Introduction
In everyday practice, psychiatrists serve as members of medical teams in providing treatment to patients who have delirium, dementia, or other cognitive disorders. Psychiatrists often see these patients in hospitals, nursing homes, and other institutional settings. A psychiatrist usually acts as a consultant to a primary care physician or to a hospital service. Psychiatrists help primary care physicians understand the degree to which medical illness contributes to psychiatric symptoms or confusion. Proper treatment of the medical problem may lead to substantial improvement in psychiatric or neurobehavioral symptoms. Psychotropic medication may be helpful in the management of the patient’s illness. Psychiatrists must consider medical diagnoses, treatments, drug interactions, and side effects when they prescribe psychotropics as part of their role on the medical team.
Patients who have cognitive disorders are often unable to give a reliable history, and the history obtained from third parties usually does not totally reveal the diagnosis. The psychiatrist must rely heavily on data obtained from the physical examination and from laboratory tests, electroencephalogram (EEG) findings, and brain imaging. The medical model provides the most appropriate understanding of patient care in cases of delirium and dementia because the medical model stresses a biological etiology for the patient’s symptoms. This approach helps the physician establish crucial links between the patient’s medical pathology and the neurobehavioral or psychiatric symptoms. Once links have been established, the psychiatrist can recommend drug therapy and psychotherapy integrated in a comprehensive medical treatment plan.
Patients with delirium and the behavioral complications of dementia often require complicated therapeutic regimens. In some older patients, treatment is not well tolerated and may produce cognitive changes. This is particularly true when patients are receiving treatment for medical disorders. The clinician should understand the behavioral side effects of medical therapies. Removing drugs that produce confusion can help reestablish cognitive function.
Psychiatrists may attempt to treat agitation or hallucinations by adding psychotropics, but these drugs may worsen the patient’s condition. Psychiatrists must be prepared to analyze the possibility of multiple drug interactions before launching into psychopharmacotherapy.
Physicians who treat cognitive disorders need to cross the traditional boundaries between psychiatry and neurology. More often than not, older patients have multiple disorders. Delirium, dementia, and affective disorder often coexist. The psychiatrist should not only treat depression and other correctable disorders, but also determine the existence of dementia and establish a prognosis, in order to plan appropriate treatment.
The physician must educate the patient and the family about the nature of the specific illness and the rationale for treatment. Disease processes that cause cognitive deficits may be very complex. Families are often exceedingly anxious because they anticipate the need to accept change in a meaningful relationship. They demand answers. Serious social and financial hardships add to a sense of dread about the future. Most families benefit from a thorough explanation of the patient’s condition. Ultimately, the physician must be prepared to explain the contribution made by the various disease processes. The physician must know how to deliver bad news so that family members can take proper steps to prepare for the future. In the process, families expect the physician to respect the dignity of the cognitively-impaired patient. Whenever possible, the psychiatrist must try to help the family salvage hope and meaning.
The Aging Brain
Although organic mental disorders occur at any age, they are more common in older patients. As the number of elderly people increases, clinicians will more frequently encounter patients with these disorders. The diagnosis of cognitive disorders is more complex in older patients because physical problems interact with emotional and social factors. The psychiatrist must be familiar with the cognitive changes associated with normal aging before determining the impact of a neurological illness or a psychiatric disorder. Assessment of these patients requires meticulous attention to the mental status examination. If physicians are not thorough in the cognitive assessment of their geriatric patients, they may miss significant deficits, some of which may be treatable.
Delirium, dementia, and memory disorders become more common with advancing age; as a person ages, the brain becomes more vulnerable to a variety of insults. Brain weight and volume attain their maximal values in teenage years, and the brain loses both weight and volume as it ages. Significant atrophy of the brain has begun by the time that most people reach their 60s. By the 10th decade, the ratio of the brain to the skull cavity has fallen from 93% to 80%. When cortical neurons decrease in number, the cortical ribbon thins. Large neurons decrease in number whereas the number of small neurons increases.
