Delirium, also referred to as encephalopathy, or acute confusional state, is defined as a transient disorder of cognition and attention accompanied by disturbances of the sleep-wake cycle and psychomotor behavior.[1] The key feature of delirium is the inability to maintain a coherent stream of thought or action, along with an impairment in attention and/or arousal. The recognition of an attentional deficit as the fundamental problem in delirium was established by Geschwind (1982).[2] Patients cannot maintain focused attention; this attentional disorder underlies many of the other cognitive deficits. Delirious patients are distractible, often hypersensitive to stimuli, and they cannot prioritize important from irrelevant environmental sounds or sights. A mother's ability to hear only the cry of her baby and ignore the street noises, creaking floors, plumbing noises, or music from next door, exemplifies the focused attention that is disrupted by delirium.
Most patients with delirium have associated cognitive deficits such as altered perception (including hallucinations, illusions, and delusions, such as thinking that IV tubing is a snake or misinterpreting shadows on the ceiling as animals); memory loss (especially distorted memories, approximate answers, and misidentification of people or places); language deficits (especially writing); disorientation; difficulty with calculations, abstraction, insight, and judgment; and mood disorders, which can include fear, elation, anxiety, or depression. Some patients have relatively preserved orientation, language, and other cognitive functions, but they simply cannot maintain focus on a conversation, talking about irrelevant details such as the sound of a beeper or a pattern on the wall.
Central to delirium is an alteration of consciousness, either alert and agitated, or somnolent, along with psychomotor abnormalities such as restlessness, agitation, and sleep-wake cycle disturbance. Another common set of associated symptoms in delirium are autonomic disturbances such as tachycardia, hypertension, fever, sweating, and piloerection.
The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,Text Revision (DSM-IV-TR)[3] defines delirium as the following:
Disturbance of consciousness (ie, reduced clarity of awareness of the environment) with reduced ability to focus, sustain, or shift attention
A change in cognition (such as memory deficit, disorientation, language disturbance) or the development of a perceptual disturbance that is not better accounted for by a preexisting, established, or evolving dementia
The disturbance develops over a short period of time (usually hours to days) and tends to fluctuate during the course of the day.
Evidence from the history, physical examination, or laboratory findings shows that the disturbance is caused by the direct physiological consequences of a general medical condition.
Delirium has been subdivided into 4 motoric subtypes, based on the alteration of level of consciousness.[4]
Hypoactive delirium with low psychomotor behavioral activity
Hyperactive delirium with high psychomotor activity
Mixed delirium with features of both hypo- and hyperactivity
Delirium without psychomotor behavioral changes
Hypoactive delirium has in the past been less recognized than the hyperactive variety, but recent evidence indicates that it is much more common than the hyperactive variants, especially in intensive care patients.[5]
Delirium is distinguished from dementia, which consists of a nonacute, usually progressive cognitive deficit usually reflecting deficits of multiple cognitive functions (negative symptoms in the Hughlings Jackson sense) and usually much less associated with the psychomotor, autonomic, and level of consciousness alterations (positive symptoms) that characterize delirium.
Delirium is a syndrome, or a symptom complex, rather than a disease; the pathophysiology of delirium depends largely on the etiology of the syndrome. The syndrome can be attributed to numerous causes including, but not limited to, the following.
Pulmonary disease (eg, hypoxia)
Other abnormal systemic metabolic conditions such as hepatic or renal dysfunction
Endocrine disorders such as thyroid or adrenal hypofunction or hyperfunction
Ingestion of toxins or side effects of single or multiple interacting medications or withdrawal from alcohol or drugs
Electrolyte imbalances, especially abnormalities in sodium, BUN, creatinine, glucose, calcium, magnesium, and phosphorus
Nutritional deficiencies such as thiamine, cobalamin, or niacin
Sepsis or systemic infections including simple urinary tract infections, and CNS infections such as meningitis or encephalitis, including those related to infection with HIV, herpes simplex, and West Nile virus
Seizures or postictal states
Inflammatory or autoimmune conditions such as paraneoplastic disorders, Hashimoto encephalopathy, and vasculitis
Acute structural lesions such as cerebral infarctions or hemorrhages.
An overlap exists with acute psychiatric disorders (especially acute mania).
Patients with preexisting dementia can deteriorate into delirium with seemingly minor stressors such as urinary tract infections, traumatic injuries, or even environmental change. Focal CNS disorders in strategic locations can also cause delirium. Strokes are frequent causes of delirium. Lesion loci associated with acute confusional states include the basal forebrain (eg, infarction as complication of surgery to repair an anterior communicating artery aneurysm), the caudate nucleus, and thalamic lesions that affect Papez circuit (anterior nucleus, fornix, mammillothalamic tract), and hippocampal lesions, such as acute posterior cerebral artery territory strokes or herpes simplex encephalitis.
