype, the disorder,
and, at times, specifically the hyperactive motoric subtype of
delirium [54–56].
2. Recognizing that “not all deliria are created equal,” this model posits
multiple distinct pathophysiological types. That is, there are many
routes that lead to the disruption of critical brain networks (e.g.,
anesthesia, intoxicated states, sepsis, uremia, anticholinergic effect),
and not all of them are equally or even necessarily pathogenic. As
such, the delirium phenotype should be understood as important both
as a herald and for its associated behavioral and psychological
symptoms but perhaps epiphenomenal in relation to
neuropathology.
M.A. Oldham
3. The model acknowledges that delirium phenotype implies underlying
encephalopathy and, as a result, encourages the characterization of
pathophysiology even—or especially—in the absence of a known,
treatable proximal precipitant. Efficacious treatments of specific
pathophysiological disturbances would transform clinical practice,
such as when the original cause is ambiguous, elusive, not readily
reversible, historical (e.g., surgery or traumatic brain injury), or
already resolved. The availability of such interventions could upend
the standard watchful waiting approach.
4. It predicts causal contingencies within the disorder. It suggests that
many of these relationships may be necessary but insufficient. It also
hints at how factors that are often perceived to be “strictly psycho­
logical” may contribute mechanistically to delirium neuro­
pathophysiology by way of psychophysiological disturbances.
5. Clinically, delirium disorder offers a broader palette of treatment
targets. Rather than focusing solely on underlying causes, this model
differentiates delirium (phenotype) along with its behavioral and
psychological symptoms, pathophysiology, precipitants, and pro-
cognitive factors.
9. Reflections
As characterized in the model of delirium disorder, the relationship
between delirium (phenotype) and acute encephalopathy (pathobi­
ology) mirrors the relationship between the mind and the brain, and the
tension between them is emblematic of the perennial mind/brain
problem. Yet the very nature of acute neurocognitive syndromes, in
which the affected person’s thinking is muddled, has projected itself into
our muddled thinking about this set of conditions. As a proposal to
integrate these two disparate models into one, delirium disorder sug­
gests that their historical non-union could be due to an omission com­
mon to both: namely, a set of discrete pathophysiological subtypes
underlying the convergent delirium phenotype and spanning various
subsets of proximal precipitants.
The mind–brain system has been slow to divulge its secrets, yet
several aspects of this set of conditions are clear. Among these are that
the delirium-spectrum phenotype implies an underlying acute enceph­
alopathy. Acute encephalopathy is no more serious a condition than the
multi-physiological construct indexed by the delirium phenotype. This
set of acute neurocognitive syndromes—both in its immediate and, far
more importantly, long-term effects [57]—demands a coherent clinical
approach. Ultimately, we need clinical pathways that are triggered in
response to the convergent delirium-spectrum phenotype while simul­
taneously pursuing interventions that target specific neurophysiological
disturbances. The tension between the pulls for unity and diversity must
be harmonized to provide effective care to the patients plagued by this
confusing syndrome of confusion.
Funding
This work received no funding.
Disclosures
The authors report no proprietary or commercial interest in any
product mentioned or concept discussed in this article.
Acknowledgements
The author is indebted to Arjen Slooter and E. Wes Ely for their
thoughtful comments on this manuscript and whose work on this topic
has served as a personal inspiration.
37
General Hospital Psychiatry 74 (2022) 32–38
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