Normal aging and dementia affect specific areas of the brain, especially the association cortices of the frontal, temporal, and parietal lobes. The limbic system, the substantia nigra, the locus coeruleus, the hippocampus and the parahippocampal regions, and the deep frontal nuclei all exhibit a sizable loss of neurons. Despite the loss of neurons, the aged brain continues to undergo dynamic remodeling. In normal older people, dendrites in the hippocampal regions continue to show plasticity. When dendritic arborization fails, mental powers begin to decline.
The relationship between cognitive functions and the morphologic changes that occur as the brain ages is incompletely understood. The volume of the cerebral ventricles increases with age, but the range of ventricular size is greater in old age than in youth. Increases in the size of ventricles, sulci, and subarachnoid spaces are observed easily with modern imaging techniques.
On a microscopic level, lipofuscin granules collect in neurons of aging brains. Fibrous astrocytes increase in size and number. The hippocampus exhibits granulovacuolar changes. Senile plaques and neurofibrillary tangles may occur in the brains of normal older individuals. The number of plaques and tangles in normal brains is less than the number observed in the brains of patients with Alzheimer’s disease (AD). The overlap between patients with seemingly normal cognition and those with mild AD, however, can be difficult to discriminate in an individual brain. Small infarcts and ischemic white matter lesions are observed in the brains of many normal older people, both at autopsy and in brain imaging studies.
Aging brains have a diminished capacity to respond to metabolic stress. The brain’s demand for glucose decreases. EEG activity slows. Blood flow declines, and oxygen use diminishes. Glucose metabolism is crucial because it contributes to the synthesis of the neurotransmitters acetylcholine, glutamate, aspartate, gamma amino butyric acid (GABA), and glycine. Effects of slight abnormalities in glucose metabolism are obvious even in the resting state. The senile brain shows impaired transmitter synthesis and reduced transmitter levels.
Acetylcholine has been studied because of its role in memory. Older people exhibit a decrease in the synthesizing enzyme for acetylcholine, choline acetyl transferase. Uptake of circulating choline into the brain decreases with age. Decreased levels of acetylcholine in the hippocampus may relate to age-related declines in short-term memory. In AD, damage to the ascending cholinergic system plays an important role in the loss of memory and in other cognitive deficits.
Decreased catecholamines are linked more closely to affective changes than to cognitive changes in older people. Noradrenergic cell bodies in the locus coeruleus appear to decline in number with aging, but concentrations of norepinephrine appear to remain normal in target areas. The synthetic enzyme tyrosine hydroxylase increases with aging, whereas the degradative enzyme monoamine oxidase increases. Research also suggests reduced serotonergic innervation in the aging neocortex.
Loss of dopaminergic innervation of the neostriatum is a prominent age-related change that corresponds with the loss of dopaminergic cell bodies from the substantia nigra. Age-related decreases in basal ganglia dopamine make older patients more sensitive to the side effects of neuroleptics. Dopaminergic innervation of the neocortex and the neostriatum are not affected.
Studies of the brains of older patients have revealed a decrease in norepinephrine, serotonin, acetylcholine, and dopamine receptors. A decrease in β-receptor density results in reduced cyclic adenosine monophosphate and decreased adaptability to the external environment.
In contrast, older patients exhibit an increase in benzodiazepine-GABA receptor inhibitory activity and an increased sensitivity to benzodiazepines.
The capacity of mitochondria declines with age. Mitochondrial oxidants may be the chief source of the mitochondrial lesions that accumulate with age. The brain becomes susceptible to injury by free radicals that damage mitochondrial DNA, proteases, and membranes. Free radicals are likely a major contributor to cellular and tissue aging.
Changes in cognitive performance related to aging vary greatly. Information processing, particularly verbal speed and working memory, show the most pronounced changes. The number of correct answers required for the same IQ score in a 70-year-old, as compared to a 25-year-old, is approximately 50%. On the other hand, some cognitive skills are resistant to aging. Vocabulary and ability to read quickly tend to remain preserved and can be used to estimate premorbid IQ in cognitively impaired senior citizens. Older people who possess highly developed cognitive abilities can mask memory defects for a time. This “cognitive reserve” is especially noted in topics related to the person’s long-term reading. Even the Mini Mental State examination, a relatively crude test of cognitive function, shows major effects of education on performance. These resistant aspects of cognition are often referred to as “crystallized intelligence,” as compared to the “fluid intelligence” of memory and attention that is less resistant to aging. These studies encourage all of us to stay mentally active, continue reading in our professional disciplines, as we age.
