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Literature review current through: Oct 2018. | This topic last updated: Aug 22, 2014.

INTRODUCTION — Delirium and confusional states are among the most common mental
disorders encountered in patients with medical illness, particularly among those who are
older. They are associated with many complex underlying medical conditions and can be
hard to recognize. Systematic studies and clinical trials are difficult to perform in patients
with cognitive impairment. Recommendations for evaluating and treating delirium are
based primarily upon clinical observation and expert opinion [1].

Knowledge of the clinical epidemiology of delirium and confusional states in various

settings has substantially increased as a result of applying standardized diagnostic
methods. These prospective observational studies provide a basis for understanding and
managing the disorder.

The epidemiology, pathogenesis, clinical features, and diagnosis of delirium and

confusional states will be reviewed here. The prevention and treatment of these disorders
are discussed separately. (See "Delirium and acute confusional states: Prevention,
treatment, and prognosis".)

DEFINITION AND TERMINOLOGY — The American Psychiatric Association's Diagnostic

and Statistical Manual, 5th edition (DSM-V) lists five key features that characterize delirium
[2]:

●Disturbance in attention (reduced ability to direct, focus, sustain, and shift attention)
and awareness.

●The disturbance develops over a short period of time (usually hours to days),
represents a change from baseline, and tends to fluctuate during the course of the
day.

●An additional disturbance in cognition (memory deficit, disorientation, language,

visuospatial ability, or perception)

●The disturbances are not better explained by another preexisting, evolving or

established neurocognitive disorder, and do not occur in the context of a severely
reduced level of arousal, such as coma

●There is evidence from the history, physical examination, or laboratory findings that
the disturbance is caused by a medical condition, substance intoxication or
withdrawal, or medication side effect.

Additional features that may accompany delirium and confusion include the following:
 ●Psychomotor behavioral disturbances such as hypoactivity, hyperactivity with
increased sympathetic activity, and impairment in sleep duration and architecture.

●Variable emotional disturbances, including fear, depression, euphoria, or perplexity.

There is no generally accepted consensus regarding the distinction between delirium and
confusional states. The terms "acute confusional state" and "encephalopathy" are often
used synonymously with delirium. The more general term "confusion" is used to indicate a
problem with coherent thinking. Confused patients are unable to think with normal speed,
clarity, or coherence [3]. Confusion is typically associated with a depressed sensorium and
a reduced attention span, and it is an essential component of delirium.

The term "acute confusional state" refers to an acute state of altered consciousness
characterized by disordered attention along with diminished speed, clarity, and coherence
of thought [3]. Although this definition encompasses delirium as well, some experts use
"confusional state" to convey the additional meaning of reduced alertness and altered
psychomotor activity [3]. In this paradigm, delirium is a special type of confusional state
characterized by increased vigilance, with psychomotor and autonomic overactivity; the
delirious patient displays agitation, excitement, tremulousness, hallucinations, fantasies,
and delusions.

In this discussion, the term delirium will be used in the sense of the DSM-V definition. The
additional components of agitation, tremor, and hallucinations are allowed for but are not
essential diagnostic features of delirium in the DSM-V usage. Confusion and other states
of altered consciousness are encompassed by the DSM-V definition of delirium.

EPIDEMIOLOGY — Delirium and confusion have primarily been studied in hospital

settings. Nearly 30 percent of older medical patients experience delirium at some time
during hospitalization [4,5]. Among older surgical patients, the risk for delirium varies from
10 to greater than 50 percent; the higher figures are associated either with frail patients
(eg, those who have fallen and sustained a hip fracture) or complex procedures such as
cardiac surgery [6].

In general, delirium can be found wherever there are sick patients. When standardized
screening and diagnostic tools (see 'Evaluation' below) have been applied prospectively to
consecutive patients, high rates of delirium have been demonstrated in intensive care units
(70 percent) [7], emergency departments (10 percent) [8], hospice units (42 percent) [9],
and postacute care settings (16 percent) [10]. Now that the care of sicker patients has
become fragmented across a variety of venues, clinicians are challenged to identify and
manage delirium efficiently across a wide variety of settings.

PATHOGENESIS — The pathophysiology of delirium and confusion is poorly understood.

Most theories are overly simplified. With so many disparate etiologies (table 1), it is highly
unlikely that a single mechanism is universally operative.
The biologic basis of delirium and confusion is poorly understood in part because it is
difficult to study severely ill patients with conventional electrophysiologic tests, brain
imaging, or neurotransmitter assays. Rarely can the observed phenomena attributed to
delirium be separated reliably from that of underlying illness and drug treatment. Animal
models for delirium have been proposed but are in their infancy and still not validated.

