5 - Delirium and Dementia
Editors: Shader, Richard I.
Title: Manual of Psychiatric Therapeutics, 3rd Edition
Copyright 2003 Lippincott Williams & Wilkins
> Table of Contents > 5 - Delirium and Dementia
5
Delirium and Dementia
Sandra A. Jacobson
Richard I. Shader
Historically, two dysfunctional states, delirium and dementia, were considered pure or prototypical organic disorders. In the 17th century, dementia was synonymous with madness or insanity of all origins; now, it primarily refers to a pathologic process that is often progressive and that, carried to its end point, leaves the patient literally without mind. Intellect, personality, and cognitive abilities deteriorate. Attendant psychiatric and behavioral dysfunction becomes prominent, and self-care ultimately becomes impossible. Estimates suggest that between 2.8 and 6.8 million people in the United States have dementia.
Delirium literally refers to being off-track, a term that is derived from the Latin lira, meaning rows or furrows. In delirium, reduced awareness and altered attention are of recent and usually rapid onset. Consciousness ranges between normal wakefulness and stupor; dramatic fluctuations may be seen in the course of a day.
The decision to review delirium and dementia at this point in the manual is based on the goal of giving those who might be reading the chapters consecutively a perspective on differential diagnosis. The scales contained in Appendices IV, V, and VI may be helpful aids when screening for delirium or dementia.
I. Delirium
A. Diagnosis and General Observations
Delirium is a syndrome of disturbed consciousness, attention, and cognition or perception that develops acutely and fluctuates during the course of the day. Delirium is always is attributable to a medical disorder. Delirious patients are often confused and intermittently agitated, and they experience delusions, as well as hallucinations (often visual). Delirium is common in hospitalized patients, and it is associated with high morbidity from events such as falls and self-extubation. Mortality rates are also high, secondary in part to noncompliance but mostly attributable to associated disease. The presence of delirium predicts a longer hospital stay, cognitive decline after hospitalization, and a loss of independent living in the community. The most important fact about delirium, however, is that it always signals the presence of an underlying medical or surgical condition and, in some cases, a life-threatening one. Table 5.1 contains some of the more frequently encountered causes of delirium.
Delirium is part of the differential diagnosis for the cognitively impaired patient, and the need to determine the etiology drives much of the diagnostic workup for cognitive dysfunction. The initial evaluation includes a history and physical examination; the latter includes both neurologic and mental status assessments. The clinician-administered Mini Mental State Examination is a useful indicator of global cognitive dysfunction, which is disturbed in delirium, as it is in dementia (see Appendix V). The presence of a disturbance of consciousness with prominent attentional difficulties distinguishes delirium from dementia. An electroencephalogram can be useful in patients who are difficult to assess. The electroencephalogram is an extremely sensitive indicator of functional changes in delirium.
At this stage of the evaluation, a syndromal diagnosis is made (e.g., delirium; dementia; or single-domain impairment, such as amnestic disorder), and a differential diagnosis of etiology is formulated. Laboratory examination then helps to identify the etiology.
The standard laboratory workup for a delirious patient includes hematology (complete blood count with differential, platelet count, sedimentation rate), albumin, blood urea nitrogen, creatinine, electrolytes, glucose, liver and thyroid function tests, drug levels or toxic screen, urinalysis, electrocardiogram, and chest
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x-ray. The chest x-ray, electrocardiogram, and urinalysis are particularly important for elderly delirious patients. Depending on the findings from this initial evaluation and the particular presentation of the patient, further laboratory evaluation may be performed, including computed tomography or magnetic resonance imaging of the brain, lumbar puncture, electroencephalogram, arterial blood gases, cardiac enzymes, or blood cultures.
TABLE 5.1. SELECTED ETIOLOGIES OF DELIRIUM | |
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B. Treatment
Definitive treatment of the cause of delirium (e.g., correction of hyponatremia, treatment of infection) always takes precedence over symptomatic treatment. Definitive treatment is specific to the cause(s) of delirium, and thus it is not discussed further here.
Environmental interventions are useful in most cases of delirium. These include close observation; consistent staffing; orienting cues, such as a clock and calendar; familiar personal effects, such as photos; and visits from family and friends. The patient usually appreciates reassurance, even if he or she does not have good recall of specific information or explanations.