After age 70, brain functions and capabilities decline more rapidly. Cognitive decline related to aging produces impaired memory, diminished capacity for complex ideas, mental rigidity, cautious responses, and behavioral slowing. Slowing of responses is the most consistent cognitive change. As a result, it takes longer to provide professional services to older people.
Physicians who spend sufficient time testing mental status in older individuals are more likely to obtain accurate results than physicians who rush through the examination. Given enough time, older people will complete the following tasks accurately: (1) random digits forward, (2) un-timed serial arithmetic problems, (3) simple vigilance tests, (4) basic orientation, and (5) immediate memory. Unfamiliar stimuli, complex tasks, and time demands cause difficulty for older people. When older patients are asked to reorganize material (e.g., repeating digits backward), they often become anxious. Immediate memory continues to be normal in most patients, but if the memory task calls for split attention or reorganization, older people will have a harder time. Whenever the items to be remembered exceed primary memory capability, seniors show a decrement in memory acquisition and retrieval. Seniors have more difficulty remembering names and objects when they are not in a familiar routine. They do poorly on memory tasks that involve speed, unfamiliar material, or free recall. Although older people have a hard time organizing information, their memory performance improves if they control the rate of presentation. Practice also improves performance. Cognition does not operate in isolation from personality or social relationships. Because learning and memories occur within a range of contexts, a more useful test is one that emphasizes real-life memory.
Seniors usually perceive themselves as less effective than when they were younger, a perception that affects performance. The memory complaints of older adults are often related to low self-confidence or other personality variables. As a result, when seniors experience an increase in self-esteem and motivation their objective performance also improves. Similarly, lack of confidence reduces cognitive expectations even further.
Delirium
Delirium is one of the most dramatic presentations in psychiatry and neurology. Delirious patients become acutely agitated, disoriented, and unable to sustain attention, form memories, or reason. In the past, the term delirium was reserved for an agitated, hyperactive state, whereas encephalopathy applied to confusional states in which the level of consciousness was normal or depressed. Currently, no distinction is made between these two conditions. In fact, delirium is now synonymous with “acute brain syndrome,” encephalopathy, acute confusional state, and toxic psychosis.
Delirium is an extremely common clinical problem in hospitalized patients. An estimated 30–50% of hospitalized elderly people become delirious, amounting to an overall incidence of about 10% of all hospitalizations. Delirium increases morbidity and mortality for any hospitalization, and the cost to society is enormous.
The definition of delirium from the DSM-IV follows, below. Delirium, like dementia, involves multiple cognitive functions, including attention, memory, reasoning, language, and executive function. In contrast to dementia, delirium typically develops relatively acutely and fluctuates more from hour to hour and day-to-day. Delirium involves alterations in level of consciousness, agitation and hypervigilance or drowsiness, disturbed perception (hallucinations, delusions), psychomotor abnormalities (restlessness, agitation), and autonomic nervous system hyperactivity (tachycardia, hypertension, fever, diaphoresis, tremor). All of these phenomena are less common in dementia.
DSM-IV Diagnostic Criteria
Delirium Due to General Medical Condition
Disturbance of consciousness (i.e., 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.
There is evidence from the history, physical examination, or laboratory findings that the disturbance is caused by the direct physiological consequences of a general medical condition.
Substance Intoxication Delirium
Disturbance of consciousness (i.e., 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.
There is evidence from the history, physical examination, or laboratory findings of either (1) or (2):
the symptoms of Criteria A and B developed during substance intoxication
medication use is etiologically related to the disturbance
Substance Withdrawal Delirium
Disturbance of consciousness (i.e., 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.
There is evidence from the history, physical examination, or laboratory findings that the symptoms of Criteria A and B developed during, or shortly after, a withdrawal syndrome.
(Reprinted with permission, from Diagnostic and Statistical Manual of Mental Disorders, 4th edn. Copyright 1994 American Psychiatric Association.)
