Diagnosis of delirium and confusional states

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 [1,2].

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 of Mental Disorders, fifth edition (DSM-5) lists five key features that characterize delirium [3]:

●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 [4]. 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 [4]. Although this definition encompasses delirium as well, some experts use "confusional state" to convey the additional meaning of reduced alertness and altered psychomotor activity [4]. 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-5 definition. The additional components of agitation, tremor, and hallucinations are allowed for but are not essential diagnostic features of delirium in the DSM-5 usage. Confusion and other states of altered consciousness are encompassed by the DSM-5 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 [5,6]. 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 with complex procedures such as cardiac surgery [7].

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 (ICUs; 70 percent) [8], emergency departments (10 percent) [9], hospice units (42 percent) [10], and postacute care settings (16 percent) [11]. 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 [12]. 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 [13]. 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 [14,15]. Anticholinergic drugs cause delirium when given to healthy volunteers and are even more likely to lead to acute confusion in frail older adults. 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 [14,16]. 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 [17,18]. Psychotropic drugs, in particular, are likely to cause detectable serum anticholinergic activity at doses typically administered to older patients. Some older 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 [14].

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 gamma-aminobutyric acid (GABA), among others [13]. However, it is difficult to exclude the confounding effects of underlying illness or dementia.

Proinflammatory 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 [19], and acute hip fracture [20].

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 [21].

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 [22]. Often, the dementia went unrecognized prior to the onset of delirium. Similarly, in a study of 78 older 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 [23].

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) [3]. 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 semicomatose 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 (eg, 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 older 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.

Older 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 [24]. Delirium that does not resolve before discharge is also a risk factor for nursing home placement [25].

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 [24].

Clinical confirmation — The Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) criteria (see 'Definition and terminology' above) form a practical framework for assessing delirium [26]:

●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 "The mental status examination in adults", section on 'Cognitive screening tests'.)

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 [NCSE]). 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 older adults 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 "Approach to 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 central nervous system (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 electroencephalography (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 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 [27,28]. The CAM has become a standard screening device in clinical studies of delirium, conducted across multiple settings including emergency departments and long-term care [29]. 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 Examination as the least accurate test [30].

The CAM-intensive care unit (ICU) instrument has been developed and validated for identification of delirium in the ICU [31-33]. 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 Screening Checklist (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 [34,35].

Investigating medical etiologies — Virtually any medical condition can precipitate delirium in a susceptible person; multiple underlying conditions are often found [36]. 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 older adults

Less common causes that should be considered include hypoxemia, hypercarbia, Wernicke encephalopathy, adrenal failure, primary CNS infection, seizures, trauma, and paraneoplastic syndromes.

A cost-effective work-up for delirium focuses upon these most likely possibilities.

Medication review — Drug toxicity accounts for approximately 30 percent of all cases of delirium [17]. Thus, the most important initial step is a medication review. The most common offenders are listed in the table (table 2) [17]. 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 [37]. 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 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 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 Klüver-Bucy syndrome (apathy, visual agnosia, increased sexual activity, and increased oral behavior) may be seen.

●Occipital – Anton 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 [38-41]. One retrospective study of 127 consecutive neurology consultations for isolated acute mental status change found stroke as the cause in nine patients (7 percent) [39]. 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 preexisting cognitive impairment, infection, right hemispheric stroke, anterior circulation large vessel stroke, and greater stroke severity [41].

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

Nonconvulsive status epilepticus — Nonconvulsive status epilepticus (NCSE) is underrecognized, particularly in older patients. NCSE requires an electroencephalogram (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 "postictal state," automatisms (lip smacking, chewing, or swallowing movements), and acute aphasia or neglect without a structural lesion [42]. NCSE should also be considered in the absence of these findings when the etiology of a confusional state remains obscure [43].

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, and 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 computed tomography (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 [44]. Examples of retrospective studies include:

●In a retrospective study of 294 patients with acute confusion, abnormal CTs were found in 14 percent [45]. 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 (ICU) patients, new CT findings were present in 26, leading to a change in diagnosis in 11 and a new treatment plan in six [38]. Most studies were performed for an indication of "altered mental status" and findings included cerebral infarction in 13, intracranial hemorrhage in two, and tumor in three.

●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 [40]. 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 magnetic resonance imaging (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 [46]. 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 older 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 [47]. 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 [48].

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, 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 [49,50]:

●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 (NCSE) 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 NCSE in 74 (37 percent) [51]. In another study, continuous EEG monitoring was performed for unexplained decrease in consciousness or detection of subclinical seizures in 570 critically ill patients [52]. 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 [53,54]. 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 [42]. 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 [51].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Delirium and confusional states in older adults" and "Society guideline links: Adult with altered mental status in the emergency department".)

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 5^th to 6^th 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 10^th to 12^th 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

●Definition – 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.)

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

●Clinical features – A disturbance of consciousness and altered cognition are essential components of delirium. Some patients are drowsy and lethargic; others are agitated and confused. (See 'Clinical presentation' above.)

Visual hallucinations, tremulousness, and myoclonus/asterixis are variably present. (See '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.)

●Evaluation – 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 (EEG) 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.)