Symptomatic treatment with a pharmacologic agent is not always required, but, when it is (e.g., for control of agitation or psychosis), a conventional high-potency antipsychotic agent, such as haloperidol, is currently the drug of choice. This approach is appropriate for all delirious patients, except for those undergoing alcohol or sedative withdrawal (see below) and those with significant hepatic impairment. Patients posing a danger to self or others are best treated with parenteral preparations, preferably intravenous (i.v.), but oral dosing can be used. For the nonelderly patient, dosing guidelines are as follows: haloperidol, 2 mg i.v. for mild agitation, 5 mg i.v. for moderate agitation, and 10 mg i.v. for severe agitation. For elderly patients, smaller doses are used as follows: 0.25 to 0.5 mg i.v. for mild agitation, 1 mg i.v. for moderate agitation, and 2 mg i.v. for severe agitation. The dose can be repeated or doubled every 30 to 60 minutes until the patient is calm. Most patients respond to one or two doses. When bolus doses of haloperidol reach the range of 5 to 10 mg, consideration should be given to the adjunctive use of a benzodiazepine, such as lorazepam. As an alternative, an infusion of haloperidol, starting at 1 mg per h, may be used, with titration to response. Rates as high as 15 to 25 mg per h of haloperidol have been
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documented in younger patients. When i.v. haloperidol therapy is used, the QTc interval must be monitored, because the use of i.v. haloperidol can be associated with prolongation of the QTc interval and a torsade de pointes pattern of ventricular tachycardia. Prolongation of the QTc interval beyond 25% of baseline or to greater than 450 ms may predict the development of torsade de pointes. When this is observed, haloperidol use should be discontinued. Droperidol, which is faster acting and more sedating, has been recommended as an alternative to haloperidol. However, droperidol has recently been shown to have a more significant effect on QTc prolongation. Droperidol is no longer available in some countries.
When behavioral control has been achieved, the patient requires a continuation of the haloperidol to prevent the reemergence of symptoms. Exact dosing is guided by frequent clinical assessments. A commonly used regimen for a nongeriatric patient is 1 mg i.v. every 8 hours; for a geriatric patient, the dose is 0.25 mg i.v. every 8 hours. When the symptoms begin to clear, the haloperidol is tapered over 3 to 5 days.
Atypical antipsychotic agents are in use for the treatment of delirium in some centers, although neither United States Food and Drug Administration approval nor controlled studies for this indication exist. The requirement for gradual dosage titration with all atypical antipsychotic agents limits their usefulness in delirium. Recently, intramuscular forms of olanzapine and ziprasidone have been approved, but the place of these formulations in delirium treatment is still unclear.
The cholinesterase inhibitor donepezil is in use for the symptomatic treatment of delirium in many hospital settings. Data from controlled studies are not available. Anecdotal experience suggests that donepezil (5 mg per d orally [p.o.]) can be effective and well tolerated but that it may not be as immediately effective as haloperidol. Because of the long half-life of donepezil (more than or equal to 72 hours), some clinicians prefer the shorter-acting cholinesterase inhibitors rivastigmine and galantamine.
For critically ill patients, such as those on ventilators or intraaortic balloon pumps in whom agitation poses a medical hazard, and for terminally ill cancer patients, more aggressive treatment of agitation may be needed. One highly effective regimen is a combination of haloperidol, lorazepam, and hydromorphone that is administered i.v.
For patients with alcohol or sedative withdrawal delirium, benzodiazepines may be used to prevent the development of severe withdrawal symptoms (see Chapter 12). An assessment tool, such as the Clinical Institute Withdrawal Assessment for Alcohol Scale, can be useful in this context; a score of 10 or more indicates that treatment with a benzodiazepine is likely to be useful. The scale can be readministered serially (see Additional Reading). For elderly patients and for those with hepatic impairment, lorazepam is currently the drug of first choice because it is not significantly metabolized by the liver and because it can be given intramuscularly (i.m.) if needed. Other patients may benefit from diazepam. In general, for withdrawal prophylaxis, lorazepam, 0.5 mg three times a day to 1 mg four times a day, is given p.o., i.m., or i.v. When mild to moderate withdrawal symptoms are already present, lorazepam, 2 mg four times a day (or more, to control symptoms), is given i.m. or i.v.; haloperidol, 0.5 to 2 mg every 6 to 12 hours i.m. or i.v., may be added for persistent hallucinations. The risk in using an antipsychotic agent in this context is in its potential for lowering the seizure threshold.