In addition, Wernicke aphasia and mirror-image lesions of the area analogous to the Wernicke area in the right temporal lobe can also present with acute confusion or agitation, as can some thalamic lesions causing aphasia. Strokes are more likely to be associated with delirium when they occur in elderly patients with preexisting cerebral atrophy, and also when they are accompanied by seizures. Multifocal strokes in embolic conditions, vasculitis, or hypoxic-ischemic encephalopathy are also frequent causes of delirium.
Acute encephalopathies develop in 30-50% of hospitalized patients older than age 70; since nearly half of hospital populations are elderly, a conservative estimate is that approximately 10% of hospitalized patients on medical or surgical units have delirium at any given time.[6, 7, 8, 9] This estimate would be considerably higher in intensive care settings, where more than half of elderly patients experience delirium.[6, 8] In addition, delirium follows surgical procedures[10] at an incidence of about 50% in some series.
Delirium represents the most common complication in hospitalized older patients.
Delirium has been associated with longer hospital stays, increased mortality, and also a risk of nearly 50% of permanent neurocognitive impairment in survivors.[8, 11, 12, 13, 14, 15]
Delirium is estimated to affect more than 2 million persons in the United States each year, and the excess hospital cost associated with delirium exceeds $4 billion.[7, 11, 16]
As the population of older Americans increases, the frequency and cost of delirium are likely to increase. Several studies have investigated risk factors for the development of delirium during hospitalization.[16, 17, 18, 19, 20, 21] Perhaps the easiest to use is provided by Inouye and colleagues for patients older than age 70.[19] Five independent risk factors were preexisting dementia or cognitive impairment, vision impairment, functional impairment, high comorbidity, and use of physical restraints. Rates for low risk (0-1 factors), intermediate risk (2-3 factors), and high risk (4-5 factors) were 4%, 18%, and 63%, respectively. Other studies have found the presence of fractures, infections, and use of sedative or narcotic analgesic drugs to be predictors of delirium.
International
Delirium is common throughout the world. A review by Brown and Boyle in the British Medical Journal estimated that a fourth of hospitalized patients older than age 65 develop delirium during hospitalization.[20]
Mortality/Morbidity
Delirium is associated with high rates of mortality and morbidity, especially if undiagnosed. Inouye estimated in-hospital mortality of more than 20%, and mortality within a year of 35-40%.[9, 11] Ely and colleagues also found that delirium was an independent predictor of both mortality and longer hospital stays.[11] The morbidity and mortality rates depend heavily on the patient's reason for admission and associated medical illnesses.
Although delirium usually subsides over time, residual cognitive deficits often remain.[12, 13, 14, 15] These deficits are often not addressed, and patients find difficulty readjusting to their premorbid lives.
Race
Available studies on risk factors for delirium have not identified race as a specific predictor of delirium.
Sex
A recent study of delirium in older patients admitted to a general internal medicine service found male gender to be an independent risk factor for delirium, along with several other factors.[7] Most studies of delirium have not reported gender as a major predictor.
Age
Virtually all studies of delirium have found age to be a predictor of acute confusional states. Aging changes in the brain, and especially preexisting cognitive deficits or strokes, render the nervous system more sensitive to toxic or metabolic insults, such as medication side effects, electrolyte imbalances, endocrine disorders and renal or hepatic failure, and infections, among many other conditions.
Elderly patients may have exaggerated responses to over-the-counter and prescription medications with anticholinergic activity. These include diphenhydramine (Benadryl, Tylenol PM), bladder antispasmodics such as oxybutynin, and atropine sulfate (eg, Lomotil, diphenoxylate, atropine). Thioridazine (Mellaril), a prescription antipsychotic medication, and tricyclic antidepressants such as amitriptyline (Elavil) also have anticholinergic activity. Even atypical antipsychotic agents such as olanzapine (Zyprexa), quetiapine (Seroquel), and risperidone (Risperdal) may have a paradoxical effect in increasing delirium in some patients. These drugs may cause exaggerated adverse effects, including sundowning. Other medications implicated in delirium are narcotic analgesics, benzodiazepines, theophylline, and antiparkinson medications.
Patients presenting with an acute confusional state should be evaluated first with a careful history, taken from a reliable person who knows the patient well (if possible), and a physical examination. The history should include details of prior illnesses, a complete medication list, and a historical baseline level of function. It also should include the temporal course of the changes in mental status.
The context of the syndrome is especially important—the location of the patient when the condition was first noticed, eg, the intensive care unit, nursing home, or psychiatric ward.
Underlying or past medical conditions such as diabetes, hypertension, infections, and prior strokes should be documented.
The historian should ascertain whether the patient has suffered confusional episodes before and whether he or she recovered. Preexisting cognitive deficits or dementia are potent risk factors for the development of delirium in association with illness, hospitalization, or surgery.
The features of confusion should be elucidated. Is the patient wakeful and alert, or sleepy; agitated, or calm; aphasic, or with normal language and speech?
Alcohol and substance abuse history should be documented.
All medications currently being administered to the patient should be reviewed, as well as reconciliation with home medications. Withdrawal from sedative or hypnotic drugs such as benzodiazepines can mimic alcohol withdrawal or delirium tremens.