The prevalence of delirium in general hospital patients is 10–30%. Up to 50% of surgical patients become delirious in the postoperative period. Delirium accompanies the terminal stages of many illnesses. It occurs in 25–40% of patients who have cancer and in up to 85% of patients with advanced cancer. Close to 80% of terminal patients will become delirious before they die.
Distinguishing delirium from depression in this population is important because physicians can treat both conditions and improve quality of life for the terminally ill. Many patients today make living wills or assign loved ones a durable power of attorney for health care. By explaining the causes and treatment of delirium to family members, the physician empowers them to decide what is best for the patient.
Age is the most widely identified risk factor for delirium. Patients with dementia are at high risk for delirium. Forty-one percent of dementia patients have delirium on admission to the hospital. Twenty-five percent of patients who are admitted to the hospital with delirium will ultimately be diagnosed as having dementia. Other factors that predict delirium in hospitalized patients include: Prior brain disease, vision or hearing loss, presence of a fracture on admission, symptomatic infection, stress or major environmental change, neuroleptic, anticholinergic, sedative medications or substance use or withdrawal, sleep deprivation, and use of restraints, a bladder catheter, or any surgical procedure during the admission.
The incidence of delirium in nursing homes is also quite high. Because the onset of delirium is more insidious in seniors than in young people, there is an even higher probability that delirium will be overlooked in nursing homes. Illnesses such as unrecognized urinary tract infection may cause delirium. More serious, life-threatening illnesses can also present with delirium. Hospital staff must be trained to recognize delirium at an early stage so that they can identify and promptly treat the primary medical condition. Common causes of delirium in older people include hypoxia, hypoperfusion of the brain, hypoglycemia, hypertensive encephalopathy, intracranial hemorrhage, CNS infection, and toxic-confusional states. Even when delirium is recognized and treated promptly, it predicts future cognitive decline. Many elderly patients who have been delirious never fully recover.
A variety of conditions lead to delirium. These conditions can be categorized into four major groups: (1) systemic disease secondarily affecting the brain, (2) primary intracranial disease, (3) exogenous toxic agents, and (4) withdrawal from substances of abuse. The Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) classifies delirium according to the presumed etiology. If delirium is due to a systemic medical condition or to primary intracranial disease, then the medical cause is listed in the Axis I diagnosis. Substance-induced delirium and substance withdrawal delirium are classified separately. Substance-induced delirium includes delirium caused by toxins and by drugs of abuse. If the etiology is not found, the diagnosis is delirium not otherwise specified. In most clinical situations, delirium is caused by multiple factors.
Delirium can be caused by any type of systemic disease. When a medical condition causes delirium, the primary disease has caused either failure in cerebral blood flow or failure in cerebral metabolism. Cardiac conditions cause delirium by decreasing cerebral perfusion. Patients who have experienced cardiac arrest, cardiogenic shock, severe hypertension, or congestive heart failure are at risk of delirium. Organ failure syndromes such as renal, hepatic, and respiratory insufficiency can all cause delirium. Endocrine and metabolic disturbances affect brain metabolism. Hyponatremia and hypoglycemia may be the most prevalent causes in this category. Hypothyroidism is a common endocrine factor.
Central nervous system (CNS) causes of delirium include vasculitis, stroke, and seizure. Paraneoplastic phenomena in the brain (e.g., limbic encephalitis) may cause altered mental status in cancer patients.
Nutritional status also contributes to delirium; the most notable examples are vitamin B1 deficiency in alcoholic patients, vitamin B12 deficiency, and pellagra. Infections may affect the nervous system directly, as in meningitis and encephalitis, but more often they cause delirium indirectly through toxins. In elderly patients who have generalized sepsis or even local infections such as urinary tract infections, altered mental status may precede both fever and leukocytosis. Mental status change may be the only manifestation of infection. In at least half the cases, the cause of delirium is multi-factorial. Urinary tract infection, low serum albumin, elevated white blood cell count, and proteinuria are among the most significant risk factors. Other risk factors include hyponatremia, hypernatremia, severity of illness, dementia, fever, hypothermia, psychoactive drug use, and azotemia.
