4  Delirium

Mario F. Mendez, Claudia R. Padilla

CHAPTER OUTLINE Despite this long history, physicians, nurses, and other cli-
nicians often fail to diagnose delirium (Wong et al., 2010),
and up to two-thirds of delirium cases go undetected or mis-
CLINICAL CHARACTERISTICS diagnosed (O’Hanlon et al., 2014). Healthcare providers often
Acute Onset with Fluctuating Course miss this syndrome more from lack of recognition than mis-
Cognitive and Related Abnormalities diagnosis. The elderly in particular may have a “quieter,” more
Behavioral and Emotional Abnormalities subtle presentation of delirium that may evade detection.
PATHOPHYSIOLOGY Adding to the confusion about delirium are the many terms
used to describe this disorder: acute confusional state, altered
DIAGNOSIS mental status, acute organic syndrome, acute brain failure,
Predisposing and Precipitating Factors acute brain syndrome, acute cerebral insufficiency, exogenous
Mental Status Examination psychosis, metabolic encephalopathy, organic psychosis, ICU
Diagnostic Scales and Criteria psychosis, toxic encephalopathy, toxic psychosis, and others.
Physical Examination Clinicians must take care to distinguish delirium from
Laboratory Tests dementia, the other common disorder of cognitive function-
ing. Delirium is acute in onset (usually hours to a few days)
DIFFERENTIAL DIAGNOSIS whereas dementia is chronic (usually insidious in onset and
Common Causes of Delirium progressive). The definition of delirium must emphasize an
Special Problems in Differential Diagnosis acute behavioral decompensation with fluctuating attention,
PREVENTION AND MANAGEMENT regardless of etiology or the presence of baseline cognitive
deficits or dementia. Complicating this distinction is the fact
PROGNOSIS that underlying dementia is a major risk factor for delirium.
Clinicians must also take care to define the terms used with
delirium. Attention is the ability to focus on specific stimuli to
the exclusion of others. Awareness is the ability to perceive or
Delirium is an acute mental status change characterized by be conscious of events or experiences. Arousal, a basic prereq-
abnormal and fluctuating attention. There is a disturbance in uisite for attention, indicates responsiveness or excitability
level of awareness and reduced ability to direct, focus, sustain, into action. Coma, stupor, wakefulness, and alertness are states
and shift attention (APA, 2013). These difficulties additionally of arousal. Consciousness, a product of arousal, means clarity
impair other areas of cognition. The syndrome of delirium can of awareness of the environment. Confusion is the inability for
be a physiological consequence of a medical condition or stem clear and coherent thought and speech.
from a primary neurological cause.
Delirium is by far the most common behavioral disorder CLINICAL CHARACTERISTICS
in a medical-surgical setting. In general hospitals, the preva-
lence ranges from 15% to 24% on admission. The incidence The essential elements of delirium are summarized in Boxes
ranges between 6% and 56% of hospitalized patients, 11% to 4.1 and 4.2. Among the revised American Psychiatric Associa-
51% postoperatively in elderly patients, and 80% or more of tion’s criteria (APA, 2013) for this disorder is a disturbance
intensive care unit (ICU) patients (Alce et al., 2013; Inouye that develops over a short period of time; tends to fluctuate;
et al., 2014). The consequences of delirium are serious: they and impairs awareness, attention, and other areas of cogni-
include prolonged hospitalizations, increased mortality, high tion. In general, awareness, attention, and cognition fluctuate
rates of discharges to other institutions, severe impact on care­ over the course of a day. Furthermore, delirious patients have
givers and spouses, and between $143 billion and $152 billion disorganized thinking and an altered level of consciousness,
annually in direct healthcare costs in the United States (Kerr perceptual disturbances, disturbance of the sleep/wake cycle,
et al, 2013; Leslie and Inouye, 2011). increased or decreased psychomotor activity, disorientation,
Physicians have known about this disorder since antiquity. and memory impairment. Other cognitive, behavioral, and
Hippocrates referred to it as phrenitis, the origin of our word emotional disturbances may also occur as part of the spectrum
frenzy. In the first century AD, Celsus introduced the term of delirium. Delirium can be summarized into the 10 clinical
delirium, from the Latin for “out of furrow,” meaning derail- characteristics that follow.
ment of the mind, and Galen observed that delirium was
often due to physical diseases that affected the mind “sympa-
thetically.” In the nineteenth century, Gowers recognized that
Acute Onset with Fluctuating Course
these patients could be either lethargic or hyperactive. Bonho- Delirium develops rapidly over hours or days, but rarely over
effer, in his classification of organic behavioral disorders, more than a week, and fluctuations in the course occur
established that delirium is associated with clouding of con- throughout the day. There are lucid intervals interspersed with
sciousness. Finally, Engel and Romano (1959) described the daily fluctuations. Gross swings in attention and aware-
alpha slowing with delta and theta intrusions on electroen- ness, arousal, or both occur unpredictably and irregularly and
cephalograms (EEGs) and correlated these changes with clini- become worse at night. Because of potential lucid intervals,
cal severity. They noted that treating the medical cause medical personnel may be misled by patients who exhibit
resulted in reversal of both the clinical and EEG changes of improved attention and awareness unless these patients are
delirium. evaluated over time.
23
24 PART I  Common Neurological Problems

BOX 4.1  Clinical Characteristics of Delirium Cognitive and Related Abnormalities

Attentional Deficits
Acute onset of mental status change with fluctuating course
Attentional deficits A disturbance of attention and consequent altered awareness
Confusion or disorganized thinking is the cardinal symptom of delirium. Patients are distractible,
Altered level of consciousness and stimuli may gain attention indiscriminately, trivial ones
Perceptual disturbances often getting more attention than important ones. All compo-
Disturbed sleep/wake cycle nents of attention are disturbed, including selectivity, sustain-
Altered psychomotor activity ability, processing capacity, ease of mobilization, monitoring
Disorientation and memory impairment of the environment, and the ability to shift attention when
Other cognitive deficits necessary. Although many of the same illnesses result in a
Behavioral and emotional abnormalities spectrum of disturbances from mild inattention to coma,
delirium is not the same as disturbance of arousal.

BOX 4.2  DSM-5 Diagnostic Criteria: Delirium*

A. A disturbance in attention (i.e. reduced ability to direct, focus, Criteria A and C predominate in the clinical picture and when
sustain, and shift attention) and awareness (reduced orientation they are sufficiently severe to warrant clinical attention.
to the environment). • Coding note: The ICD-9-CM and ICD-10CM codes for the
B. The disturbance develops over a short period of time (usually [specific substance] intoxication delirium are indicated in the
hours to a few days), represents a change from baseline table below. Note that the ICD-10-CM code depends on
attention and awareness, and tends to fluctuate in severity whether or not there is a comorbid substance use disorder
during the course of a day. present for the same class of substance. If a mild substance
C. An additional disturbance in cognition (e.g., memory deficit, use disorder is comorbid with the substance intoxication
disorientation, language, visuospatial ability, or perception). delirium, the 4th position character is “1,” and the clinician
D. The disturbances in Citeria A and C are not better explained by should record “mild [substance] use disorder,” before the
another pre-existing, established, or evolving neurocognitive substance intoxication delirium (e.g., “mild cocaine use
disorder and do not occur in the context of a severely reduced disorder is comorbid with the substance intoxication delirium”).
level of arousal, such as coma. If a moderate or severe substance use disorder is comorbid
E. There is evidence from the history, physical examination, or with the substance intoxication delirium, the 4th position
laboratory findings that the disturbance is a direct physiological character is “2,”and the clinician should record “moderate
consequence of another medical condition, substance [substance] use disorder” or “severe [substance] use
intoxication or withdrawal (i.e., due to a drug of abuse or to a disorder,” depending on the severity of the comorbid
medication), or exposure to a toxin, or is due to multiple substance use disorder. If there is no comorbid substance
etiologies. use disorder (e.g., after a one0time heavy use of the
Specify whether: substance), then the 4th position character is “9,”and the
clinician should record only the substance intoxication
Substance intoxication delirium: This diagnosis should be delirium.
made isntaed of substance intoxication when the symptoms in