If the patient is unable to communicate verbally, the examiner should evaluate whether he or she can communicate with eye blinking and vertical eye movements (ie, locked-in syndrome). The examiner should also look for evidence of subtle seizures, such as eye blinks, facial twitches, or automatisms.
The physician must also look for signs such as fever, confusion, and seizures (as in herpes encephalitis), or stiff neck and fever (as in meningitis or subarachnoid hemorrhage). These are true medical emergencies. One should also determine whether systemic diseases with neurologic ramifications have been diagnosed. For a few specific examples, eosinophilia and asthma might suggest Churg-Strauss syndrome; peripheral neuropathy and renal disease might suggest polyarteritis nodosa; hemoptysis might suggest Wegener granulomatosis.
Careful review of laboratory studies is imperative, especially the complete blood count, electrolytes, BUN, creatinine, glucose, liver function tests, thyroid function tests, and urinalysis. Brain imaging (CT or MRI scanning) is mandatory in any patient with focal abnormalities on neurologic examination.
The examination should be complete enough to consider diseases of virtually any organ system. The neurologic examination should look especially at disorders of higher function, such as aphasia or neglect. Other focal neurologic findings such as eye movement and other cranial nerve abnormalities, motor, sensory, and cerebellar findings should be noted.
Examine the general behavior and comment on level of arousal, alertness, and agitation.
Patients with delirium, in addition to their "negative" symptoms and signs of deficient cognitive functions, have "positive" symptoms such as agitation, restlessness and hyperactivity, delusional thinking, hallucinations, and anxiety.
Patients with delirium, unlike those with dementia, frequently have autonomic abnormalities such as tachycardia, hypertension, fever, sweating, and piloerection.
Examine vital signs, neck stiffness, airflow, lungs, heart, and any abnormal movements such as tremor, myoclonus, tonic-clonic activity, or asterixis.
Specific neurologic signs should also be sought carefully. These include a detailed examination of higher functions; wakefulness and arousal should be tested first.
Language should be tested carefully, including the ability to name, repeat, comprehend, read, write, and utter spontaneous speech. Aphasia is frequently mistaken for confusion by emergency department staff.
Hemispatial attention should be checked (attention to the left side of the body and/or the left side of space is often abnormal in focal disorders of right hemisphere) by asking the patient to draw, point to people in the room, or read. If not specifically sought, the neglect syndrome will be missed.
Look for subtle movements of the face or eyes that are indicative of seizures.
Eye movements to command should be checked if the patient appears unable to communicate (i.e., locked-in syndrome).
Extinction to double simultaneous stimulation (visual, auditory, tactile, or somatosensory) may be features of the neglect syndrome. Assess whether the patient recognizes his or her illness and deficits. Anosognosia is defined as the denial or neglect of illness, commonly occurring after right hemisphere injuries.
The cranial nerve, motor, sensory, and cerebellar examinations should be geared toward discovering other neurologic signs that can help with localization or uncover an underlying condition. Specific examples of examination findings and their significance follow.
The cranial nerve examination should include funduscopic examination. Subhyaloid hemorrhages may be seen in cases of subarachnoid hemorrhage or trauma, and papilledema or absent venous pulsations may indicate increased intracranial pressure.
The visual fields should be checked with finger counting or response to threat, to discover subtle visual field defects or visual neglect/extinction.
Facial symmetry can usually be assessed, as can gag reflex. A swallow test may be needed to determine if the patient can safely swallow oral food, liquids, and medications.
Motor examination may show a subtle hemiparesis (eg, pronator drift, subtle proximal or distal unilateral weakness).
Focal long-tract signs (eg, hyperreflexia, Babinski sign), unilateral incoordination (ie, cerebellar lesion), and crossed sensory findings (eg, Brown-Sequard syndrome, brainstem lesion) can be the key to diagnosis of a focal lesion.
Evaluating whether the patient can walk is crucial. Cerebellar hemorrhages and infarctions may be missed unless gait testing is performed.
Potential causes of delirium are numerous. A good clinician is thorough and systematic in the evaluation.
Intoxication
Intoxicants can include prescription and over-the-counter medications, as well as alcohol and illicit drugs. Although these causes often are suspected in the emergency department (ED), they may be unsuspected in other settings (eg, postoperative delirium tremens in closet alcoholics).
Iatrogenic toxicity can occur in patients taking prn (as needed) sedatives, especially elderly patients, or can be due to unsuspected drug interactions. Antipsychotic medications, for example, may worsen memory in patients with underlying Lewy body disease, a type of progressive dementia.
Anticholinergic medications cause acute confusion and amnesia. Scopolamine patches, antidepressants such as amitriptyline, antispasmodics for irritable bowel syndrome, medications for neurogenic bladder such as oxybutynin, or tranquilizers such as haloperidol all have anticholinergic effects.[22]
Prescription medicines may be used inappropriately. Prednisone, dexamethasone, and other corticosteroids can cause paradoxical confusion, as can a host of other medications.