No matter what systemic illness causes delirium, the clinical consequences are stereotypical. The diverse insults that cause delirium appear to act via similar metabolic and cellular pathways. A cascade of pathology in central neurotransmitter systems destabilizes cerebral function. Factors include oxidative stress, reductions in dopamine, norepinephrine, and acetylcholine, changes in either direction in serotonin, depolarization of neurons, and effects of stress such as sympathetic discharges and activation of the hypothalamic–pituitary–adrenocortical system. Ultimately, dysfunctional second messenger systems may provide the cellular mechanism of metabolic delirium.
Delirium can be caused by lesions in a variety of brain regions. Vascular pathology is more likely to cause confusional states if lesions are present in the basal nuclei and thalamus. Bilateral lesions of the thalamus or caudate nuclei are especially associated with delirium. Delirium is also more likely to accompany strokes in patients with preexisting brain atrophy or seizures. In traumatic brain injury, deeper brain lesions are associated with longer periods of delirium. Frontal lobe syndromes can also mimic delirium.
Delirium due to substances may occur as the result of substance abuse or as an undesirable effect of medical therapies. Patients with delirium may exhibit symptoms suggesting pathology in specific neurotransmitter systems. Delirium in substance abusers who overdose provides the best example of a neurotransmitter-specific delirium.
Stimulants act through dopamine and other catecholamine pathways. Stimulant overdoses can cause confusion, seizures, dyskinesia, and psychomotor agitation, however, the most common presentation is that of an agitated paranoid state. Patients with stimulant-induced delirium can be dangerous, to which the saying “speed kills” attests. People who abuse stimulants are involved in violent acts more often than are those who abuse other substances. The dopamine excess observed in stimulant-induced delirium may provide a model to understand delirium in other general medical conditions. The effectiveness of dopamine-blocking agents such as haloperidol in the treatment of delirium suggests that excess dopamine relative to acetylcholine may produce delirium in general medical conditions and in stimulant-induced delirium.
d-Lysergic acid diethylamide (LSD) causes a different form of delirium through its action on serotonin receptors. This hallucinogen causes intensification of perceptions, depersonalization, derealization, illusions, hallucinations, and incoordination. Patients with delirium due to medical conditions may also experience illusions and hallucinations. Serotonin systems also may be affected in these patients. Under certain circumstances patients who are taking selective serotonin reuptake inhibitor (SSRI) antidepressants, especially when combined with other serotonergic medications, develop the serotonin syndrome, of which delirium can be a prominent feature.
Disruption of pathways served by N-methyl-d-aspartate (NMDA), a subtype of glutamate receptor, induces patients who are intoxicated with phencyclidine to display yet another symptom complex. Phencyclidine overdose is well recognized because of its tendency to produce assaultive behavior, agitation, diminished responsiveness to pain, ataxia, dysarthria, altered body image, and nystagmus. The NMDA receptor is also involved in the biological effects of alcoholism, such as intoxication and delirium tremens. Ethanol-induced up-regulation of NMDA receptors may underlie withdrawal seizures. The NMDA receptor also mediates some of the more damaging effects of ischemia during a stroke. Stimulation of NMDA receptors can lead to permanent brain damage. For this reason, conditions that lead to NMDA stimulation should be treated promptly.
Activation of brain GABA receptors causes some manifestations of sedative or alcohol overdose. Sedative intoxication causes slurred speech, incoordination, unsteady gait, nystagmus, and impairment in attention or memory. Some manifestations of hepatic encephalopathy may be the result of excessive stimulation of GABA receptors. Delirium tremens occurs when insufficient stimulation of GABA receptors results from withdrawal from benzodiazepines or alcohol. Treatment with benzodiazepines improves delirium tremens.
Drugs that have anticholinergic properties are very likely to contribute to delirium. In hospitalized patients, symptoms of delirium occur when serum anticholinergic activity is elevated. Total serum anticholinergic activity also helps to predict which patients in intensive care units become confused. Symptoms of anticholinergic delirium include agitation, pupillary dilation, dry skin, urinary retention, and memory impairment.