ICD-10-CM
With use With use disorder, Without use
ICD-9-CM disorder, mild moderate or severe disorder
Alcohol 291.0 F10.121 F10.221 F10.921
Cannabis 292.81 F12.121 F12.221 F12.921
Phencyclidine 292.81 F16.121 F16.221 F16.921
Other hallucinogen 292.81 F16.121 F16.221 F16.921
Inhalent 292.81 F18.221 F18.221 F18.921
Opiod 292.81 F11.121 F11.221 F11.921
Sedative, hypnotic, or anxiolytic 292.81 F13.121 F13.221 F13.921
Amphetamine (or other stimulant) 292.81 F15.121 F15.221 F15.921
Cocaine 292.81 F14.121 F14.221 F14.921
Other (or unknown) substance 292.81 F19.221 F19.221 F19.921

Substance withdrawal delirium: This diagnosis should be made • Coding note: The ICD-9-CM code for [specific medication]-
instead of substance withdrawal when the symptoms in Criteria induced delirium is 292.81. The ICD-10-CM code depends on
A and C predominate in the clinical picture and when they are the type of medication. If the medication is an opioid taken
sufficiently severe to warrant clinical attention. as prescribed, the code is F11.921. If the medication is a
• Code [specific substance] withdrawal delirium: 291.0 sedative, hypnotic, or anxiolytic taken as prescribed, the code
(F10.231) alcohol; 292.0 (F11.23) opioid; 292.0 (F13.231) is F13.921. If the medication is an amphetamine-type or other
sedative, hypnotic, or anxiolytic; 292.0 (F19.231) other (or stimulant taken as prescribed, the code is F15.921. For
unknown) substance/medication. medications that do not fit into any of the classes (e.g.,
Medication-induced delirium: This diagnosis applies when the dexamethasone) and in cases in which a substance is judged
sympotoms in Criteria A and C arise as a side effect of a to be an etiological factor but the specific class of substance
medication taken as prescribed. is unknown, the code is F19.921.
 Delirium 25

BOX 4.2  DSM-5 Diagnostic Criteria: Delirium (Continued) 4

293.0 (F05) Delirium due to another medical condition: There encephalopathy, 293.0 [F05] delirium due to hepatic failure;
is evidence from the history, physical examination, or laboratory 291/0 [F10.231] alcohol withdrawal delirium). Note that the
findings that the disturbance is attributable to the physiological etiological medical condition both appears as a separate code
consequences of another medical condition. that precedes the delirium code and is substituted into the
• Coding note: Use multiple spate codes reflecting specific delirium due to another medical condition rubric.
delirium etiologies (e.g., 572.2 [K72.90] hepatic Specify if:
encephalopathy, 293.0 [F05] delirium due to hepatic
Acute: Lasting a few hours or days.
encephalopathy). The other medical condition should also be
Persistent: lasting weeks or months.
coded and listed separately immediately before the delirium
due to another medical condition (e.g., 572.2 [K72.90] hepatic Specify if:
encephalopathy; 293.0 [F05] delirium due to hepatic Hyperactive: The individual has a hyperactive level of
encephalopathy). psychomotor activity that may be accompanied by mood lability,
293.0 (F05) Delirium due to multiple etiologies: agitation, and/or refusal to cooperate with medical care.
There is evidence from the history physical examination, or Hypoactive: The individual has a hypoactive level of psychomotor
laboratory findings that the delirium has more than one etiology activity that may be accompanied by sluggishness and lethargy
(e.g., more than one etiological medical condition; another that approaches stupor.
medical condition plus substance intoxication or medication side Mixed level of activity: The individual has a normal level of
effect). psychomotor activity even though attention and awareness are
• Coding note: Use multiple separate codes reflecting disturbed. Also includes individuals whose activity level rapidly
specific delirium etiologies (e.g., 572.2 [K72.90] hepatic fluctuates.

Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (© 2013). American Psychiatric Association.

*Previously referred to in DSM-IV as “dementia, delirium, amnestic, and other cognitive disorders.”
Note: The following supportive features are commonly present in delirium but are not key diagnostic features: sleep/wake cycle disturbance, psychomotor
disturbance, perceptual disturbances (e.g., hallucinations, illusions), emotional disturbances, delusions, labile affect, dysarthria, and EEG abnormalities
(generalized slowing of background activity).

Confusion or Disorganized Thinking those in the hyperactive subtype. They are most common in
the visual sphere and are often vivid, three-dimensional, and
Delirious patients are unable to maintain the stream of in full color. Patients may see lilliputian animals or people
thought with accustomed clarity, coherence, and speed. There that appear to move about. Hallucinations are generally
are multiple intrusions of competing thoughts and sensations, unpleasant, and some patients attempt to fight them or run
and patients are unable to order symbols, carry out sequenced away with fear. Some hallucinatory experiences may be release
activity, and organize goal-directed behavior. phenomena, with intrusions of dreams or visual imagery into
The patient’s speech reflects this jumbled thinking. Speech wakefulness. Psychotic auditory hallucinations with voices
shifts from subject to subject and is rambling, tangential, and commenting on the patient’s behavior are unusual.
circumlocutory, with hesitations, repetitions, and persevera-
tions. Decreased relevance of the speech content and decreased Disturbed Sleep/Wake Cycle
reading comprehension are characteristic of delirium. Con-
fused speech is further characterized by an abnormal rate, Disruption of the day/night cycle causes excessive daytime
frequent dysarthria, and nonaphasic misnaming, particularly drowsiness and reversal of the normal diurnal rhythm.
of words related to stress or illness, such as those referable to “Sundowning”—with restlessness and confusion during the
hospitalization. night—is common, and delirium may be manifest only at
night. Nocturnal peregrinations can result in a serious problem
when the delirious patient, partially clothed in a hospital
Altered Level of Consciousness gown, has to be retrieved from the hospital lobby or from the
Consciousness, or clarity of awareness, may be disturbed. Most street in the middle of the night. This is one of the least specific
patients have lethargy and decreased arousal. Others, such as symptoms and also occurs in dementia, depression, and other
those with delirium tremens, are hyperalert and easily aroused. behavioral conditions. In delirium, however, disruption of
In hyperalert patients, the extreme arousal does not preclude circadian sleep cycles may result in rapid eye movement or
attentional deficits because patients are indiscriminate in their dream-state overflow into waking.
alertness, are easily distracted by irrelevant stimuli, and cannot
sustain attention. The two extremes of consciousness may Altered Psychomotor Activity
overlap or alternate in the same patient or may occur from the
There are three subtypes of delirium, based on changes in
same causative factor.
psychomotor activity. The hypoactive subtype is characterized
by psychomotor retardation. These are the patients with leth-
Perceptual Disturbances argy and decreased arousal. The hyperactive subtype is usually
The most common perceptual disturbance is decreased per- hyperalert and agitated, and has prominent overactivity of the
ceptions per unit of time; patients miss things that are going autonomic nervous system. Moreover, the hyperactive type is
on around them. Illusions and other misperceptions result more likely to have delusions and perceptual disorders such
from abnormal sensory discrimination. Perceptions may be as hallucinations. About half of patients with delirium mani-
multiple, changing, or abnormal in size or location. Halluci- fest elements of both subtypes, called mixed subtype, alternat-
nations also occur, particularly in younger patients and in ing between hyperactive and hypoactive. Only about 15% are
26 PART I  Common Neurological Problems

strictly hyperactive. In addition to the patients being younger,

the hyperactive subtype has more drug-related causes, a shorter
hospital stay, and a better prognosis.