Use of serotonergic drugs can result in serotonin syndrome, a potentially life-threatening condition.[23, 24] Current housestaff hour limits were brought on by the case of Libby Zion, a young woman who became delirious and then died, as a result of treatment with multiple antidepressant and other psychotropic medications, as well as narcotic analgesics when she became agitated, resulting in the serotonin syndrome.[25]
Neuroleptic malignant syndrome is another drug-induced condition, usually brought about by dopamine-blocking agents such as neuroleptics. Delirium, diffuse rigidity, and hyperthermia can result. Treatment includes both dopaminergic agents and general supportive care.
Polypharmacy is a major cause of delirium. Patients may receive antidepressant or antianxiety medications from a psychiatrist, sleep aids from an internist, and anticholinergic medications from a urologist or gastroenterologist, and these drugs may be additive in their cognitive effects. Narcotic analgesics are also factors in many postoperative delirium cases.
Alcohol
Confusional states due to alcohol are sufficiently important, complex, and common to merit their own category.
The discussion of alcoholic dementia overlaps with that of nutritional dementia, traumatic dementia, epileptic dementia, vascular dementia, and toxic dementia due to illegal drugs, as these conditions tend to exist in the same patients.
Alcohol withdrawal leads to the prototypic delirium, delirium tremens.
Patients with alcoholism are typically malnourished and are at risk for Wernicke-Korsakoff disease, which includes confusion and memory loss, eye movement abnormalities, and ataxia. Administration of thiamine is essential to prevent permanent deficits.
The CT scans may show atrophy and hemorrhage due to thiamine deficiency, orbitofrontal or temporal contusions that may be signatures of prior trauma, or subdural hematomas. EEG results may be significant for seizure activity.
Closet alcoholics can present with delirium tremens several days after admission to the hospital. Electrolyte imbalances are common.
Metabolic, nutritional, and endocrine disorders
Organ failure syndromes
Azotemia
Chronic lung disease with hypercarbia or hypoxia
Hepatic failure
Hyperammonemia (Asterixis may be a clue to hyperammonemia.)
Nutritional deficiencies
Pellagra
Wernicke-Korsakoff syndrome (thiamine deficiency)
Vitamin B-12 deficiency
Endocrine syndromes
Hypothyroidism or hyperthyroidism, Hashimoto encephalopathy
Cushing syndrome
Hyperparathyroidism
Diabetic ketoacidosis
Metabolic disorders
Hyponatremia
Hypercalcemia
Hypoglycemia or hyperglycemia
Focal brain lesions
Focal brain lesions occasionally cause acute confusion. Subdural hematomas, strokes, cerebral hemorrhages, and mass lesions such as brain tumors or abscesses may be found on CT and MRI scans. Contrasted scans are more sensitive for mass lesions. If the confusion is due to increased intracranial pressure, as in a subdural hematoma, arousal may be most affected, and the patient may be sleepy. If the confusion is due to a stroke, aphasia may have been misdiagnosed as confusion. On the other hand, delirium has been reported frequently with infarctions in specific vascular territories, especially the posterior cerebral artery, the anterior cerebral artery territory, or the inferior division of the middle cerebral artery (left hemisphere stroke with Wernicke aphasia or the homologous area of the right hemisphere).[26, 27, 28]
Deep lesions of the caudate nucleus, thalamus, or basal forebrain have also been associated with delirium and amnesia.
Strokes are more likely to be associated with delirium if the patient is elderly, has coexistent cortical atrophy on imaging studies, or has associated seizures.[29, 30]
Brain tumors often develop slowly, allowing the brain to compensate; therefore, they are somewhat less likely to present as acute confusional states. Seizures, infections, or medication effects can induce delirium in a patient with a brain tumor.
Infections
Urinary tract infections and pneumonias are common infections that cause confusion in debilitated, nursing home, and other elderly patients.
Meningitis and encephalitis are causes of delirium. The association of delirium with fever or stiff neck should trigger evaluation for these conditions with urgent brain imaging and lumbar puncture. Chronic meningitis is not the exclusive domain of the immunosuppressed; in fact, cryptococcal meningitis, tuberculous meningitis, and carcinomatous meningitis may occur even with minimal symptoms, such as mild headache or confusion. Diabetics and elderly patients may have bacterial meningitis with minimal fever. Elderly nursing home residents may have Listeria meningitis that responds to ampicillin rather than third-generation cephalosporins. Patients from areas of endemic tuberculosis may be susceptible to tuberculous meningitis.
Syphilis used to be a common cause of delirium. In the current era, HIV and related opportunistic infections, West Nile encephalitis, herpes simplex encephalitis, and Lyme disease are common infectious causes of delirium.
Epilepsy
Epileptic seizure states can present with confusion. Patients may have nonconvulsive status epilepticus, a condition that can be easily diagnosed and treated. Two principal types of nonconvulsive status epilepticus have been recognized: absence status and complex partial status epilepticus. Both types may occur in patients without a history of prior seizures. These types are differentiated by the EEG findings. In absence epilepsy, spike-and-wave discharges are seen at a rate of 3 per second. In complex partial status epilepticus, the more common type, a focal discharge pattern may be seen.