Despite these limitations, some important data regarding the pathophysiology of delirium
have been reported. Risk factors for the development of delirium have also been identified.

Neurobiology of attention — Since a disorder of attention is a universal feature of

confusional states, it helps to understand the neurobiology of attention.

●Arousal and attention may be disrupted by brain lesions involving the ascending
reticular activating system (ARAS) from the mid-pontine tegmentum rostrally to the
anterior cingulate regions.

●Attention in both right and left aspects of extrapersonal space is governed by the
"nondominant" parietal and frontal lobes. Thus with inattention, there is typically some
disruption of the integrated function of these regions.

●Insight and judgment are dependent on intact higher order integrated cortical
function. Since insight into perceptions is often reduced with delirium and confusional
states, it seems likely that higher order cortical function is therefore impaired,
especially regarding frontal lobe involvement in scrutinizing incoming sensory
information.

Cortical versus subcortical mechanisms — Seminal work in the 1940s using

electroencephalography (EEG) in acutely ill patients established that delirium was a
disturbance of global cortical function, characterized by slowing of the dominant posterior
alpha rhythm and the appearance of abnormal slow-wave activity [11]. These findings
correlated with the level of consciousness and other observed behaviors regardless of the
underlying etiology, suggesting a final common neural pathway. The major exception
appeared to be that of delirium accompanying alcohol and sedative drug withdrawal, in
which low voltage, fast-wave activity predominated. These findings are so consistent that
EEG can be used to resolve uncertainty in patients in whom the diagnosis of delirium is in
doubt.

The results of brainstem auditory evoked potential, somatosensory evoked potentials, and
neuroimaging studies have supported an important role for subcortical (eg, thalamus,
basal ganglia, and pontine reticular formation) as well as cortical structures in the
pathogenesis of delirium [12]. These findings correlate with clinical reports that patients
with subcortical strokes and basal ganglia abnormalities (including Parkinson disease)
have a higher susceptibility to delirium.
Neurotransmitter and humoral mechanisms — Acetylcholine plays a key role in the
pathogenesis of delirium [13,14]. Anticholinergic drugs cause delirium when given to
healthy volunteers and are even more likely to lead to acute confusion in frail elderly
persons. This effect can be reversed with cholinesterase inhibitors such as physostigmine.
(See "Anticholinergic poisoning".)

Further support for the role of acetylcholine is derived from observations that medical
conditions precipitating delirium, such as hypoxia, hypoglycemia, and thiamine deficiency,
decrease acetylcholine synthesis in the central nervous system (CNS). In addition, serum
anticholinergic activity, measured with binding assays employing purified preparations of
brain muscarinic receptors, correlates with the severity of delirium in postoperative and
medical patients [13,15]. Finally, Alzheimer disease, which is characterized by a loss of
cholinergic neurons, increases the risk of delirium due to anticholinergic medications.

The anticholinergic mechanism is important for clinicians to keep in mind, since many
drugs used by older adults (including several not traditionally viewed to have
"anticholinergic effects") can lead to detectable serum anticholinergic activity measured by
competitive radioreceptor binding [16,17]. Psychotropic drugs, in particular, are likely to
cause detectable serum anticholinergic activity at doses typically administered to older
patients. Some elderly patients with delirium also have elevated serum anticholinergic
activity in the absence of anticholinergic drug use, raising the possibility that endogenous
anticholinergic substances may play a role in delirium [13].

Drugs that are agonists or antagonists of a number of other neurotransmitters can produce
delirium-like effects, although the precise role of these neurotransmitter systems is difficult
to determine. Cerebrospinal fluid (CSF) studies of patients with delirium reveal alterations
in neuropeptides (eg, somatostatin), endorphins, serotonin, norepinephrine, and GABA,
among others [12]. However, it is difficult to exclude the confounding effects of underlying
illness or dementia.

Pro-inflammatory cytokines such as interleukins and tumor necrosis factor alpha also may
have a role in the pathogenesis of delirium. These agents have strong CNS effects when
injected into experimental animals or when administered for therapeutic purposes (eg,
interferons in chronic hepatitis). Cytokine activation may account for delirium (particularly
hyperactive forms of the disturbance) in situations such as sepsis (where mental changes
may actually precede fever), cardiopulmonary bypass [18], and acute hip fracture [19].

Risk factors — Delirium is a multifactorial disorder. Factors that increase the risk for
delirium and confusional states can be classified into those that increase baseline
vulnerability and those that precipitate the disturbance [20].