Disorientation and Memory Impairment

FINISHING
Disturbances in orientation and memory are related. Patients
are disoriented first to time of day, followed by other aspects
of time, and then to place. They may perceive abnormal jux-
tapositions of events or places. Disorientation to person—in
the sense of loss of personal identity—is rare. Disorientation
is one of the most common findings in delirium but is not
specific for delirium; it occurs in dementia and amnesia as
well. Among patients with delirium, recent memory is dis-
rupted in large part by the decreased registration caused by
attentional problems.
In delirium, reduplicative paramnesia, a specific memory-
related disorder, results from decreased integration of recent
observations with past memories. Persons or places are
“replaced” in this condition. In general, delirious patients tend
PRESIDENT (top is cursive, bottom is printing)
to mistake the unfamiliar for the familiar. For example, they
tend to relocate the hospital closer to their homes. In a form
of reduplicative paramnesia known as Capgras syndrome,
however, a familiar person is mistakenly thought to be an
unfamiliar impostor.

Other Cognitive Deficits

Disturbances occur in visuospatial abilities and in writing.
Higher visual-processing deficits include difficulties in visual
object recognition, environmental orientation, and organiza-
tion of drawings and other constructions.
IF HE IS NOT CAREFUL, THE STOOL WILL FALL.
Writing disturbance may be the most sensitive language
abnormality in delirium. The most salient characteristics are Fig. 4.1  Writing disturbances in delirium. Patients were asked to
abnormalities in the mechanics of writing: The formation of write indicated words to dictation. (Reprinted with permission from
letters and words is indistinct, and words and sentences sprawl Chédru, J., Geschwind, N., 1972. Writing disturbances in acute con-
in different directions (Fig. 4.1). There is a reluctance to write, fusional states. Neuropsychologia 10, 343–353.)
and there are motor impairments (e.g., tremors, micrographia)
and spatial disorders (e.g., misalignment, leaving insufficient
space for the writing sample). Sometimes the writing shows the elderly, in whom decreased activities of daily living,
perseverations of loops in aspects of the writing. Spelling and urinary incontinence, and frequent falls are among the major
syntax are also disturbed, with spelling errors particularly manifestations of this disorder.
involving consonants, small grammatical words (prepositions
and conjunctions), and the last letters of words. Writing is easily PATHOPHYSIOLOGY
disrupted in these disorders, possibly because it depends on
multiple components and is the least used language function. The pathophysiology of delirium is not entirely understood,
but it depends on widely distributed neurological dysfunction.
Delirium is the final common pathway of many pathophysi-
Behavioral and Emotional Abnormalities ological disturbances that reduce or alter cerebral oxidative
Behavioral changes include poorly systematized delusions, metabolism. These metabolic changes result in diffuse impair-
often with persecutory and other paranoid ideation and per- ment in multiple neuronal pathways and systems.
sonality alterations. Delusions, like hallucinations, are prob- Several brain areas involved in attention are particularly
ably release phenomena and are generally fleeting, changing, disturbed in delirium. Dysfunction of the anterior cingulate
and readily affected by sensory input. These delusions are cortex is involved in disturbances of the management of atten-
most often persecutory. Some patients exhibit facetious humor tion (Reischies et al., 2005). Other areas include the bilateral
and playful behavior, lack of concern about their illness, poor or right prefrontal cortex in attentional maintenance and
insight, impaired judgment, and confabulation. executive control, the temporoparietal junction region in dis-
There can be marked emotional lability. Sometimes patients engaging and shifting attention, the thalamus in engaging
are agitated and fearful or depressed or quite apathetic. Dys- attention, and the upper brainstem structures in moving the
phoric (unpleasant) emotional states are the more common, focus of attention. The thalamic nuclei are uniquely posi-
and emotions are not sustained. Up to half of elderly delirious tioned to screen incoming sensory information, and small
patients display symptoms of depression with low mood, loss lesions in the thalamus may cause delirium. In addition, there
of interests, fatigue, decreased appetite and sleep, and other is evidence that the right hemisphere is dominant for atten-
feelings related to depression. There may be mood-congruent tion. Cortical blood flow studies suggest that right hemisphere
delusions and hallucinations. The mood changes of delirium cortical areas and their limbic connections are the “attentional
are probably due to direct effects of the confusional state on gate” for sensory input through feedback to the reticular
the limbic system and its regulation of emotions. nucleus of the thalamus.
Finally, more elementary behavioral changes may be the Another explanation for delirium is alterations in neuro-
principal symptoms of delirium. This is especially the case in transmitters, particularly a cholinergic-dopaminergic imbalance.
 Delirium 27

There is extensive evidence for a cholinergic deficit in delirium

(Alce et al., 2013). Anticholinergic agents can induce the BOX 4.3  Predisposing and Precipitating Factors 4
clinical and EEG changes of delirium, which are reversible for Delirium
with the administration of cholinergic medications such as
• Elderly, especially 80 years or older
physostigmine. The beneficial effects of donepezil, rivastig-
• Dementia, cognitive impairment, or other brain disorder
mine, and galantamine—acetylcholinesterase-inhibitor medi-
• Fluid and electrolyte disturbances and dehydration
cations used for Alzheimer disease—may be partly due to an
• Other metabolic disturbance, especially elevated BUN level or
activating or attention-enhancing role. Moreover, cholinergic
hepatic insufficiency
neurons project from the pons and the basal forebrain to the
• Number and severity of medical illnesses including cancer
cortex and make cortical neurons more responsive to other
• Infections, especially urinary tract, pulmonary, and AIDS
inputs. A decrease in acetylcholine results in decreased per-
• Malnutrition, low serum albumin level
fusion in the frontal cortex. Hypoglycemia, hypoxia, and other
• Cardiorespiratory failure or hypoxemia
metabolic changes may differentially affect acetylcholine-
• Prior stroke or other nondementia brain disorder
mediated functions. Other neurotransmitters may be involved
• Polypharmacy and use of analgesics, psychoactive drugs, or
in delirium, including dopamine, serotonin, norepinephrine,
anticholinergics
γ-aminobutyric acid, glutamine, opiates, and histamine.
• Drug abuse, alcohol or sedative dependency
Dopamine has an inhibitory effect on the release of acetylcho-
• Sensory impairment, especially visual
line, hence the delirium-producing effects of L-dopa and other
• Sensory overstimulation and “ICU psychosis”
anti-parkinsonism medications (Martins and Fernandes, 2012;
• Sensory deprivation
Trzepacz and van der Mast, 2002). Opiates may induce the
• Sleep disturbance
effects by increasing dopamine and glutamate activity. Poly-
• Functional impairment
morphisms in genes coding for a dopamine transporter and
• Fever, hypothermia
two dopamine receptors have been associated with the devel-
• Physical trauma or severe burns
opment of delirium (van Munster et al., 2010).
• Fractures
Inflammatory cytokines such as interleukins, interferon,
• Male gender
and tumor necrosis factor alpha (TNF-α) may contribute to
• Depression
delirium by altering blood–brain barrier permeability and
• Specific surgeries:
further affecting neurotransmission (Cole, 2004; Fong et al.,
• Cardiac, especially open heart surgery
2009; Inouye, 2006; Martins and Fernandes, 2012). The com-
• Orthopedic, especially femoral neck and hip fractures,
bination of inflammatory mediators and dysregulation of the
bilateral knee replacements
limbic–hypothalamic–pituitary axis may lead to exacerbation
• Ophthalmological, especially cataract surgery
or prolongation of delirium (Maclullich et al., 2008; Martins
• Noncardiac thoracic surgery and aortic aneurysmal repairs
and Fernandes, 2012). Finally, secretion of melatonin, a
• Transurethral resection of the prostate
hormone integral to circadian rhythm and the sleep/wake
cycle, may be abnormal in delirious patients compared to AIDS, Acquired immunodeficiency syndrome; BUN, blood urea nitrogen;
those without delirium (Fitzgerald et al., 2013). ICU, intensive care unit.