In younger patients, the Landau-Kleffner syndrome is a potentially treatable epileptic condition. Landau-Kleffner syndrome involves acquired aphasia with a convulsive disorder in previously healthy children who acutely or progressively lose language function. Patients typically have a severe comprehension defect, especially involving auditory agnosia. The seizures in Landau-Kleffner patients usually respond to anticonvulsive therapy, but the language disorder often persists.
Developmental disorders
Occasionally, a patient with an underlying developmental disorder persisting into adulthood, or a metabolic disease commonly presenting in adulthood may present with confusion. These conditions are much more common in children, and adult neurologists typically have difficulty in diagnosing developmental disorders in children. For more information on the many metabolic diseases affecting the nervous system, the interested reader is referred to textbooks of child neurology.
Developmental disorders are particularly prevalent in institutionalized patients, and tragically, only a few of the diseases are treatable. To cite just a few examples, adrenoleukodystrophy, metachromatic leukodystrophy (MLD), and cerebrotendinous xanthomatosis may present in adults. Adrenoleukodystrophy and MLD can be diagnosed by a characteristic pattern of demyelination on MRI. Cerebrotendinous xanthomatosis should be suspected in an individual with an abnormal gait and xanthomas of the Achilles tendons, eyelids, and patellae, due to deposition of cholestanol in the central and peripheral nervous systems. This disorder can be treated.
Inflammatory conditions in the CNS include the rare, but treatable, conditions of CNS vasculitis and Hashimoto encephalopathy. Of note, patients with known lupus often have strokes due to nonbacterial thrombotic endocarditis (NBTE), hypercoagulable states related to antiphospholipid antibody, hypertension, or CNS dysfunction due to antibodies to neuronal tissues (antineuronal antibodies with ribosomal p protein, with CNS appearing normal on light microscopy). More often than not the coexistence of lupus and encephalopathy leads to a diagnosis other than vasculitis.
Certain patterns of disease that suggest CNS vasculitis occur in conjunction with specific vasculitides. Their importance is related in part to the specificity of the respective treatments. Polyarteritis nodosa, a disease of small- and medium-sized blood vessels, often affects the heart and kidneys. Neurologic disease includes peripheral neuropathies, seizures, visual loss (due to involvement of optic structures), subarachnoid hemorrhage, and stroke. The survival rate is markedly better in patients who receive the therapeutic combination of cyclophosphamide (Cytoxan) and corticosteroids than in those who receive corticosteroids alone or no treatment (5-year survival rates, 18% in untreated patients; 55% in those treated with corticosteroids alone and 79% in those with combined treatment).
Wegener granulomatosis, a systemic necrotizing granulomatosis, involves the upper and lower respiratory tracts, glomeruli, peripheral nerves, and cranial nerves. Patients often have circulating antineutrophilic cytoplasmic antibodies (ANCA). The disease once was considered fatal within 4-6 months in untreated patients and within 11 months in those treated with prednisone. Long-term survival is now routine in patients treated with the combination of prednisone and cyclophosphamide. Trimethoprim-sulfamethoxazole may decrease the relapse rate in some patients.
Isolated CNS vasculitis can present with headaches, encephalopathy, and multifocal signs. Isolated CNS vasculitis should be diagnosed only according to strict criteria, including recurrent, multifocal vascular disease, exclusion of a systemic inflammatory of infectious process, angiography supportive of the diagnosis, and brain biopsy to exclude infection or neoplasia. Without the presence of these criteria, the diagnosis can be considered speculative. Therapy with cyclophosphamide and prednisone may result in long-term remission or cure.
Hashimoto encephalopathy is a condition characterized by severe encephalopathy, seizures, and high circulating titers of antithyroid antibodies. The disorder likely reflects antibody-mediated inflammation in the CNS, since most patients with the condition are clinically euthyroid. EEG findings may be moderately abnormal, and the patient may respond to corticosteroid therapy.
Dementia
Underlying dementia is present in many patients with delirium, but it should be a diagnosis of exclusion. Dementia, unlike delirium, is not readily reversible with correction of an underlying toxic, metabolic, or infectious disorder. Like delirium, dementia involves a loss of cognitive functions such as language, perception, attention, and memory. Unlike delirium, however, dementia is usually defined as a progressive or permanent state. Dementia usually lacks the alteration of consciousness, psychomotor abnormalities, and autonomic disturbances that are so common in delirium.
Dementia, once thought to be monolithic and more or less untreatable, can often be further fractionated and diagnosed by clinical examination and laboratory testing. Research is continuing into imaging characteristics and biological markers for specific dementias such as Alzheimer disease, frontotemporal dementia, Lewy body dementia and Parkinson disease with dementia, vascular dementia, and Creutzfeldt-Jakob disease.