Delirium tremens (DTs) can be so severe as to be fatal (see Chapter 12). DTs are characterized by extreme autonomic activity (e.g., fever, tachycardia, tachypnea, hypertension, tremor, diaphoresis, anxiety, insomnia) and delirium. Severe DTs represent a medical emergency that is best treated in a monitored setting with a continuous i.v. infusion or bolus dosing of lorazepam. Bolus dosing is usually initiated with 1 to 2 mg i.v. doses given every 10 minutes until the patient is calm; this is followed by 1 to 3 mg i.v. boluses given every 1 to 3 hours. These patients also require rehydration; correction of glucose, magnesium, and phosphate imbalances; supplementation
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with thiamine and multiple vitamins; and other supportive measures. Severely psychotic or agitated patients with DTs may also be treated with haloperidol (usual dosage is 0.5 to 2 mg i.v. every 4 hours).
II. Dementia
A. Diagnosis and General Considerations
Identifying the etiology of dementia is imperative because the specific treatment depends on the cause. Diagnostic criteria have been formulated for Alzheimer disease (AD) (McKhann et al., 1984), vascular dementia (Roman et al., 1993), and dementia with Lewy bodies (McKeith et al., 1996) and have been proposed for frontotemporal dementia and alcohol-related dementia (see Additional Reading).
The course of dementias varies, but typically progressive deterioration is seen in patients with AD; in vascular dementia, the deterioration is usually step-wise, with periods of stability between periods of decline. Vascular dementia comprises about 10% to 50% of all dementia patients (partially depending on the geographic location), whereas vascular pathology is found in about one-fourth of all dementias, either as a primary or contributing factor.
Dementias can be categorized as cortical or subcortical, depending on whether deficits derive from pathology involving mainly the cerebral cortex or structures deep to the cortex. Cortical dementia, which prominently affects functions such as memory encoding, naming, and face recognition, is exemplified by AD. Subcortical dementia, which prominently affects memory retrieval, motor function, and mood, is exemplified by the acquired immunodeficiency syndrome dementia complex. Table 5.2 lists the likely causes of dementia categorized by typical age at onset.
A detailed history is the best source of information relevant to etiology. Laboratory investigation, mainly to rule out reversible causes of dementia,
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is also helpful. Minimally, the laboratory workup should include a complete blood count, chemistries, liver function tests, thyroid function tests (thyroid-stimulating hormone), vitamin B12 and folate levels, serum total homocysteine, and serology for syphilis.
TABLE 5.2. CAUSES OF DEMENTIA AND LIKELY AGES AT ONSET | |||||||||
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Neuroimaging study, preferably magnetic resonance imaging, is required for the differential diagnosis of vascular dementia. If the etiologic diagnosis of dementia remains unclear, neuropsychologic testing should be performed. Genotyping for apolipoprotein E may help to increase the specificity of diagnosis in the patient who meets the clinical diagnostic criteria for AD. Other tests, such as single photon emission computed tomography, functional magnetic resonance imaging, positron emission tomography, lumbar puncture, human immunodeficiency virus testing, and heavy metal screening, should be considered in cases where the etiology of dementia remains unclear, particularly in younger patients.
B. Definitive Treatment
Acquired immunodeficiency syndrome dementia complex (human immunodeficiency virus encephalopathy). No specific treatment for this entity exists, but the antiretroviral therapies currently in use clearly can be associated with improvement in cognitive function that is sometimes marked and immediate. These agents may also prevent the development of secondary mania, furthering their neuroprotective effect.