DIAGNOSIS
Diagnosis is a two-step process. The first step is the recognition predispose to delirium: vision impairments (<20/70 binocu-
of delirium, which requires a thorough history, a bedside lar), severity of illness, cognitive impairment, and dehydra-
mental status examination focusing on attention, and a review tion (high ratio of blood urea to creatinine) (Inouye, 2006).
of established diagnostic scales or criteria for delirium. The Among these, cognitive impairment or dementia is worth
second step is to identify the cause from a large number of emphasizing. Elderly patients with dementia are five times
potential diagnoses. Because the clinical manifestations offer more likely to develop delirium than those without demen-
few clues to the cause, crucial to the differential diagnosis are tia and it is associated with increased cognitive decline,
the general history, physical examination, and laboratory admission to institutions, and mortality (Elie et al., 1998;
assessments. Inouye et al., 2014). Patients with dementia may develop
The general history assesses several elements. An abrupt delirium after minor medication changes or other relatively
decline in mentation, particularly in the hospital, should be insignificant precipitating factors (Inouye et al., 2014). More-
presumed to be delirium. Although patients may state that over, premorbid impairment in executive functions may be
they cannot think straight or concentrate, family members or independently associated with greater risk of developing
other good historians should be available to describe the delirium (Rudolph et al., 2006). Other important predispos-
patient’s behavior and medical history. The observer may have ing factors for delirium are advanced age, especially older
noted early symptoms of delirium such as inability to perform than 80 years, and the presence of chronic medical illnesses
at a usual level, decreased awareness of complex details, (Johnson, 2001). Many of these elderly patients predisposed
insomnia, and frightening or vivid dreams. It is crucial to to delirium have cerebral atrophy or white matter and basal
obtain accurate information about systemic illnesses, drug use, ganglia ischemic changes on neuroimaging. Additional pre-
recent trauma, occupational and environmental exposures, disposing factors are the degree of physical impairment, hip
malnutrition, allergies, and any preceding symptoms leading and other bone fractures, serum sodium changes, infections
to delirium. Furthermore, the clinician should thoroughly and fevers, and the use of multiple drugs, particularly those
review the patient’s medication list. with narcotic, anticholinergic, or psychoactive properties.
The predisposing factors for delirium are additive, each new
factor increasing the risk considerably. Moreover, frail elderly
Predisposing and Precipitating Factors patients often have multiple predisposing factors, the most
The greater the number of predisposing factors, the fewer or common being functional dependency, multiple medical
milder are the precipitating factors needed to result in delir- comorbidities, depression, and polypharmacy (Laurila et al.,
ium (Anderson, 2005) (Box 4.3). Four factors independently 2008).
28 PART I  Common Neurological Problems

In most cases, the cause of delirium is multifactorial, result- three-step motor sequence (palm-side-fist), which is also a test
ing from the interaction between patient-specific predisposing of frontal functions. These attentional tests are not overly
factors and multiple precipitating factors (Inouye et al., 2014; sensitive or specific, and they can be affected by the patient’s
Inouye and Charpentier, 1996; Laurila et al., 2008). Five spe- educational background, degree of effort, or presence of other
cific factors that can independently precipitate delirium are cognitive deficits. In sum, the best assessment of attention may
use of physical restraints, malnutrition or weight loss (albumin be general behavioral observations and an appraisal of how
levels less than 30 g/L), use of indwelling bladder catheters, “interviewable” the patient is.
adding more than three medications within a 24-hour period, Attentional or arousal deficits may preclude the opportu-
and an iatrogenic medical complication (Inouye and Char- nity to pursue the mental status examination much further,
pentier, 1996). Other precipitating factors for incident delir- but the examiner should attempt to assess orientation and
ium, which is the term used to describe a delirium that newly other areas of cognition. Patients who are off 3 days on the
occurs during the course of a stay in a clinical setting, include date, 2 days on the day of the week, or 4 hours on the time of
electrolyte disturbances (hyponatremia, hypercalcemia, etc.), day may be significantly disoriented to time. The examiner
major organ system disease, occult respiratory failure, occult should inquire whether the patient knows where he or she is,
infection, pain, specific medications such as sedative-hypnotics what kind of place it is, and in what circumstances he or she
or histamine-2 blockers, sleep disturbances, and alterations in is there. Disturbed recent memory is demonstrated by asking
the environment. Novel situations and unfamiliar surround- the patient to retain the examiner’s name or three words for
ings contribute to sensory overstimulation in the elderly, and 5 minutes. A language examination should distinguish
sensory overload may be a factor in producing “ICU psycho- between the language of confusion and that of a primary
sis.” Ultimately, delirium occurs in patients from a synergistic aphasia (see Special Problems in Differential Diagnosis, later
interaction of predisposing factors with precipitating factors. in this chapter). Attempts at simple constructions such as
In addition to the risk factors already discussed, heritability copying a cube may be unsuccessful. Hallucinations can some-
of delirium is an area of investigation. The presence of genes times be brought out by holding a white piece of paper or an
such as apolipoprotein E (APOE), dopamine receptor genes imaginary string between the fingers and asking the patient to
DRD2 and DRD3, and the dopamine transporter gene, describe what he or she sees.
SLC6A3, are possible pathophysiological vulnerabilities for
delirium (van Munster et al., 2009, 2010). Despite conflicting
data, there is evidence for an association between APOE ε4
Diagnostic Scales and Criteria
carriers and a longer duration of delirium (van Munster et al., The usual mental status scales and tests may not help in dif-
2009). Polymorphisms in SLC6A3 and DRD2 have occurred ferentiating delirium from dementia and other cognitive dis-
in association with delirium from alcohol and in elderly delir- turbances. Specific criteria and scales are available for the
ious patients with hip fractures (van Munster et al., 2009, diagnosis of delirium. Foremost among these are the Diagnostic
2010). and Statistical Manual of Mental Disorders, fifth edition (DSM-V;
APA, 2013), criteria for delirium (see Box 4.2). The confusion
assessment method (CAM) is a widely used instrument for
Mental Status Examination screening for and diagnosing delirium (Ely et al., 2001) (Box
Initial general behavioral observations are an important part 4.4). The Delirium Rating Scale-Revised-98 (DRS-R-98), a revi-
of the neurological mental status examination. The most sion of the earlier delirium rating scale (DRS), is a 16-item
important are observations of attentiveness and arousability. scale with 13 severity items and three diagnostic items that
Attention may wander so much that it must constantly be reliably distinguish delirium from dementia, depression, and
brought back to the subject at hand. General behavior may schizophrenia (Trzepacz et al., 2001). Both the CAM and the
range from falling asleep during the interview to agitation and DRS-R-98 are best used in combination with a cognitive test
combativeness. Slow and loosely connected thinking and (Adamis et al., 2010). The Memorial Delirium Assessment
speech may be present, with irrelevancies, perseverations, rep- Scale (MDAS) is a 10-item scale designed to quantify the
etitions, and intrusions. Patients may propagate their errors in
thinking and perception by elaboration or confabulation.
Finally, the examiner should evaluate the patient’s general
appearance and grooming, motor activity and spontaneity, BOX 4.4  Diagnosis of Delirium by the Confusion
mood and affect, propriety and witticisms, and the presence Assessment Method
of any special preoccupations or inaccurate perceptions.
Bedside tests of attention can be divided into serial recita- The diagnosis of delirium by the confusion assessment method
tion tasks, continuous performance tasks, and alternate (CAM) requires the presence of features 1, 2 and either 3 or 4
response tasks. The digit span test is a serial recitation task in (Inouye et al., 1990).
which a series of digits is presented, one digit per second, and Feature 1: Acute onset and fluctuating course
the patient is asked to repeat the entire sequence immediately Was there an acute change from the patient’s baseline? Did
after presentation. Perceptual clumping is avoided by the use the (abnormal) behavior fluctuate in severity?
of random digits and a regular rhythm of presentation. Correct Feature 2: Inattention
recitation of seven (plus or minus two) digits is considered Did the patient have difficulty keeping track of what was being
normal. The serial reversal test is a form of recitation task in said?
which the patient recites backward a digit span, the spelling Feature 3: Disorganized thinking
of a word such as world, or the results of counting by ones, Was the patient’s thinking disorganized or incoherent (rambling
threes, or sevens from a predetermined number. Continuous conversation, unclear or illogical flow of ideas)?
performance tasks include the A vigilance test, in which the Feature 4: Altered level of consciousness
patient must indicate whenever the letter A is heard among Overall, would you rate this patient’s level of consciousness as
random letters presented one per second. This can also be alert (normal), vigilant (hyperalert), lethargic (drowsy, easily
done visually by asking the patient to cross out every instance aroused), stupor (difficulty to arouse), or coma
of a particular letter in a magazine or newspaper paragraph. (unarousable)?
Alternate response tasks are exemplified by the repetition of a
 Delirium 29