Physicians must be cautious when prescribing psychoactive drugs to seniors. One of the most common causes of delirium is iatrogenic. Common agents such as digoxin may induce cognitive dysfunction in older people, even with therapeutic digoxin levels. In the intensive care unit, antiarrhythmic agents such as lidocaine or mexiletine may cause confusion. Among the narcotics, meperidine is particularly likely to cause confusion and hallucinations. Benzodiazepines, other narcotics, and antihistamines are also frequent contributors to delirium. In psychiatric patients, tricyclic antidepressants (TCAs) and low-potency neuroleptics are frequent contributors. Note that these drugs have anticholinergic properties, and agents such as benztropine or trihexyphenidyl, used to combat extrapyramidal effects are also anticholinergic. The list of other drugs that may induce confusion is extensive.
The misuse of psychoactive drugs causes as many as 20% of geropsychiatric admissions. The odds of an adverse cognitive response increase as the number of drugs rises. Adverse drug reactions are a source of excess morbidity in elderly patients. A high index of suspicion, drug-free trials, and careful monitoring of drug therapy reduce this problem. Occasionally, a specific antidote is available for a drug-induced delirium. Physostigmine may reverse anticholinergic delirium and is sometimes useful in treating TCA overdoses. Narcotic-induced delirium can be reversed with naloxone. Flumazenil is an imidazobenzodiazepine that antagonizes the effects of benzodiazepine agonists by competitive interaction at the cerebral receptor. Naloxone and flumazenil have short half-lives and may have to be readministered.
Although the evaluation of delirium entails the analysis of very straightforward data, physicians often miss the diagnosis. The physician must obtain a careful history, perform a relevant physical examination, conduct a mental status examination, and review the patient’s medications and laboratory tests. Physicians who do not conduct a careful physical examination may overlook asterixis, tremors, psychomotor retardation, and other motor manifestations of delirium. An organized mental status examination is the cornerstone of the assessment. The clinician who makes assumptions about the patient’s cognitive status will make mistakes. This is particularly true in patients who are apathetic. After the physician has assessed the patient’s mental status, he or she should carefully review laboratory data and the patient’s medications.
The essential feature of delirium is an alteration in attention associated with disturbed consciousness and cognition. One of the most disconcerting clinical characteristics of delirium is its fluctuating course. Symptoms are everchanging. The patient’s mental status varies from time to time. Cognitive deficits appear suddenly and disappear just as quickly. Patients may be apathetic at one moment, yet a short time later they may be restless, anxious, or irritable. Other patients become agitated and begin hallucinating without apparent change in the underlying medical condition. Waxing and waning of symptoms and perceptual disturbances may reflect the fact that the nondominant cortex is involved.
Common features of delirium include sleep disturbance and either decreased or agitated level of consciousness. Delirium may first present as sundowning with daytime drowsiness and nighttime insomnia with confusion. As the patient becomes more ill, disorientation and inattention dominate the clinical picture. Nonetheless, consciousness does not always follow the course of the underlying illness. When the patient’s sleep is disturbed and the affect is labile, delirium usually lasts longer. This cluster of symptoms points to involvement of the reticular activating system of the brainstem and ascending pathways in delirium. Symptoms usually resolve quickly when the underlying disorder is treated, but a degree of confusion can last as long as 1 month after the medical condition has resolved, and some patients are even left with a longterm dementia.
The Mini-Mental Status Exam (MMSE) is often used to quantify cognitive impairment, but only specific items on the MMSE are useful for evaluating delirium. Delirious patients have the most difficulty with calculation, orientation, attention, memory, and writing. The other higher cortical functions and language are usually preserved. The MMSE may be normal in as many as one-third of patients with clinical delirium. More specific delirium scales can be helpful. The Confusion Assessment Method is a rapid test designed to be administered by trained nonpsychiatrists. The Delirium Rating Scale is a 10-item scale for assessment of delirium severity. One study found that patients whose delirious episode improved within 1 week had much lower Delirium Rating Scale scores at the time of psychiatric consultation than did patients whose delirium lasted more than 1 week. The Trail Making Test (Parts A and B) and clock drawing tests are psychomotor tasks that are sensitive and easy to administer. Unfortunately, these tests measure specific cognitive functions that may not be impaired in delirium. For the busy clinician, the MMSE is the most practical tool, however, the clock drawing test also provides useful information in a short time.