Visual hallucinations and a paradoxical response to antipsychotic medications make Lewy body disease, rather than Alzheimer disease, the likely diagnosis. Prominent behavioral or language disturbance increases the possibility of Pick disease or frontotemporal dementia. Marked apraxia of one hand makes the diagnosis of corticobasal ganglionic degeneration more likely.
Presence of abnormal eye movements (especially vertical eye movements) may indicate progressive supranuclear palsy, although the physician should not forget to consider thiamine deficiency or Whipple disease in this situation.
Again, dementias can underlie or accompany delirium. The diagnosis usually does not require lumbar puncture, except in the case of Whipple disease or suspected infectious illnesses such as chronic meningitis.
Vascular dementia
Vascular dementia refers to dementia related to vascular disorders, especially strokes. The strokes may be cortical and have localizing features, depending upon the strategic locations of cortical infarctions.
Vascular dementia also refers to dementia due to multiple subcortical strokes, which are caused by extensive disease of the smallest caliber blood vessels.
This has been known by multiple names, including Binswanger disease, état lacunaire, leukoaraiosis (referring to the radiographic or MRI appearance of white matter rarefaction), and others.
Up to 30% of strokes are followed within 1 year by significant cognitive dysfunction or dementia. Strokes involving the left thalamus, thalamocortical radiations, or cortical areas are particularly likely to be associated with dementia. These strategic locations of stroke, or multiple strokes, carry the highest risk of dementia.
Notably, the presence of subcortical strokes, even extensive ones, does not preclude Alzheimer disease.
Clinically, patients with Binswanger disease have not only the radiographic characteristics but also distinct presenting features. These may include gait abnormalities and difficulties with memory, such as 3-word recall, and frontal lobe tests, such as the Thurstone or the go, no go paradigm.
Typically, such patients do not have cortical cognitive syndromes such as anomia, apraxia, agnosia, and neglect, typically seen with cortical lesions.
Some cases are associated with severe hypertension or elevation of the fibrinogen level.
Laboratory tests that should be considered routinely include sodium, chloride, BUN, creatinine, glucose, calcium, magnesium, phosphorus, CBC and differential, liver function tests, and toxicology screen.
Other tests to be considered urgently are arterial blood gases, urinalysis and culture, chest radiograph, antiepileptic drug levels, alcohol levels, plasma ammonia, and lumbar puncture.
Albumin and cholesterol can serve as markers for nutritional status.
Cobalamin levels (with or without levels of precursors homocysteine and methylmalonic acid), thyroid function tests (including thyroid antibodies), syphilis serology, antinuclear antibody, and sedimentation rate are also important in cases of unexplained delirium.
If the condition is acute, CT scan of the head or MRI should be performed.
MRI diffusion-weighted images are sensitive for acute stroke, gradient echo or T2* sequences are sensitive for blood products, and fluid-attenuated inversion recovery (FLAIR) images are especially sensitive to lesions associated with delirium.
Angiography is necessary to confirm the diagnosis of cerebral vasculitis. Multiple ischemic lesions on MRI and evidence of inflammation in the CSF, such as elevated protein and pleocytosis, on lumbar puncture, may be used as screening tests for vasculitis, along with the clinical features of multifocal stroke syndromes accompanied by headache. Markers for systemic vasculitis such as the sedimentation rate, ANA, and ANCA are also helpful.
EEG can help to detect and diagnose seizures, prion disease, hepatic encephalopathy, and focality related to stroke, and it can help differentiate psychiatric from organic disease (EEG findings are normal in virtually all purely psychiatric disorders).
Patients with seizures typically have abnormal EEG findings (about 70% of the time).
EEG findings are typically at least moderately abnormal, often nonspecifically, in an infectious or inflammatory condition of the cerebrospinal fluid (CSF), whereas they are likely to be only mildly abnormal in a straightforward dementia.
Patients with herpes encephalitis often have periodic lateralizing epileptiform discharges that are, in the appropriate setting, nearly diagnostic.
Patients with Creutzfeldt-Jakob disease may have periodic sharp waves, although the finding is more specific than sensitive and may not occur until late in the disease. Slowing of the background rhythms tends to be present even early in the disease.
Patients with psychiatric disease, such as mania, have normal EEG findings, whereas patients with delirium usually have diffuse slowing of the background rhythm. Although neurologic disease is not excluded by normal EEG findings, a normal EEG can be a clue that the problem is psychiatric.
Lumbar puncture should be performed if CT scan findings are negative and neurologic infection is suspected, or if the patient is elderly or diabetic or has reason not to have fever with an episode of meningitis.
The CSF should be sent for glucose, protein, cells and differential, Gram stain, and cultures.
Cryptococcal antigen, acid-fast bacilli (AFB), cytology, and Venereal Disease Research Laboratory test (VDRL) also may be sent.
If a preexisting dementia is suspected, the CSF can also be sent for markers of Alzheimer disease, especially A-beta-42, and in a subacute to acute dementia the 14-3-3 protein associated with Creutzfeldt-Jakob disease.