severity of delirium in medically ill patients (Breitbart et al., radiographs; electrocardiogram; urinalysis; and urine drug
1997). While it may also be useful as a diagnostic tool, it is screening. Less routine tests, such as antibody tests against Hu 4
best used after the initial delirium diagnosis is made (Adamis or NMDA receptors, should be considered when routine labs
et al., 2010). The delirium symptom interview is also a valuable are unrevealing and there is a suspicion for malignancy.
instrument but may not distinguish delirium from dementia. Although they are nonspecific, evoked potential studies often
The Neelon and Champagne (NEECHAM) Confusion Scale show prolonged latencies.
(Neelon et al., 1996) is an easily administered screening tool Since most cases of delirium are due to medical conditions,
widely used in the nursing community. It combines behavioral lumbar puncture and neuroimaging are needed in only a
and physiological signs of delirium, but it has been suggested minority of delirious patients (Inouye, 2006). The need for a
that the NEECHAM measures acute confusion rather than lumbar puncture, however, deserves special comment. This
delirium (Adamis et al., 2010). The confusion assessment valuable test, which is often neglected in the evaluation of
method for ICU (CAM-ICU) and the intensive care delirium delirious patients, should be performed as part of the workup
screening checklist (ICDSC) are two validated critical care when the cause is uncertain. The lumbar puncture should be
assessment tools used to easily and relatively quickly screen preceded by a computed tomographic (CT) or magnetic reso-
for delirium in the ICU (Alce et al., 2013). nance imaging (MRI) scan of the brain, especially if there are
The diagnosis of delirium is facilitated by the use of the focal neurological findings or suspicions of increased ICP, a
CAM, DRS-R-98, MDAS, the delirium symptom interview, the space-occupying lesion, or head trauma. The yield of func-
delirium index (McCusker et al., 2004), or the NEECHAM, tional imaging is variable, showing global increased metabo-
along with the history from collateral sources such as family lism in patients with delirium tremens and global decreased
and nursing notes, a mental status examination focusing on metabolism or focal frontal hypoactivity in many other deliri-
attention, and specific tests such as a writing sample. ous patients.

Physical Examination DIFFERENTIAL DIAGNOSIS

The physical examination should elicit any signs of Common Causes of Delirium
systemic illness, focal neurological abnormalities, meningis-
The following discussion is a selective commentary that illus-
mus, increased intracranial pressure (ICP), extracranial cere-
trates some basic principles and helps organize the approach
brovascular disease, or head trauma. In delirium, less specific
to working through the large differential diagnosis. Almost
findings include an action or postural tremor of high fre-
any sufficiently severe medical or surgical illness can cause
quency (8–10 Hz), asterixis or brief lapses in tonic posture
delirium, and the best advice is to follow all available diag-
(especially at the wrist), multifocal myoclonus or shock-
nostic leads (Table 4.1). (For further discussion of individual
like jerks from diverse sites, choreiform movements, dysar-
entities, the reader should refer to corresponding chapters in
thria, and gait instability. Patients may manifest agitation or
this book.) The confusion-inducing effects of these distur-
psychomotor retardation, apathy, waxy flexibility, catatonia, or
bances are additive, and there may be more than one causal
carphologia (“lint-picking” behavior). The presence of hyper-
factor, the individual contribution of which cannot be eluci-
activity of the autonomic nervous system may be life threaten-
dated. Nearly half of elderly patients with delirium have more
ing because of possible dehydration, electrolyte disturbances,
than one cause of their disorder, and clinicians should not
or tachyarrhythmias.
stop looking for causes when a single one is found. Of the
causes for delirium, the most common among the elderly are
Laboratory Tests metabolic disturbances, infection, stroke, and drugs, particu-
larly anticholinergic and narcotic medications. The most
Despite false-positive and false-negative rates on single trac-
common causes among the young are drug abuse and alcohol
ings (Inouye, 2006), EEG changes virtually always accompany
withdrawal.
delirium when several EEGs are obtained over time (see
Chapter 34). Disorganization of the usual cerebral rhythms
and generalized slowing are the most common changes, as
Metabolic Disturbances
illustrated in Engel and Romano’s classic paper (1959). The Metabolic disturbances are the most common causes of delir-
mean EEG frequency or degree of slowing correlates with the ium (see Chapters 58 and 83–86). Fortunately, the examina-
degree of delirium. Both hypoactive and hyperactive subtypes tion and routine laboratory tests screen for most acquired
of delirium have similar EEG slowing; however, predominant metabolic disturbances that might be encountered. Because of
low-voltage fast activity is also present on withdrawal from the potential for life-threatening or permanent damage, some
sedative drugs or alcohol. Additional EEG patterns from of these conditions—particularly hypoxia and hypoglycemia—
intracranial causes of delirium include focal slowing, asym- must be considered immediately. Also consider dehydration,
metric delta activity, and paroxysmal discharges (spikes, sharp fluid and electrolyte disorders, and disturbances of calcium
waves, and spike–wave complexes). Periodic complexes such and magnesium. The rapidity of change in an electrolyte level
as triphasic waves and periodic lateralizing epileptiform dis- may be as important a factor as its absolute value for the
charges may help in the differential diagnosis (see Chapter development of delirium. For example, some people tolerate
34). EEGs are of value in deciding whether confusional behav- chronic sodium levels of 115 mEq/L or less, but a rapid
ior may be due to an intracranial cause, in making the diag- fall to this level can precipitate delirium, seizures, or even
nosis of delirium in patients with unclear behavior, in central pontine myelinolysis, particularly if the correction of
evaluating demented patients who might have a superim- hyponatremia is too rapid. Hypoxia from low cardiac output,
posed delirium, in differentiating delirium from schizophre- respiratory insufficiency, or other causes is another common
nia and other primary psychiatric states, and in following the source of delirium. A cardiac encephalopathy may ensue from
course of delirium over time. heart failure, increased venous pressure transmitted to the
Other essential laboratory tests include a complete blood dural venous sinuses and veins, and increased ICP (Caplan,
cell count; measurements of glucose, electrolytes, blood 2006). Also consider other major organ failures such as liver
urea nitrogen, creatinine, transaminase, and ammonia levels; and kidney failure, including the possibility of unusual causes
thyroid function tests; arterial blood gas studies; chest such as undetected portocaval shunting or acute pancreatitis
30 PART I  Common Neurological Problems

