Confusional States and Acute Memory Disorders

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Background

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:

Delirium has been subdivided into 4 motoric subtypes, based on the alteration of level of consciousness.[4]

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.

Pathophysiology

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.

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.

Epidemiology

Frequency

United States

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.

History

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.

Physical

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.

Causes

Potential causes of delirium are numerous. A good clinician is thorough and systematic in the evaluation.

Intoxication

Alcohol

Metabolic, nutritional, and endocrine disorders

Focal brain lesions

Infections

Epilepsy

Developmental disorders

Dementia

Vascular dementia

Laboratory Studies

Imaging Studies

Other Tests

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).

Procedures

Medical Care

Surgical Care

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.

Consultations

Diet

Activity

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.

Medication Summary

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).

Thiamine (Thiamilate, Vitamin B-1)

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.

Class Summary

These agents are essential for normal DNA synthesis and various metabolic processes.

Naloxone (Narcan)

Clinical Context:  Quickly reverses coma due to opiate ingestion. Appropriately given in emergency settings in which opiate intoxication is suspected or considered.

Class Summary

This agent inhibits opiate effects.

Flumazenil (Mazicon)

Clinical Context:  Quickly reverses intoxication due to benzodiazepines. Appropriately given in settings in which benzodiazepine intoxication suspected as cause of coma.

Class Summary

This agent inhibits benzodiazepine effects.

Acyclovir (Zovirax)

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.

Class Summary

These agents are used to inhibit viral growth.

Further Inpatient Care

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.

Deterrence/Prevention

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]

Complications

If the patient is not evaluated thoroughly, complications may occur. Usually, if the diagnosis is made, the treatment is obvious.

Prognosis

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]

Author

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

Disclosure: Ingelheim Pharmaceuticals, Inc Honoraria Advisory Board; Teva Neuroscience Honoraria Advisory Board; Impax Pharmaceuticals Honoraria Advisory Board; UCB, Inc Honoraria Advisory Board; GE Healthcare Honoraria Advisory Board; IPSEN Pharmaceuticals Honoraria Advisory Board; Novartis Pharmaceuticals Advisory Board; Parkinson Study Group Honoraria Advisory Board; Solvay Pharmaceuticals Honoraria Advisory Board; Quintiles Honoraria Advisory Board

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.

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