The most commonly identified risk factors are underlying brain diseases such as dementia,
stroke, or Parkinson disease; these are present in nearly one-half of older patients with
delirium. In a meta-analysis of published prospective studies of delirium, the prevalence of
delirium superimposed upon dementia ranged from 22 to 89 percent [21]. Often, the
dementia went unrecognized prior to the onset of delirium. Similarly, in a study of 78
elderly patients with femoral neck fractures who were followed for five years, dementia
developed in 69 percent of the 29 patients with postoperative delirium versus only 20
percent of the 49 patients without postoperative delirium [22].

Other factors that increase the vulnerability to delirium include advanced age and sensory
impairment.

Precipitating factors — Factors that may precipitate delirium are numerous and varied
(table 1). Some common examples include polypharmacy (particularly psychoactive
drugs), infection, dehydration, immobility (including restraint use), malnutrition, and the use
of bladder catheters. Drugs that may precipitate delirium and confusion are noted in the
Table (table 2).

CLINICAL PRESENTATION — As previously noted, several key features characterize

delirium and confusional states (see 'Definition and terminology' above) [2]. A disturbance
of consciousness and altered cognition are essential components. The condition typically
develops over a short period of time and tends to fluctuate during the course of the day.
The disturbance is typically caused by a medical condition, substance intoxication, or
medication side effect. These criteria form a useful framework for understanding the
clinical presentation of the disorder.

Disturbance of consciousness — One of the earliest manifestations of delirium is a

change in the level of awareness and the ability to focus, sustain, or shift attention. This
loss of mental clarity is often subtle and may precede more flagrant signs of delirium by
one day or more. Thus, family members or caregivers who report that a patient "isn't acting
quite right" should be taken seriously, even if delirium is not obvious to the examining
clinician.

Distractibility, one of the hallmarks of delirium, is often evident in conversation. It is

important that the examiner be sensitive to the patient's flow of thought and not attribute
tangential or disorganized speech to age, dementia, or fatigue.

Patients will appear obviously drowsy, lethargic, or even semi-comatose in more advanced
cases of delirium. The opposite extreme, hypervigilance, may also occur in cases of
alcohol or sedative drug withdrawal, but such a presentation is less common in older
persons. (See "Management of moderate and severe alcohol withdrawal syndromes".)

Change in cognition — Delirious individuals have cognitive and perceptual problems,

including memory loss, disorientation, and difficulty with language and speech. Formal
mental status testing can be used to document the degree of impairment, but more
important than the test score are the patient's overall accessibility and attentiveness while
attempting to answer the questions. It is important to ascertain the patient's level of
functioning prior to the onset of delirium from family members, caregivers, or other reliable
informants, since dementia can impair cognitive ability and frequently underlies delirium.

Perceptual disturbances typically accompany delirium. Patients may misidentify the

clinician or believe that objects or shadows in the room represent a person. Vague
delusions of harm often accompany these misperceptions. Hallucinations can be visual,
auditory or somatosensory, usually with lack of insight - the patients believe they are real.
Hallucinations can be simple, e.g., shadows or shapes, or complex, as people and faces.
Sounds can also consist of simple sounds or hearing voices with clear speech.

A variety of language difficulties can occur. Patients may lose the ability to write or to
speak a second language. One personal experience involved a patient who immigrated to
North America as an adolescent; she spoke only Italian during her delirium, recovering her
grasp of English after her pneumonia was treated.

Temporal course — Delirium develops over hours to days and typically persists for days
to months. The acuteness of the presentation is the most helpful feature in differentiating
delirium from dementia. In addition, the features of delirium are unstable, typically
becoming most severe in the evening and at night. It is not unusual for a patient with
delirium to appear relatively lucid during morning rounds. Clinicians, particularly
physicians, are apt to miss the diagnosis if they rely upon only a single point assessment;
evidence of the behavior change should be actively solicited from all staff, especially those
working evening and night shifts.

There is often a prodromal phase, especially in elderly patients, that later blends
into quiet/hypoactive delirium or erupts into an agitated confusional state. Prodromal
features include complaints of fatigue, sleep disturbance (excessive daytime somnolence
or insomnia), depression, anxiety, restlessness, irritability and hypersensitivity to light or
sound. With progression there are perceptual disturbances and cognitive impairment.
These symptoms may fluctuate. Hypoactive delirium can, however, begin without a
prodromal phase and agitated behavior may appear as the first manifestation of delirium
without a prodromal or hypoactive phase.

Elderly patients — Patients with delirium are sick by definition. However, older patients
with delirium often do not look sick apart from their behavioral change. Thus, delirium may
be the only finding suggesting acute illness in older demented patients. Caregivers must
be educated that sudden changes in mental functioning are not expected with most
progressive dementias and require prompt medical attention.