TABLE 4.1  Major Causes of Delirium over-the-counter cold preparations, antihistamines, antide-
pressants, and neuroleptics. Patients with anticholinergic
METABOLIC Electrolytes: hypo/hypernatremia, hypo/
intoxication present “hot as a hare, blind as a bat, dry as a
hypercalcemia, hypo/hypermagnesemia,
hypo/hyperphosphatemia
bone, red as a beet, and mad as a hatter,” reflecting fever,
Endocrine: hypo/hyperthyroidism, hypo/ dilated pupils, dry mouth, flushing, and delirium. Other
hypercortisolism, hypo/hyperglycemia important groups of drugs associated with delirium, especially
Cardiac encephalopathy, hepatic in the elderly, are sedative hypnotics such as long-acting
encephalopathy, uremic encephalopathy benzodiazepines, narcotic analgesics and meperidine, and
Hypoxia and hypercarbia histamine-2 receptor blockers. Anti-parkinsonism drugs result
Vitamin deficiencies: thiamine, vitamin B12, in confusion with prominent hallucinations and delusions in
nicotinic acid, folic acid patients with Parkinson disease who are particularly suscepti-
Toxic and industrial exposures: carbon
ble. Corticosteroid psychosis may develop in patients taking
monoxide, organic solvent, lead, manganese,
mercury, carbon disulfide, heavy metals
the equivalent of 40 mg/day or more of prednisone. The
Porphyria behavioral effects of corticosteroids often begin with euphoria
and hypomania and proceed to a hyperactive delirium. Any
TOXIC Intoxication and overdose drug administered intrathecally, such as metrizamide, is prone
Withdrawal: alcohol, benzodiazepines,
to induce confusional behavior. Drug withdrawal syndromes
barbiturates, amphetamines, cocaine, coffee,
phencyclidine, hallucinogens, inhalants,
can be caused by many agents including barbiturates and
meperidine, and other narcotics other minor tranquilizers, sedative hypnotics, amphetamines,
Drugs: anticholinergic, benzodiazepines, cocaine or “crack,” and alcohol. Delirium tremens begins 72
opiates, antihistamines, antiepileptics, muscle to 96 hours after alcohol withdrawal, with profound agitation,
relaxants, dopamine agonists, monoamine tremulousness, diaphoresis, tachycardia, fever, and frightening
oxidase inhibitors, levodopa, corticosteroids, visual hallucinations.
fluoroquinolone and cephalosporin Excited delirium syndrome, also known as agitated delir-
antibiotics, beta-blockers, digitalis, lithium, ium is a drug-related alteration in mental status with com­
clozapine, tricyclics antidepressants,
bativeness or aggressiveness (Vilke et al., 2012). Similar to
calcineurin inhibitors
delirium tremens, these patients can develop severe psychomo-
INFECTIOUS Urinary tract infection, pneumonia, sepsis, tor agitation, anxiety, hallucinations, elevated body tempera-
meningitis, encephalitis ture, tachycardia, diaphoresis, tolerance to significant pain,
NEUROLOGIC Vascular: ischemic stroke, intracerebral or violent and bizarre behavior, and “superhuman strength.”
subarachnoid hemorrhage, vasculitis Excited delirium patients are commonly found to have acute
Neoplastic: brain tumors, carcinomatous drug intoxication or history of drug abuse. Most patients with
meningitis, paraneoplastic limbic encephalitis excited delirium syndrome will survive, although there still is
Seizure-related: postictal state, nonconvulsive a high fatality rate around 10% (Vilke et al., 2012). Awareness
status epilepticus
among medical personnel regarding this syndrome is crucial
Trauma: concussion, subdural hematoma
for intervention and proactive treatment to prevent deaths.
PERIOPERATIVE Surgery: thoracic (cardiac and noncardiac),
vascular, and hip replacement, anesthetic Infections
and drug effects, hypoxia and anemia,
hyperventilation, fluid and electrolyte Infections and fevers often produce delirium. The main
disturbances, hypotension, embolism, offenders are urinary tract infections, pneumonia, and septi-
infection or sepsis, untreated pain, cemia. In a sporadic encephalitis or meningoencephalitis,
fragmented sleep, sensory deprivation or important causal considerations are herpes simplex virus,
overload Lyme disease, and acquired immunodeficiency syndrome
MISCELLANEOUS Hyperviscosity syndromes (AIDS) (see Chapter 77). Patients with AIDS may be delirious
because of the human immunodeficiency virus (HIV) itself or
because of an opportunistic infection. Immunocompromised
patients are at greater risk of infection, and any suspicion of
with the release of lipases. Delirium due to endocrine dysfunc- infection should prompt culture of urine, sputum, blood, and
tion often has prominent affective symptoms such as hyper- cerebrospinal fluid.
thyroidism and Cushing syndrome. Delirium occasionally
results from toxins including industrial agents, pollutants, and Strokes
heavy metals such as arsenic, bismuth, gold, lead, mercury,
Delirium can be the nonspecific consequence of any acute
thallium, and zinc. Other considerations are inborn errors of
stroke, but most postinfarct confusion usually resolves in 24
metabolism such as acute intermittent porphyria. Finally, it is
to 48 hours (see Chapters 65 and 66). Sustained delirium can
particularly important to consider thiamine deficiency. In
result from specific strokes, including right middle cerebral
alcoholics and others at risk, thiamine must be given imme-
artery infarcts affecting prefrontal and posterior parietal areas,
diately to avoid precipitating Wernicke encephalopathy with
and posterior cerebral artery infarcts resulting in either bilat-
the administration of glucose.
eral or left-sided occipitotemporal lesions (fusiform gyrus).
The latter lesions can lead to agitation, visual field changes,
Drugs and even Anton syndrome (see Chapter 16). Delirium may
Drug intoxication and drug withdrawal are among the most also follow occlusion of the anterior cerebral artery or rupture
common causes of delirium. Approximately 50% of patients of an anterior communicating artery aneurysm with involve-
over the age of 65 take five or more chronic medications daily, ment of the anterior cingulate gyrus and septal region. Tha-
and medications contribute to delirium in up to 39% of these lamic or posterior parietal cortex strokes may present with
patients (Inouye and Charpentier, 1996). Drug effects are severe delirium, even with small lesions.
additive, and drugs that are especially likely to cause delirium Other cerebrovascular conditions that can produce delir-
are those with anticholinergic properties, including many ium include high-grade bilateral carotid stenosis, hypertensive
 Delirium 31