Alzheimer disease. Currently, the following three types of treatment are available for AD: cognition enhancers, antioxidants, and drugs that are associated with a reduced risk of developing AD. The currently available cognition enhancers of choice are the cholinesterase inhibitors donepezil (a noncompetitive inhibitor), galantamine (a competitive and reversible inhibitor and allosteric nicotinic receptor agonist), and rivastigmine (a pseudo-irreversible inhibitor that is metabolized by the same enzyme it inhibits cholinesterase), each having shown evidence of cognitive and functional improvement in some patients with mild to moderate AD. These drugs may have disease-modifying effects, as well as symptomatic effects. Moreover, they can be associated with a reduction in the behavioral disturbances associated with AD, particularly in later stages of the disease. In the early stages of AD, these drugs are used for cognition enhancement; in the later stages of AD, they enhance behavioral control. In current practice, treatment with cholinesterase inhibitors is initiated as soon as possible after the diagnosis of probable AD is established, and their use is continued throughout the disease progression.
Donepezil is started at 5 mg per day (usually every night [qhs]) and is titrated to the target dose of 10 mg per day at 4 to 6 weeks. Rivastigmine is started at 1.5 mg twice a day and is increased by 1.5 mg twice a day every 2 weeks to the target dose of 6 mg twice a day. Galantamine is started at 4 mg twice a day (with meals) and is increased to 8 mg twice a day after 4 weeks. After another 4 weeks, it can be increased to 12 mg twice a day. These drugs are usually well tolerated when titrated slowly; the cholinergic side effects, such as nausea, diarrhea, and insomnia, typically are transient. The effects of cholinesterase inhibitors are usually apparent by 12 weeks.
Assessing the value of cholinesterase inhibitors in individual patients may be difficult. However, long-term studies clearly indicate that, in the aggregate, patients do benefit; the differences between treated and untreated (control) patients become even more apparent as the duration of therapy increases. Because disease progression is not linear, particularly in the middle stages of AD, discontinuing treatment based on rate or extent of deterioration is generally unwise. Although no evidence indicates that cholinesterase inhibitors alter the underlying dementing process in AD, preclinical data suggest that cholinergic enhancement decreases the production of plaque amyloid, and clinical trial data suggest that patients on cholinesterase inhibitors do better than those who
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have never been given cholinesterase inhibitors or than those started later in the course of their illness.Limited evidence suggests that an herbal extract of ginkgo biloba (40 mg p.o., three times a day) may be effective in slowing disease progression. In some AD and vascular dementia patients, it may improve cognition. The effects of this extract are not as robust as those from the cholinesterase inhibitors, however, and the extract may be less convenient because of the need for three times a day dosing. In addition, case reports have associated ginkgo with episodes of serious bleeding (hematoma and intracranial hemorrhage), and concerns about product purity and potency may exist because ginkgo biloba is a dietary supplement not currently regulated by the United States Food and Drug Administration.
The antioxidant vitamin E (2,000 IU daily) and the monoamine oxidase inhibitor selegiline (10 mg p.o. daily) have been found to slow the rate of progression of AD in patients with moderate dementia. (Note: No additional benefit has been found from combined therapy.) Because vitamin E has fewer drug interactions and a more benign side effect profile than selegiline, vitamin E (1,000 IU p.o. twice a day) is recommended for all AD patients, except in those with vitamin K deficiency.
Nonsteroidal antiinflammatory drugs may theoretically affect the pathogenesis of AD by controlling the inflammatory response to amyloid and by suppressing or delaying amyloid deposition. To be clinically effective in AD prevention, however, sustained exposure to these drugs is needed, and this exposure must predate disease onset by several years.
To date, the most promising risk reduction efforts have been directed toward decreasing the production or deposition of -amyloid protein. -hydroxy- -methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (i.e., statins ) that are thought to block -amyloid protein production are currently under study in AD.
Epidemiologic evidence suggests that the long-term use of estrogen also reduces the risk of developing AD. Among postmenopausal women, estrogen may reduce the risk to as low as one-third that of the control group. No prospective studies have as yet corroborated this finding. That estrogen exposure must take place during a critical period for effective risk reduction appears likely. In addition, whether estrogen alternatives (e.g., selective estrogen receptor modifiers, such as raloxifene) will convey the same advantage is not clear.
A vaccine for AD containing a synthetic form of -amyloid protein is currently being tested.