Other features — Delirium may present with a variety of clinical manifestations that are
not essential diagnostic features, including psychomotor agitation, sleep-wake reversals,
irritability, anxiety, emotional lability, and hypersensitivity to lights and sounds. These
features are not seen in all patients with delirium and can be evident in patients with
dementia; their presence neither rules in nor rules out the diagnosis. The most common
presentation in older patients is a relatively quiet, withdrawn state that frequently is
mistaken for depression.

The relationship between clinical manifestations and outcome has not been well studied,
although a report of outcomes of delirium following hip fracture repair suggested that
patients with more severe delirium, including psychomotor agitation, had higher rates of
mortality and nursing home placement [23]. Delirium that does not resolve before
discharge is also a risk factor for nursing home placement [24].

EVALUATION — There are two important aspects to the diagnostic evaluation of delirium:
recognizing that the disorder is present and uncovering the underlying medical illness that
has caused delirium.

Recognizing the disorder — As previously mentioned, clinicians often fail to recognize

delirium; in some reports, this happens in more than 70 percent of cases. Behavioral
problems or cognitive impairment may be readily apparent but wrongly attributed to the
patient's age, to dementia, or to other mental disorders. In one study, over 40 percent of
patients referred to a consulting liaison psychiatrist for the evaluation or treatment of
depression ultimately were found to have delirium [23].

Clinical confirmation — The DSM-V criteria (See 'Definition and terminology' above.)
form a practical framework for assessing delirium [25]:

●A change in the level of consciousness is often the first observable clue. Clinicians
must not "normalize" lethargy or somnolence by assuming that illness, sleep loss,
fatigue, or anxiety are causing the changes.

●In cases where the patient appears awake, the ability to focus, sustain, or shift
attention can be assessed during attempts to obtain a history; a global assessment of
the patient's "accessibility" during conversation or the performance of a mental status
examination is a sensitive indicator of delirium.

●Conversation with the patient may elicit memory difficulties, disorientation, or speech
that is tangential, disorganized, or incoherent. The clinician should be aware of
superficially appropriate conversation that follows social norms but is poor in content.

●When in doubt, formal mental status testing should be performed, such as the Mini-
Mental State Examination or brief bedside tests of attention (table 3). Serial-sevens
and spelling a word such as “farm” or “world” backward are other simple tests of
attention. (See "Evaluation of cognitive impairment and dementia", section on 'Mini-
Mental State Examination'.)

Determining that cognitive impairment or perceptual problems are not due to a prior or
progressing dementia can be challenging and requires knowledge of the patient's baseline
level of functioning. The diagnosis is made more easily if there has been a prior
assessment of cognitive abilities. In other instances, informants must be immediately
sought to establish chronology. These should include formal caregivers (eg, nursing staff
familiar with the patient), family members, and informal caregivers, particularly those who
may have observed fluctuations in the patient's mental functions.

History — Some historical clues to the underlying etiology of delirium and confusion can
be obtained from relatives, eg, recent febrile illness, history of organ failure, a medication
list, history of alcoholism or drug abuse, or recent depression. It is otherwise often difficult
to impossible to obtain a history in the confused or uncooperative patient. As an example,
myocardial infarction may cause sufficient confusion that the patient cannot relate a history
of chest pain.

General examination — A comprehensive physical examination is often difficult or

impossible in the confused or uncooperative patient. Clinicians should instead perform a
focused assessment, concentrating upon vital signs, the state of hydration, skin condition,
and potential infectious foci.

The patient's general appearance may be suggestive, eg, the dusky appearance seen with
chronic pulmonary disease, the jaundiced appearance of hepatic failure, or the stigmata of
renal failure. Needle tracks strongly suggest drug abuse. Cherry-red lips indicate possible
carbon monoxide poisoning. The breath may smell of alcohol, fetor hepaticus, uremic fetor
or ketones. Hyperventilation offers a limited number of possible etiologies.
(See 'Diagnostic tests' below.)

A bitten tongue or posterior fracture-dislocation of the shoulder suggests a convulsive

seizure (over 40 percent of such patients remain in nonconvulsive status epilepticus).
There may also be signs of head injury. Subhyaloid or retinal hemorrhages raise the
possibility of an intracranial hemorrhage, usually from a ruptured berry aneurysm.

Alcohol or sedative-drug withdrawal may cause a delirium characterized by autonomic

nervous system activation (tachycardia, sweating, flushing, dilated pupils) in younger
persons, but these responses are blunted or absent in the geriatric population.
Anticholinergic toxicity in elders can cause delirium without peripheral signs
of atropine poisoning (eg, fever, mydriasis, tachycardia). Sepsis may present as delirium
without obvious fever (sometimes even with hypothermia) or localizing signs (eg, rebound
tenderness from a perforated viscus). (See "Evaluation of infection in the older adult".)