encephalopathy, subarachnoid hemorrhage, and central and atrophy or subcortical ischemic changes on neuroimaging
nervous system (CNS) vasculitides such as systemic lupus ery- are particularly susceptible. Electroconvulsive therapy often 4
thematosus, temporal arteritis, and Behçet syndrome. Migraine produces a delirium of one week or more. Head trauma can
can present with delirium, particularly in children. It must be result in delirium as a consequence of brain concussion, brain
emphasized that the frequency of delirium in transient contusion, intracranial hematoma, or subarachnoid hemor-
ischemic attacks, even in vertebrobasilar insufficiency, is low. rhage (see Chapters 66 and 67). Moreover, subdural hemato-
Transient ischemic attacks should not be considered the cause mas can occur in the elderly with little or no history of head
of delirium unless there are other neurological signs and an injury. Rapidly growing tumors in the supratentorial region
appropriate time course. are especially likely to cause delirium with increased ICP.
Paraneoplastic processes produce limbic encephalitis and
Epilepsy multifocal leukoencephalitis. Delirium can result from acute
demyelinating diseases and other diffuse multifocal lesions,
Abnormal brain electrical activity is associated with delirium
and from communicating or noncommunicating hydrocepha-
in four conditions: (1) ictally, with absence status, complex
lus. Some patients with transient global amnesia have initial
partial status, tonic status without convulsions, or periodic
delirium before the pathognomonic and prominent antero-
lateralizing epileptiform discharges; (2) postictally, after
grade amnesia. Transient global amnesia patients also have
complex partial or generalized tonic-clonic seizures; (3)
limited retrograde amnesia for the preceding hours and
interictally manifested as increasing irritability, agitation, and
improve within 24 hours. In Wernicke encephalopathy, delir-
affective symptoms associated with the prodrome of impend-
ium accompanies oculomotor paresis, nystagmus, ataxia, and
ing seizures; and (4) from the cognitive effects of anticonvul-
frequently residual amnesia (Korsakoff psychosis).
sant medications.
Miscellaneous Causes
Postoperative Causes
Various other disturbances can produce delirium. Bone frac-
The cause of delirium in postoperative patients is often mul- tures are associated with delirium in the elderly, and about
tifactorial (Robinson et al., 2009; Winawer, 2001). Predispos- 50% of those admitted with a hip fracture have delirium.
ing factors to postoperative delirium include age older than Time from admission to operation in these patients is an
70 years, pre-existing CNS disorders such as dementia and additional risk factor for development of preoperative delir-
Parkinson disease, severe underlying medical conditions, a ium (Juliebo et al., 2009). In orthopedic cases, the possibility
history of alcohol abuse, impaired functional status, and of fat emboli requires evaluation of urine, sputum, or cerebro-
hypoalbuminemia. Precipitating factors include residual anes- spinal fluid for fat. ICU psychosis is associated with sleep
thetic and drug effects (especially after premedication with deprivation, immobilization, unfamiliarity, fear, frightening
anticholinergic drugs), postoperative hypoxia, perioperative sensory overstimulation or sensory deprivation, isolation,
hypotension, electrolyte imbalances, infections, psychological transfer from another hospital ward, mechanical ventilation,
stress, and multiple awakenings with fragmented sleep. There psychoactive medications, and use of drains, tubes, and cath-
is no clear correlation of delirium with specific anesthetic eters (Van Rompaey et al., 2009). Delirium results from blood
route. Upon the cessation of general anesthesia, clinicians may dyscrasias including anemia, thrombocytopenia, and dissemi-
observe the emergence of excitation, or an “emergence delir- nated intravascular coagulopathy. Finally, physical factors
ium” (Silverstein and Deiner, 2012). Otherwise, postoperative such as heatstroke, electrocution, and hypothermia may be
delirium may start at any time but often becomes evident causal.
about the third day and abates by the seventh, although it may
last considerably longer. Clinicians may refer to a postopera-
tive delirium that occurs 24–72 hours after the completion of Special Problems in Differential Diagnosis
a surgical procedure as an “interval delirium.”
A number of surgeries are associated with a high rate of Delirium must be distinguished from dementia, Wernicke
postoperative delirium. Between 30% and 40% of patients aphasia, and psychiatric conditions (see Chapters 7, 9, 10, and
experience delirium after open heart or coronary artery bypass 13). The main differentiating features of dementia are the
surgery. Patients older than 60 years are at special risk for longer time course and the absence of prominent fluctuating
postoperative delirium after cardiac surgery. Additional factors attentional and perceptual deficits. Chronic confusional states
are decreased postoperative cardiac output and length of time lasting 6 months or more are a form of dementia. Patients
on cardiopulmonary bypass machine, with its added risk for with delirium that becomes chronic tend to settle into a lethar-
microemboli. In addition to an already high rate of delirium gic state without the prominent fluctuations throughout the
following fractures (up to 35.6% after hip fracture), ortho- day, and they have fewer perceptual problems and less disrup-
pedic surgeries, particularly femoral neck fractures and bilat- tion of the day/night cycle. In addition, delirium and demen-
eral knee replacements, further increase the frequency of tia often overlap because demented patients have increased
delirium by about 18%. Emergency hip fracture repair is asso- susceptibility for developing a superimposed delirium. The
ciated with a higher risk of delirium than elective hip surgery prevalence of delirium superimposed on dementia in com-
(Bruce et al., 2007). Elective noncardiac thoracic surgery is munity and hospital setting ranges from 22 to 89% (Morandi
also associated with a 9% to 14% frequency of delirium in the et al., 2012). Demented patients who suddenly get worse
elderly. Cataract surgery is associated with a 7% frequency of should always be evaluated for delirium. Moreover, distin-
delirium, possibly because of sensory deprivation. Patients guishing delirium from certain forms of dementia such as
who have undergone prostate surgery may develop delirium vascular dementia and dementia with Lewy bodies may be
associated with water intoxication as a result of absorption of particularly difficult. Patients with vascular dementia may
irrigation water from the bladder. have an acute onset or sharp decline in cognition similar
to delirium. Patients with dementia with Lewy bodies have
fluctuations in attention and alertness and visual hallucina-
Other Neurological Causes tions that can look identical to delirium. Most of these
Other CNS disturbances predispose to delirium. In general, patients, however, have parkinsonism, repeated falls, or other
patients with dementia, Lewy body disease, Parkinson disease, supportive features. Nevertheless, the differential diagnosis of
32 PART I  Common Neurological Problems

TABLE 4.2  Special Problems in the Differential Diagnosis of Delirium*

Stroke with
Clinical feature Delirium Dementias Wernicke aphasia Schizophrenia Depression
Course Acute onset; hours, Insidious onset†; Sudden onset; Insidious onset, 6 Insidious onset, at
days, or more months or years; chronic, stable months or more; least 2 weeks,
progressive deficit acute psychotic often months
phases
Attention Markedly impaired Normal early; Normal Normal to mild Mild impairment
attention and arousal impairment later impairment
Fluctuation Prominent in attention Prominent Absent Absent Absent
arousal; disturbed fluctuations absent;
day/night cycle lesser disturbances
in day/night cycle
Perception Misperceptions; Perceptual Normal Hallucinations, May have
hallucinations, usually abnormalities much auditory with mood-
visual, fleeting; less prominent‡; personal congruent
paramnesia paramnesia reference hallucinations
Speech and language Abnormal clarity, speed, Early anomia; empty Prominent Disorganized, with Decreased
and coherence; speech; abnormal paraphasias and a bizarre theme amount of
disjointed and comprehension neologisms; speech
dysarthric; empty speech;
misnaming; abnormal
characteristic comprehension
dysgraphia
Other cognition Disorientation to time, Disorientation to time, No other necessary Disorientation to Mental slowing;
place; recent memory place; multiple deficits person; concrete indecisiveness;
and visuospatial other higher interpretations memory retrieval
abnormalities cognitive deficits difficulty
Behavior Lethargy or delirium; Disinterested; Paranoia possibly Systematized Depressed mood;
nonsystematized disengaged; ensuing delusions; anhedonia; lack
delusions; emotional disinhibited; paranoia; bizarre of energy; sleep
lability delusions and behavior and appetite
other psychiatric disturbances
symptoms
Electroencephalogram Diffuse slowing; Normal early; mild Normal Normal Normal
low-voltage fast slowing later
activity; specific
patterns
*The characteristics listed are the usual ones and are not exclusive.
†
Patients with vascular dementia may have an abrupt decline in cognition.
‡
Patients with dementia with diffuse cortical Lewy bodies often have a fluctuating mental status and hallucinations.