Vascular dementia. Treatment of vascular dementia involves the reduction of stroke risk, the enhancement of cerebral perfusion, and the treatment of associated neuropsychiatric symptoms. Stroke risk may be substantially reduced by antiplatelet agents, such as aspirin (81 to 325 mg per day). For those unable to tolerate aspirin because of gastrointestinal bleeding or those who have evidence of continued ischemia on aspirin therapy, the antiplatelet agent clopidogrel is used. Aggrenox (a proprietary combination agent of aspirin and extended-release dipyridamole) confers greater protection against stroke than aspirin alone for those who have had a transient ischemic attack or an ischemic stroke in the past, but it is no better in lowering mortality in this population. It is also more expensive than aspirin.
For patients with vascular dementia secondary to large-vessel disease ( multiinfarct dementia), systolic blood pressure should be lowered to the range of 135 to 150 mm Hg, where cerebral blood flow and cognitive performance are optimized. HMG-CoA reductase inhibitors such as atorvastatin and simvastatin are known to reduce cholesterol levels significantly, and they clearly lower stroke risk. Embolism secondary to atrial fibrillation is controlled with either warfarin or aspirin, and embolism after myocardial infarction is prevented with warfarin (when its
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use is not contraindicated because of risk of falls or intracranial hemorrhage). Embolism from complicated carotid plaques may be prevented by endarterectomy.Improvement in cerebral perfusion is correlated with an improvement in cognitive and global functioning. Many of the interventions designed to lower stroke risk (e.g., lowering lipid levels) are also associated with improved perfusion. Treatment with pentoxifylline (400 mg p.o. three times a day) has been found to result in improved cognitive and global functioning and to slow the progression of the disease in patients with multiinfarct dementia. Estrogen use is associated with increased cerebral perfusion in postmenopausal women. In addition, because cigarette smoking has complex effects that are known to promote ischemia, smoking cessation is associated with improved cerebral blood flow and improved cognition.
A recent study suggests that galantamine may have benefit in patients with mixed vascular and AD clinical presentations.
Lewy body dementia. This is a progressive dementia with cognitive and motor symptoms that are characteristic of both AD and Parkinson disease. Psychiatric symptoms are prominent, including vivid visual hallucinations, delusions, and depression. Unusual features include dramatic fluctuations in symptoms, repeated falls, and frequent transient episodes of loss of consciousness. Lewy body dementia patients may benefit even more than AD patients from treatment with cholinesterase inhibitors, such as donepezil, galantamine, or rivastigmine, when used as described above for AD. In responders, not only cognitive but also motor and behavioral improvements are seen. Patients with Lewy body dementia are very sensitive to the extrapyramidal effects of conventional antipsychotic agents, so conventional antipsychotic agents should be avoided in this population.
C. Treatment of Psychiatric and Behavioral Syndromes
Individuals with dementia often come to clinical attention not because of cognitive difficulties but because of behavioral and psychiatric problems related to the declining brain function. These may include significant anxiety, psychosis, depression, aggression, and agitation. Although improvement may be observed with treatment of the core neurotransmitter deficits, symptomatic treatment is often necessary. Behavioral interventions for wandering include door alarms, exits demarcated by octagonally shaped STOP signs, and, in some situations, by simply clearing a safe circular path for walking. Behavioral interventions for agitation include the insulation of the patient during times of high activity in the milieu and the appropriate management of bath time and other activities that are stressful to the patient.
Benzodiazepines and other anxiolytic agents. Patients with dementia with acute anxiety may benefit from the short-term use of lorazepam (0.5 mg p.o. twice a day). For longer term treatment, buspirone at doses ranging from 5 mg p.o. twice a day to 20 mg p.o. three times a day or a low dose of a selective serotonin reuptake inhibitor (SSRI) may be useful. For those with insomnia, short-term intermittent use of zolpidem or zaleplon (5 to 10 mg at bedtime) may be helpful. An emerging treatment for dementia-related anxiety is the use of the anticonvulsant gabapentin at a dose of 100 to 300 mg three times a day. Gabapentin has recently become available in an oral solution (250 mg per mL), which could make even smaller doses feasible for the old-old patient. Gabapentin should be avoided or used with caution in patients with renal impairment.