Pitfalls in the examination must be kept in mind: temperature may be under 38.3ºC (101ºF)
even in the presence of serious infections; auscultatory and radiographic findings of
pneumonia may be subtle or absent; and abdominal catastrophes may present without
peritoneal signs in frail older patients. False-positive findings occur as well (eg, nuchal
rigidity may not signify meningitis).

Neurologic examination — The neurologic examination is often confounded by

inattention and altered consciousness in patients with delirium. Certain aspects of the
examination may be difficult or unreliable in uncooperative patients (eg, sensory testing),
or reflect chronic rather than acute CNS conditions. However, an assessment emphasizing
the level of consciousness, degree of attention or inattention, visual fields, and
unambiguous cranial nerve and motor deficits, is important to identify individuals with a
higher likelihood of focal neurologic disease. Posterior cortical strokes, for example, can
present as delirium with few findings other than hemianopia, and in some cases may
present with no focal symptoms or signs.

The absence of focal examination findings does not exclude the possibility of focal or
multifocal neurologic lesions as the cause of the delirium. In the absence of an obvious
cause for delirium, further testing including neuroimaging, lumbar puncture, and EEG is
indicated.

The physical signs of metabolic/toxic delirium can include nonrhythmic, asynchronous

muscle jerking (multifocal myoclonus), flapping motions of an outstretched, dorsiflexed
hand (asterixis), and postural action tremor. These are nonspecific findings and do not
help establish any particular medical etiology within the metabolic/toxic category. Selective
loss of the vestibular-ocular reflex, or nystagmus with unexplained ocular palsies that
spare pupillary reactivity to light, raise the possibility of Wernicke's encephalopathy.

Clinical instruments — The Confusion Assessment Method (CAM) is a simple tool that
can be used by clinicians to integrate their observations and identify when delirium is the
most probable diagnosis (table 4). In medical and surgical settings, the CAM has a
sensitivity of 94 to 100 percent and a specificity of 90 to 95 percent [26]. The CAM has
become a standard screening device in clinical studies of delirium, conducted across
multiple settings including emergency rooms and long-term care [27]. It takes five minutes
to administer and may be particularly helpful when incorporated into the routine bedside
assessment. A review of 11 bedside instruments used to identify the presence of delirium
in adults concluded that the best evidence supported the use of the CAM as the best, and
the Mini Mental State Exam as the least accurate test [28].

The CAM-ICU instrument has been developed and validated for identification of delirium in
the intensive care unit (ICU) [29-31]. In mechanically ventilated patients who are unable to
communicate verbally, the instrument considers observed behaviors and nonverbal
responses to simple questions, as well as visual and auditory recognition tasks (table 4).

Another instrument, the Intensive Care Delirium Checklist for Screening (ICDSC), has also
been validated in the diagnosis of delirium in the ICU setting and had high agreement
rates with the CAM-ICU in one study [32,33].

Investigating medical etiologies — Virtually any medical condition can precipitate

delirium in a susceptible person; multiple underlying conditions are often found [34]. The
history and physical examination will guide most of the investigations. The conditions
noted most commonly in prospective studies of the disorder include:
 ●Fluid and electrolyte disturbances (dehydration, hyponatremia and hypernatremia)

●Infections (urinary tract, respiratory tract, skin and soft tissue)

●Drug or alcohol toxicity

●Withdrawal from alcohol

●Withdrawal from barbiturates, benzodiazepines, and selective serotonin reuptake

inhibitors

●Metabolic disorders (hypoglycemia, hypercalcemia, uremia, liver failure,

thyrotoxicosis)

●Low perfusion states (shock, heart failure)

●Postoperative states, especially in the elderly

Less common causes that should be considered include hypoxemia, hypercarbia,

Wernicke encephalopathy, adrenal failure, primary central nervous system infection,
seizures, trauma, and paraneoplastic syndromes.

A cost-effective work-up for delirium focuses upon these most likely possibilities.
(See "Delirium and acute confusional states: Prevention, treatment, and prognosis".)

Medication review — Drug toxicity accounts for approximately 30 percent of all cases of
delirium [16]. Thus, the most important initial step is a medication review. The most
common offenders are listed in the Table (table 2) [16]. Clinicians should be careful not to
neglect over-the-counter agents, drugs prescribed by other physicians, or drugs belonging
to other household members. A simple but high-yield diagnostic procedure is to ask a
family member to clean out the medicine cabinet and bring the contents for review.