delirium and dementia with Lewy bodies may not be possible particularly if there is an acute agitated depression or a pre-
until after a diagnostic workup is completed. dominantly irritable mania. A general rule is that psychiatric
The language examination should distinguish Wernicke behaviors such as psychosis or mania may be due to delirium,
aphasia from the language of delirium. Aphasics have promi- called delirious mania, especially if they occur in someone
nent paraphasias of all types, including neologisms, and they who is 40 years or older without a prior psychiatric history.
have relatively preserved response to axial or whole-body com- They should be regarded as delirium until proven otherwise.
mands. Their agraphia is also empty of content and is para- Table 4.2 outlines the special problems that must be consid-
graphic compared with the mechanical and other writing ered in the differential diagnosis of delirium.
disturbances previously described in patients with delirium.
Psychiatric conditions that may be mistaken for delirium
include schizophrenia, depression, mania, attention deficit
PREVENTION AND MANAGEMENT
disorder, autism, dissociative states, and Ganser syndrome, As many as 30% to 40% of cases of delirium may be prevented
which is characterized by ludicrous or approximate responses with provision of high-quality care (Inouye et al., 2014). Mis-
(see Chapter 9). In general, patients with psychiatric condi- diagnosis of delirium results in inadequate management in up
tions lack the fluctuating attentional and related deficits asso- to 80% of patients (Michaud et al., 2007), and about half of
ciated with delirium. Schizophrenic patients may have a very elderly patients affected by delirium actually develop symp-
disturbed verbal output, but their speech often has an underly- toms after admission to the hospital. Early identification of
ing bizarre theme. Schizophrenic hallucinations are more patients with predisposing risk factors is important, especially
often consistent persecutory voices rather than fleeting visual in a frail geriatric population (Laurila et al., 2008). In addi-
images, and their delusions are more systematized and have tion, early intervention by geriatricians and others can reduce
personal reference. Conversely, delirious hallucinations are the rates of delirium (Deschodt et al., 2012). Multifactorial
usually visual, and the delusions are more transitory and frag- intervention programs can reduce the duration of delirium,
mented. Mood disorders may also be mistaken for delirium, length of hospital stay, and mortality (Bergmann et al., 2005;
 Delirium 33

Inouye et al., 1999; Lundstrom et al., 2005). These programs, Other medications such as valproate, ondansetron, or
like the Hospital Elder Life Program (HELP), focus on manag- melatonin may be effective and safe in selected cases. Recent 4
ing risk factors through interventions that include reorienta- evidence indicates that low dose melatonin and Ramelteon, a
tion, therapeutic activities, reduced use and dose of psychoactive melatonin receptor agonist, are effective at lowering the risk
drugs, early mobilization, promotion of sleep, maintenance of delirium (Al-ama et al., 2011; Hatta et al., 2014). There is
of adequate hydration and nutrition, and provision of vision mixed evidence to support the preventive use of haloperidol
and hearing adaptations (Inouye et al., 2014). They also focus prior to the development of delirium, though it may reduce
on educational programs for physicians and nurses in the severity and duration postoperatively, as well as duration of
detection and management of delirium. Nurses in particular hospital stay (Gosch and Nicholas, 2014; Kalisvaart et al.,
spend more time with patients than physicians do, and they 2005). The existing evidence does not support the use of ace-
may be in a better position to recognize delirium. tylcholinesterase inhibitors after surgery for prevention of
There are several steps in the management of delirium. postoperative delirium (Alce et al., 2013; Attard et al., 2008;
First, attention is aimed at finding the cause and eliminating Tabet and Howard, 2009). There is growing evidence that
it. Second, the delirium is managed with symptomatic clonidine and dexmedetomidine most commonly used in the
measures involving attention to fluid and electrolyte balance, ICU have demonstrated deliriogenic effects (Hipp et al.,
nutritional status, and early treatment of infections. Third, 2012). Dexmedetomidine, an alpha-2 agonist, has gained
management focuses on environmental interventions. Reduce popularity in the ICU due to decreased respiratory suppres-
unfamiliarity by providing a calendar, a clock, family pictures, sion and evidence from recent trials demonstrating reduced
and personal objects. Maintain a moderate sensory balance in delirium prevalence as compared with GABA-ergic drugs, like
the patient by avoiding sensory overstimulation or depriva- benzodiazepines (Hipp et al., 2012).
tion. Minimize staff changes, limit ambient noise and the
number of visits from strangers, and provide a radio or a tel-
evision set, a nightlight, and where necessary, eyeglasses and PROGNOSIS
hearing aids. Other environmental measures include provid-
The prognosis for recovery from delirium is variable. If the
ing soft music and warm baths and allowing the patient to
causative factor is rapidly corrected, recovery can be complete,
take walks when possible. Physical restraints should be avoided
with an average duration of delirium of about 8 days (2 days
if possible and a sitter used instead. Fourth, proper commu-
to 2 weeks). Delirium present at discharge is associated with
nication and support are critical with these patients. As much
a 2.6-fold increased risk of death or nursing home placement
as possible, everything should be explained. Delusions and
(McAvay et al., 2006), and delirium persisting after hospital
hallucinations should be neither endorsed nor challenged.
discharge is associated with a 2.9-fold risk of death within the
Patients should receive emotional support including frequent
following year. This risk appears to be reversible with the reso-
family visits. They also benefit from frequent reorientation to
lution of delirium (Kiely et al., 2009). The link between delir-
place, time, and situation. Finally, it is important to address
ium and subsequent long-term cognitive impairment is also
safety for the patient, family, and caregivers in order to mini-
firmly established (MacLullich et al., 2009; Morandi et al.,
mize the risks for suicidality, violence, falls, wandering, or
2012).
inadvertent self-harm (Irwin et al., 2013).
In the elderly, delirium may not be a transient disorder. For
In general, it is best to avoid the use of drugs in confused
them, the duration of delirium is often longer than that of
patients, because they further cloud the picture and may
their underlying medical problem. Moreover, after hospital
worsen delirium. All the patient’s medications should be
discharge, older patients who are delirious may not recover
reviewed, and any unnecessary drugs should be discontinued.
back to baseline (Inouye et al., 2014). In one study, 14.8% still
When medication is needed, the goal is to make the patient
met criteria for delirium 12 months after discharge, sometimes
manageable, not to decrease loud or annoying behavior or to
referred to as a “persistent delirium” (McCusker et al., 2004;
sedate them (Inouye, 2006). These patients should receive the
Morandi et al., 2012). A partial nonprogressive delirium with
lowest possible dose and should not get drugs such as pheno-
some but not all criteria for delirium may persist in many
barbital or long-acting benzodiazepines. In particular, use of
elderly patients, sometimes referred to as a “subsyndromal
benzodiazepines can have a paradoxical effect in the elderly,
delirium” (Martins and Fernendes, 2012).
causing agitation and confusion. Medication may be necessary
Delirium is an independent predictor of adverse outcomes
if the patient’s behavior is potentially dangerous, interferes
in older hospitalized patients; particularly in the presence of
with medical care, or causes the patient profound distress.
baseline cognitive impairment or dementia, it is associated
Clinicians most often use haloperidol (starting at 0.25 mg
with an increased mortality rate and may accelerate cognitive
daily) for these symptoms because of its higher dopamine
decline (Adamis et al., 2006; Inouye et al., 2014; MacLullich
receptor potency, lower anticholinergic effects, and the avail-
et al., 2009; McCusker et al., 2002). Delirium in the elderly
ability of various routes of use (Bledowski and Trutia, 2012).
predicts sustained poor cognitive and functional status and
Haloperidol may be repeated every 30 minutes, PO or IM, up
increased likelihood of nursing home placement after a
to a maximum of 5 mg/day. After the first 24 hours, 50% of
medical admission. Hypoactive delirious patients appear to be
the loading dose may be given in divided doses over the next
at particular risk because of complications from aspiration
24 hours, then the dose should be tapered off over the next
and inadequate oral nutrition as well as falls and pressure
few days (Inouye, 2004). The atypical antipsychotics—
sores. In general, however, clinicians can greatly improve
risperidone, olanzapine, quetiapine, and aripiprazole—may
prognosis with increased awareness of delirium, more rapid
be used at low doses (Attard et al., 2008). Safety and efficacy
diagnosis of the causative factor(s), and better overall
of the atypical and typical antipsychotics are similar (Toor
management.
et al., 2013). Results in favor of acetylcholinesterase inhibitors
for delirium management have not been borne out in control-
led trials, though in some cases, such as in patients with Lewy REFERENCES
body dementia, they can be helpful (Attard et al., 2008; The complete reference list is available online at https://expertconsult
Martins and Fernandes, 2012; Tabet and Howard, 2009). .inkling.com/.