Antipsychotic agents. Delusions, hallucinations, and thought disorganization in patients with dementia can be treated with a higher potency antipsychotic agent. For this indication, the optimal dose of haloperidol is 2 to 3 mg daily (divided doses) and of risperidone is 1 mg daily (usually divided twice a day). For intermittent psychotic agitation, such as sundowning, antipsychotic agents can be given 1 to 2 hours before
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the time of the usual behavioral disturbance to take advantage of any sedative properties the specific agent may have. The use of conventional antipsychotic agents to treat nonpsychotic behavioral disturbances in dementia is controversial, but atypical agents are increasingly used at low doses for longer durations for their mood-stabilizing effects. The risk of tardive dyskinesia with conventional antipsychotic agents is in the range of 30% per year in older patients. Conventional antipsychotic agents and risperidone should be avoided, if possible, in patients with Lewy body dementia.Antidepressants. Major and minor forms of depression are common among patients with dementia, and, in general, they are treated in the same way as those in nondemented patients, except that lower drug doses and lower target plasma levels may be effective. Behavioral disturbances, such as extreme irritability or refusal of care, may be manifestations of depression, and they can improve significantly with treatment. In general, nonsedating antidepressants with minimal or no anticholinergic effects, such as the SSRIs, venlafaxine, and bupropion, are preferred. Mirtazapine, on the other hand, can be very useful in elderly patients with dementia who have insomnia and anorexia, particularly at lower doses (7.5 to 15 mg qhs).
Other agents. Persistent agitation in the patient with dementia can be treated with trazodone at a standing dose ranging from 12.5 mg twice a day to 100 mg three times a day. Trazodone can also be used as needed, because it has a relatively rapid onset of action. Alternatively, a mood-stabilizing anticonvulsant, such as valproate or gabapentin, can be used (see Appendix VII for two algorithms for the treatment of agitation in patients with dementia). Despite numerous contraindications and warnings about the use of -adrenergic receptor antagonists in elderly patients, propranolol and pindolol are both used to treat agitation and aggression in patients with dementia. Propranolol is started at 10 mg twice a day, and the dose is increased every 3 to 7 days as tolerated until it is clinically effective. Pindolol may be less likely to induce hypotension and bradycardia, and it may have a faster onset of action. In geriatric patients, pindolol is started at 5 mg daily, and the dose is increased very slowly, by 5 mg every 3 to 4 weeks, to a maximum daily dose of 40 to 60 mg. For patients resistant to these treatments, estrogen, 0.625 mg daily, may be useful for both men and women.
ACKNOWLEDGMENT
The authors thank Drs. Kenneth L. Davis and Dilip V. Jeste for their suggestions and thoughtful critique of this chapter.
ADDITIONAL READING
Birkh user MH, Strnad J, K mpf C, et al. Oestrogens and Alzheimer's disease. Int J Geriatr Psychiatry 2000;15:600 609.
De Deyn PP, Rabheruk K, Rasmussen A, et al. A randomized trail of risperidone, placebo, and haloperidol for behavioral symptoms of dementia. Neurology 1999;53:946 955.
Jacobson S, Schreibman B. Behavioral and pharmacologic treatment of delirium. Am Fam Physician 1997;56:2005 2012.
Jacobson SA. Delirium in the elderly. Psychiatr Clin North Am 1997;20:91 110.
Katz IR, Jeste DV, Mintzer JE, et al. Comparison of risperidone and placebo for psychosis and behavioral disturbances associated with dementia: a randomized, double-blind trial. J Clin Psychiatry 1999;60:107 115.
The Lund and Manchester Groups. Clinical and neuropathological criteria for frontotemporal dementia. J Neurol Neurosurg Psychiatry 1994;57:416 418.
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Matthews HP, Korbey J, Wilkinson DG, et al. Donepezil in Alzheimer's disease: eighteen month results from Southampton memory clinic. Int J Geriatr Psychiatry 2000;15:713 720.
McKeith IG, Galasko D, Kosaka K, et al. Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology 1996;47:1113 1124.
McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA work group under the auspices of Department of Health and Human Services task force on Alzheimer's disease. Neurology 1984;34:939 944.
Oslin D, Atkinson RM, Smith DM, et al. Alcohol related dementia: proposed clinical criteria. Int J Geriatr Psychiatry 1998;13:203 212.
Roman GC, Tatemichi TK, Erkinjuntti T, et al. Vascular dementia: diagnostic criteria for research studies. Neurology 1993;43:250 260.
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