DIFFERENTIAL DIAGNOSIS — Careful attention to the key features of acute onset,

fluctuating course, altered consciousness, and cognitive decline should readily distinguish
delirium from depression, psychotic illness, and dementia. When in doubt, the most useful
rule-of-thumb is to assume delirium and attempt to rule out common medical etiologies.
This is true even for patients with known psychiatric illness (including dementia), since
they also are susceptible to delirium when acutely ill.

Sundowning — Delirium should be distinguished from "sundowning," a frequently seen

but poorly understood phenomenon of behavioral deterioration seen in the evening hours,
typically in demented, institutionalized patients [35]. Sundowning should be presumed to
be delirium when it is a new pattern. Patients with established sundowning and no obvious
medical illness may be suffering the effects of impaired circadian regulation or nocturnal
factors in the institutional environment (eg, shift changes, noise, reduced staffing).
Focal syndromes — A number of lobar or focal neurologic syndromes may mimic
delirium.

●Temporal-parietal — Patients with Wernicke's aphasia may appear delirious in that

they do not comprehend or obey and seem confused. However, the problem is
restricted to language, while other aspects of mental function are intact. Furthermore,
fluent paraphasias are typically present with Wernicke's and offer a major clue to the
correct diagnosis.

Bitemporal dysfunction, if transient, may produce a transient global amnesia (TGA), in

which the deficit is restricted to memory. With more extensive bitemporal dysfunction,
visual agnosia and cortical deafness (either bitemporal or left temporal) or the Kluver-
Bucy syndrome (apathy, visual agnosia, increased sexual activity, and increased oral
behavior) may be seen.

●Occipital — Anton's syndrome of cortical blindness and confabulation might be

confused with delirium. Careful examination, however, will reveal a lack of vision.

●Frontal — Patients with bifrontal lesions (eg, from tumor or trauma) often show
akinetic mutism, lack of spontaneity, lack of judgment, problems with recent or
working memory, blunted or labile emotional responses, and incontinence. These
features may closely resemble delirium. Neuroimaging may be required to
differentiate frontal lesions from delirium and confusional states in difficult cases.

Confusion or delirium due to acute or subacute brain lesions, such as stroke or multifocal
white matter inflammation, may occur without focal deficits on examination [36-39]. One
retrospective study of 127 consecutive neurology consultations for isolated acute mental
status change found stroke as the cause in nine patients (7 percent) [37]. Of these, three
patients (2.7 percent) with stroke had no focal neurologic findings, and one of these was a
subarachnoid hemorrhage. Risk factors for delirium in the setting of stroke include pre-
existing cognitive impairment, infection, right hemispheric stroke, anterior circulation large
vessel stroke, and greater stroke severity [39].

Confusion or delirium may follow head injury even in the absence of focal neurologic
deficits.

Nonconvulsive status epilepticus — Nonconvulsive status epilepticus (NCSE) is under-

recognized, particularly in older patients. NCSE requires an EEG for detection and
continuous EEG for management. Often patients show no classic ictal features, but the
following features should suggest the possibility of seizures: prominent bilateral facial
twitching, unexplained nystagmoid eye movements during obtunded periods, spontaneous
hippus, prolonged "post-ictal state," automatisms (lip smacking, chewing, or swallowing
movements), and acute aphasia or neglect without a structural lesion [40]. NCSE should
also be considered in the absence of these findings when the etiology of a confusional
state remains obscure [41].

Dementia — Dementia may sometimes be confused with delirium or confusion and vice-
versa. However, characteristic differences in progression and cognitive features usually
distinguish these disorders.

●In contrast to delirium, cognitive change in Alzheimer disease is typically insidious,

progressive, without much fluctuation, and occurs over a much longer time (months to
years). Attention is relatively intact, as are remote memories in the earlier stages.
(See "Clinical features and diagnosis of Alzheimer disease", section on 'Clinical
features'.)

●Dementia with Lewy bodies (DLB) is similar to Alzheimer disease but can be more
easily confused with delirium, because fluctuations and visual hallucinations are
common and prominent. (See "Clinical features and diagnosis of dementia with Lewy
bodies".)

Primary psychiatric illnesses — Delirium is commonly misdiagnosed as depression.

Both are associated with poor sleep and difficulty with attention or concentration. Agitated
depression may be especially problematic. However, depression is associated with
dysphoria, and there is less fluctuation than in delirium.

Mania can be confused with hyperactive delirium with agitation, delusions, and psychotic
behavior. However, mania is usually associated with a history of previous episodes of
mania or depression. In schizophrenia, the delusions are usually highly systematized, the
history is longer, and the sensorium is otherwise clear.

DIAGNOSTIC TESTS

Laboratory tests — A number of laboratory tests may be considered in the patient with
delirium. However, the desire for diagnostic completeness can increase costs and possibly
delay the prompt treatment of more obvious disorders. Targeted testing is appropriate in
most instances.