Another CSF study that may be useful diagnostically is measurement of the ratio of gamma globulin synthesis in the CSF compared to serum (IgG index) and oligoclonal bands. A positive finding, while nondiagnostic, suggests the presence of an infectious or inflammatory condition in the nervous system rather than a metabolic encephalopathy.
Brain biopsy is often considered in cases that are diagnostically puzzling. In practice, brain biopsy and biopsy of the leptomeninges can be helpful in the diagnosis and treatment of rare infectious and inflammatory conditions. Brain biopsy should always be considered a last resort, since less invasive tests can often confirm a diagnosis, and a biopsy can be nondiagnostic, leaving the clinician and patient at "square one." In actual practice, brain biopsy should be reserved for exceptional cases in which treatment is likely to be altered by the biopsy result.
The acutely confused patient must first and foremost be evaluated thoroughly. For example, in a hyponatremic, confused patient, one would not want to miss the subdural hematoma that caused the syndrome of inappropriate antidiuretic hormone (SIADH) in the first place, which resulted in the hyponatremia. In addition to diagnosis, the evaluation should include routine measures that can in some instances be life-saving.
Patients should receive thiamine, followed by glucose, on arrival to the ED, and subsequently naloxone and flumazenil. In patients treated for long periods with narcotics, eg, cancer patients, exceptionally high doses of naloxone must be administered.
Magnesium and phosphorus should be replaced and sodium should be normalized at appropriate rates. In hyponatremia, too-rapid correction may cause central pontine myelinolysis (osmotic demyelination syndrome) and paraparesis or quadriparesis.
Empiric antibiotic treatment should be given while awaiting culture results if septicemia is suspected. The specific etiology needs to be found and treated appropriately.
If delirium tremens occurs, benzodiazepines should be administered, especially lorazepam (as it is not hepatically cleared and is long acting in the CNS).
On the wards, or in the home, the physician may receive gentle suggestions from nurses, caregivers, or other health care providers to treat patients with antipsychotic medication, benzodiazepines, or other sedatives. In general, such treatment should be avoided if sedation interferes with necessary neurologic examinations. For example, a patient with an acute subdural hematoma might need to be assessed serially, perhaps every 2 hours or more often, to determine if he or she has become more lethargic; in this case medicating an agitated patient might be catastrophic, because the deterioration would be missed. In patients with less acute illness, sedation is sometimes used for the benefit of the facility rather than the patient. A rule of thumb might be to avoid giving such sedatives if the safety and well-being of the patient and caregivers is not at stake.
Inouye and colleagues[31] have developed a program to prevent delirium by correcting perceptual deficits in vision and hearing, preserving day/night cycles in the ICU, and avoiding rapid environmental changes. Moving a patient to a single room with 1:1 supervision can also be helpful.[32] In general, drug therapy for either prevention or treatment of delirium is less effective than these behavioral measures and should be minimized.[33]
Unless the patient has a surgical condition causing the confusion, surgical care is not indicated. Consider a neurosurgical referral urgently if the patient has a subdural hematoma on neuroimaging. See Workup for discussion of brain biopsy for vasculitis.
Neurologic consultation often is obtained early on, either immediately or after the initial studies have been performed in the ED.
Infectious disease consultation may be helpful to evaluate for an appropriate empiric antibiotic regimen.
Psychiatric consultation is often obtained for delirium and may be appropriate in cases of alcoholism, mania, or psychiatric illnesses. In addition, psychiatrists are familiar with pharmacotherapy and with evaluation of mental capacity.
Social service evaluation of the home setting, both to obtain additional history and to help manage the disposition, is often helpful.
Other consultations may be obtained on a case-by-case basis, depending on the etiology.
Dietary consultation may be needed if liver disease is present or if the patient is malnourished, requires nasogastric feeding, or is chronically malnourished because of living alone. A calorie count may be indicated.
If the patient is diabetic or has hepatic encephalopathy, restriction of sugar and calories, or protein, respectively, is indicated.
Patients with chronic weight loss due to alcoholic/nutritional or degenerative dementia may require caloric supplements.
Confused patients are often restrained, but other approaches should be considered. Although restraints can prevent falls and the removal of lines and tubes, the risk for these events should be reassessed daily. The presence of family or an attendant, or even a sitter, can have a calming effect on many agitated patients and preclude the need for constant restraints. If possible, the exposure of patients to sunlight and increasing out-of-bed activity can be calming and healing, limiting the necessity of restraints.
As mentioned above, Inouye and others have shown that gentle conversation, use of hearing and visual aids, frequent reminders of orientation, and other, simple measures can be effective in preventing and/or treating delirium.[31]
However, if the patient remains at a high risk for falls, restraints can be used, especially bed alarms, beds with mesh netting, and occasionally physical restraints. In an intensive setting in which the patient has arterial lines, Foley catheters, and nasogastric tubes in place, wrist restraints may be required.