●Serum electrolytes, creatinine, glucose, calcium, complete blood count, and

urinalysis and urine culture are reasonable for most patients when a cause is not
immediately obvious.

●Drug levels should be ordered where appropriate. However, clinicians must be

aware that delirium can occur even with "therapeutic" levels of such agents
as digoxin, lithium, or quinidine.

●Toxic screen of blood and urine should be obtained from patients with acute delirium
or confusion when a cause is not immediately obvious. Again, clinicians must be
 aware that some common drugs (eg, risperidone) are not assessed in routine
laboratory screens. Therefore, overdose of these drugs cannot be excluded by
negative results from a toxic screen.

●Blood gas determination is often helpful. In hyperventilating patients, respiratory

alkalosis is most commonly due to early sepsis, hepatic failure, early salicylate
intoxication, or cardiopulmonary causes. A metabolic acidosis usually reflects uremia,
diabetic ketoacidosis, lactic acidosis, late phases of sepsis or salicylate intoxication,
or toxins including methanol and ethylene glycol. A chest x-ray is usually performed.

●Further testing, such as liver function tests, should be based upon the history and
clinical examination. A report of slow cognitive decline over several months, for
example, will increase the importance of evaluating thyroid function and vitamin B12
levels.

Neuroimaging — Neuroimaging with head CT may be used selectively rather than

routinely for most patients with delirium. However, neuroimaging is necessary, if no
obvious cause of delirium is apparent on first evaluation.

The need for imaging should be guided by patient history and findings on neurologic
examination. Neuroimaging may not be necessary if a patient with acute delirium meets
the following conditions: the initial clinical evaluation discloses an obvious treatable
medical illness or problem, there is no evidence of trauma, no new focal neurologic signs
are present, and the patient is arousable and able to follow simple commands. However,
neuroimaging should be reconsidered if the patient doesn't improve as expected.

Neuroimaging may still be required if the delirium does not improve despite appropriate
treatment of the underlying medical problem. In addition, imaging should be considered if
the neurologic examination is confounded by diminished patient responsiveness or
cooperation.

There have been no well-designed prospective studies to assess the yield of neuroimaging
in patients with delirium. Abnormalities on head CT are commonly seen, but they usually
represent chronic conditions that predispose to delirium rather than acute, treatable
causes [42]. Examples of retrospective studies include:

●A retrospective study of 294 patients with acute confusion found revealed abnormal
CTs in 14 percent overall [43]. However, only 4 percent of patients without focal signs
had abnormal CT; the lowest yield of CT (2 percent) was in patients with premorbid
dementia and no focal neurologic signs.

●In a review of CT scans performed in 123 medical intensive care unit patients, new
CT findings were present in 26, leading to a change in diagnosis in 11 and a new
treatment plan in 6 [36]. Most studies were performed for an indication of "altered
 mental status" and findings included cerebral infarction in 13, intracranial hemorrhage
in 2, and tumor in 3.

●In another review of 279 head CT scans performed in the emergency department in
patients older than 70 years, 42 (15 percent) revealed an acute condition [38]. Of
these, 40 were found in patients with either significantly impaired consciousness (eg,
unable to open eyes, speak, or follow simple commands) and/or new focal neurologic
findings.

Fewer data exist for MRI evaluation of patients with delirium. However, MRI is more
sensitive than head CT for acute stroke, posterior fossa lesions, and white matter lesions,
however, such findings may not influence immediate treatment course in critically ill
patients [44]. In patients with delirium of unknown cause and negative head CT, MRI may
be useful to exclude acute or subacute stroke and multifocal inflammatory lesions (eg, as
seen in reversible posterior leukoencephalopathy and acute disseminated
encephalomyelitis).

Lumbar puncture — Older patients with bacterial meningitis are more likely to present
with delirium rather than the classic triad of fever, headache, and meningismus. Bacterial
meningitis is an uncommon disorder, and routine cerebrospinal fluid (CSF) evaluation may
not be necessary in all febrile or septic appearing older patients with delirium as long as
other infectious foci are obvious. However, CSF analysis may be the only diagnostic tool
that will identify bacterial or aseptic meningitis and encephalitis.

In a retrospective study of 81 elderly patients who were admitted to the hospital for the
evaluation of fever and mental status changes, CSF cultures were negative for bacterial
growth in 80 of 81 patients [45]. However, one case of bacterial meningitis and one case of
aseptic meningitis were diagnosed by CSF findings. In a retrospective review of 232
lumbar punctures performed in hospitalized patients for the indication of altered mental
status, 11 percent were abnormal; the yield was highest in those suspected of community-
acquired meningitis [46].

Lumbar puncture is mandatory when the cause of delirium is not obvious. Clinicians
should also have a low threshold for obtaining CSF in febrile patients with delirium, even
when alternate explanatory conditions for delirium are present or suspected.

Neuroimaging should be obtained prior to lumbar puncture in patients with coma, focal
signs, papilledema, or suspicion of increased intracranial pressure because of the very low
but real risk of precipitating transtentorial herniation. If lumbar puncture is delayed and the
suspicion of bacterial meningitis is high, empiric antibiotic treatment should be considered.
(See "Lumbar puncture: Technique, indications, contraindications, and complications in
adults", section on 'Complications' and "Clinical features and diagnosis of acute bacterial
meningitis in adults".)
EEG testing — Electroencephalography (EEG) is useful in patients with altered
consciousness in order to [47,48]:

●Exclude seizures, especially nonconvulsive or subclinical seizures

●Confirm the diagnosis of certain metabolic encephalopathies or infectious

encephalitides that have characteristic EEG patterns

Nonconvulsive seizures lack motor manifestations or convulsions, but they may impair
consciousness. Nonconvulsive status epilepticus may cause continuous or fluctuating
impairment of consciousness, and EEG is the only method that can make the diagnosis.
One report evaluated 198 EEGs performed for the indication of altered consciousness
without convulsions and found definite or probable nonconvulsive status epilepticus in 74
(37 percent) [49]. In another study, continuous EEG monitoring was performed for
unexplained decrease in consciousness or detection of subclinical seizures in 570 critically
ill patients [50]. Seizures were detected in 110 patients (19 percent), and the seizures
were exclusively nonconvulsive in 92 percent of these individuals. Coma patients
frequently required greater than 24 hours of monitoring to detect the first electrographic
seizure.

Metabolic encephalopathies may show diffuse bilateral slowing of background rhythm and
moderate or high wave amplitude. Triphasic waves are associated with hepatic
encephalopathy but can be seen in other severe metabolic disturbances including uremic
and septic encephalopathy [51,52]. Viral encephalitis is typically associated with diffuse
background slowing and occasional epileptiform activity or electrographic seizures. Herpes
simplex encephalitis may be associated with high amplitude periodic complexes in the
temporal lobe leads.

EEG evaluation should be obtained for any patient with altered consciousness of unknown
etiology [40]. Patients with a remote or recent history of head trauma, stroke, seizures, or
focal brain lesions may be at higher risk of convulsive and nonconvulsive seizures.
However, neither clinical signs nor prior history predicted which of the 198 EEGs showed
nonconvulsive status in the study cited above [49].

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education

materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are
written in plain language, at the 5th to 6th grade reading level, and they answer the four or
five key questions a patient might have about a given condition. These articles are best for
patients who want a general overview and who prefer short, easy-to-read materials.
Beyond the Basics patient education pieces are longer, more sophisticated, and more
detailed. These articles are written at the 10th to 12th grade reading level and are best for
patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail these topics to your patients. (You can also locate patient education articles
on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

●Basics topic (see "Patient education: Delirium (confusion) (The Basics)")

●Beyond the Basics topic (see "Patient education: Delirium (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Delirium is a clinical syndrome caused by a medical condition, substance

intoxication or withdrawal, or medication side effect that is characterized by a
disturbance of consciousness with reduced ability to focus, sustain, or shift attention
(See 'Definition and terminology'above.)

●Nearly 30 percent of older medical patients experience delirium at some time during
hospitalization. The incidence is higher in those with advanced age and pre-existing
brain disease (See 'Epidemiology' above.)

●A disturbance of consciousness and altered cognition are essential components of

delirium. Some patients are drowsy and lethargic, others are agitated and confused.
Visual hallucinations, tremulousness, and myoclonus/asterixis are variably present
(See 'Clinical presentation' above and 'Neurologic examination' above.).

•Focal or lateralized neurologic findings are not characteristic of delirium. A

careful neurologic examination can also distinguish between focal syndromes
that can mimic delirium (See 'Focal syndromes' above.)

●The past medical history, a review of medications, and a physical examination may
provide clues as to the underlying etiology (See 'History' above and 'General
examination' above.)

●Laboratory evaluation in patients with delirium should include serum electrolytes,

creatinine, glucose, calcium, complete blood count, and urinalysis and urine culture.
Drug levels, toxicology screen, liver function testing, and arterial blood gas should
follow if the cause remains obscure (See 'Laboratory tests' above.).

●Neuroimaging, lumbar puncture, and electroencephalogram are not required in most

patients with delirium, but are recommended in specific clinical scenarios, including in
those whose cause remains obscure after routine testing (See 'Diagnostic
tests' above.)

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