In general, a specific diagnosis must be made before selecting a medication to be used; however, treatment must begin while awaiting the results of studies, even in the absence of a diagnosis. On arrival to the ED, administration of thiamine and glucose, followed by naloxone and flumazenil, is important. Empiric antibiotics can be given if an infection is suspected. Acyclovir should be administered if the physician has any suspicion of herpes encephalitis, because early treatment can prevent long-term neurologic damage. The diagnosis of herpes encephalitis by polymerase chain reaction (PCR), or even by EEG or MRI, can be done later. Most other medications depend upon the diagnosis.
Thiamine, naloxone, flumazenil, glucose, and acyclovir are used to reverse coma due to treatable causes, including Wernicke-Korsakoff syndrome, opiate intoxication, benzodiazepine intoxication, and herpes encephalitis, respectively. In cases of vasculitis or Hashimoto encephalopathy, corticosteroids or cyclophosphamide or both may be indicated, depending on the type (see Causes).
Clinical Context:
Can quickly reverse coma, encephalopathy, or extraocular muscle paresis due to thiamine deficiency, which is seen most commonly in alcoholic/nutrition-related confusional states.
Clinical Context:
Quickly reverses coma due to opiate ingestion. Appropriately given in emergency settings in which opiate intoxication is suspected or considered.
Clinical Context:
Quickly reverses intoxication due to benzodiazepines. Appropriately given in settings in which benzodiazepine intoxication suspected as cause of coma.
Clinical Context:
Useful for treatment of herpes simplex encephalitis. Because definitive diagnosis by MRI, EEG, or DNA may be delayed by several days, patients with suspected disease should be treated until condition ruled out.
Once a diagnosis is made, the patient requires follow-up until the confusional state resolves or a plateau is reached. In general, good follow-up requires observation and also consideration of the many etiological factors in delirium discussed in this article, including monitoring of medications and laboratory parameters. The specific follow-up tests depend on the diagnosis. Many clinicians underestimate the degree of improvement that is possible in confused patients, even confused elderly patients.
Behavioral interventions may help to prevent delirium and even help limit or reverse delirium after it has developed. Inouye and colleagues[31] studied a prospective prevention program called the Elder Life Program in hospitalized patients older than 70 years, including such measures as frequent orientation reminders, the use of large clocks and calendars, avoidance of visual or auditory deprivation by use of glasses and hearing aids, use of sitters instead of restraints, mobilization during the day, and promotion of proper sleep-wake cycles by making the environment dark and quiet at night, as well as avoidance of malnutrition and dehydration. Delirium developed in 9.9% of the active group versus 15% of control group (p=0.02). This program was expensive, but simpler measures may be somewhat effective.
Flaherty and colleagues[32] reported on a similar program with the development of a “delirium room” in which patients are treated specially, with avoidance of Foley catheters and restraints, use of extra attendants to talk to patients and keep them active. Only 29% of the 69 elderly patients treated in the delirium room required benzodiazepines or atypical antipsychotic drugs. Only 9 patients (13%) lost function, and none died. These authors stated that, with proper care, most delirium is reversible.
The reader is also directed to a more comprehensive review of older literature by the author.[34]
The prognosis of confusional states is highly variable. Patients frequently become much better than the expected recovery predicted by the admitting physicians. The prognosis may depend on general medical care and attention, rather than specific management of the encephalopathy. Many patients with confusional episodes recover completely. Unfortunately, some patients are left with chronic neurocognitive deficits.[12, 13, 14, 15]
Howard S Kirshner, MD, Professor of Neurology, Psychiatry and Hearing and Speech Sciences, Vice Chairman, Department of Neurology, Vanderbilt University School of Medicine; Director, Vanderbilt Stroke Center; Program Director, Stroke Service, Vanderbilt Stallworth Rehabilitation Hospital; Consulting Staff, Department of Neurology, Nashville Veterans Affairs Medical Center
Disclosure: Nothing to disclose.
Specialty Editors
Robert A Hauser, MD, MBA, Professor of Neurology, Molecular Pharmacology and Physiology, Director, USF Parkinson's Disease and Movement Disorders Center, National Parkinson Foundation Center of Excellence, Byrd Institute, Clinical Chair, Signature Interdisciplinary Program in Neuroscience, University of South Florida College of Medicine
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Salary Employment
Richard J Caselli, MD, Professor, Department of Neurology, Mayo Medical School, Rochester, MN; Chair, Department of Neurology, Mayo Clinic of Scottsdale
Disclosure: Nothing to disclose.
Chief Editor
Michael Hoffmann, MBBCh, MD, FCP(SA), FAAN, FAHA, Professor of Neurology, University of Central Florida College of Medicine; Director of Cognitive Neurology, Director of Stroke Program, James A Haley Veterans Affairs Hospital
Disclosure: Nothing to disclose.
Additional Contributors
The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author Daniel H Jacobs, MD to the development and writing of this article.
American Psychiatric Association. American Psychiatric Association. In: Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington: Text rev; 2000.
Kirshner HS. Delirium and acute confusional states. In: Behavioral Neurology. Practical Science of Mind and Brain. 2nd ed. Boston, Mass: Butterworth Heinemann; 2002:307-24.