The vital signs are often abnormal. Common tests that often reveal the etiology of the delirium include complete blood count, sedimentation rate, electrolytes, blood urea nitrogen, glucose, liver function tests, toxic screen, electrocardiogram (ECG), chest X ray, urinalysis, and others. Blood gases or appropriate cultures may be helpful. A computed tomography (CT) scan is sometimes necessary to diagnose structural damage. Prompt lumbar puncture will confirm the diagnosis of suspected intrathecal infection.
Imaging studies are needed when the neurologic examination suggests a focal process or when initial screening tests have not revealed a treatable cause of the delirium. Even in nonneurological causes of delirium, CT scans often reveal ventricular dilatation, cortical atrophy, and ischemic changes. The right-hemisphere association cortex is often involved when some patients who are not paralyzed become delirious, suggesting a predisposing role for structural brain disease in the elderly with delirium. Subarachnoid hemorrhage, subdural hematoma, or right-hemisphere stroke can cause early mental status changes. Structural neurologic injury is sometimes the sole reason for delirium.
The EEG is useful in the evaluation of delirium when all other studies have been unrevealing. Generalized slowing is the typical pattern. A normal EEG is atypical but does not rule out delirium. Confusion and clouding of consciousness correlate partially with EEG slowing. In mild delirium, the dominant posterior rhythm is slowed. In more severe cases, theta and delta rhythms are present throughout the brain. Quantitative methods of EEG analysis supplement visual assessment in difficult cases. The severity of EEG slowing is correlated with the severity and duration of delirium and with the length of hospital stay. In more severe cases of metabolic or toxic delirium, triphasic waves replace diffuse symmetrical slowing. The appearance of periodic lateralized epileptiform discharges suggests a structural etiology. Rarely, the EEG reveals nonconvulsive status epilepticus as the cause of the delirium. In sedative or alcohol withdrawal, the EEG may show low-voltage fast activity.
Distinguishing delirium from dementia can be difficult, because many clinical findings on mental status examination are similar. According to DSM-IV, the most common differential diagnoses are as follows: whether the patient has dementia rather than delirium; whether he or she has a delirium alone; or whether the patient has a delirium superimposed on preexisting dementia. Regardless, the clinical history is the most important tool in the diagnosis. Delirium is an acute illness. Dementia is longstanding. Physical examination and mental status are also important. Tremor, asterixis, restlessness, tachycardia, fever, hypertension, sweating, and other psychomotor and autonomic abnormalities are more common in delirium than dementia. Positive neurobehavioral symptoms such as agitation, delusional thinking, and hallucinations are much more common in delirium than dementia. On the other hand, cortical disorders such as dysphasia (language impairment) or apraxia (motor impairment) are not as common in delirium as in dementia. Clinicians should remember, however, that the two conditions often coexist.
Patients with delirium frequently have altered perceptions. As a result, delirium is sometimes mistaken for a psychosis. It is usually possible to separate delirium from a psychosis because signs of cognitive dysfunction are more common in delirium than in psychotic disorders. Psychotic patients are not normally disoriented, and they can usually perform well on bedside tests of attention and memory. The EEG is normal in psychoses. When the laboratory evidence does not support a medical illness, the clinician should consider the possibility of a psychiatric cause. When a psychiatric illness causes symptoms of delirium, patients are said to have a pseudodelirium. A history of past psychiatric illness may help clarify whether a patient has delirium or a psychiatric illness with pseudodelirium (e.g., a dissociative fugue or trauma state).
In some clinical situations, the boundaries are blurred between delirium and purely psychiatric illness. Psychiatric illness causes certain populations to become prone to physical disease. As a result, delirium can be surprisingly prevalent in psychiatric patients. Delirium and depression often coexist in seniors because depressed older patients are prone to become dehydrated and malnourished. Psychiatric patients may misuse prescribed drugs or abuse street drugs. Psychiatrists must be alert for delirium in all psychiatric patients.
The correct treatment of delirium entails a search for the underlying causes and an attempt to treat the acute symptoms. Close nursing supervision to protect the patient is essential. Staff should remove all dangerous objects. Brief visits from a familiar person and a supportive environment with television, radio, a calendar, and proper lighting help orient the patient. The physician should review the patient’s medications for unnecessary drugs and stop them; he or she should also monitor the patient’s electrolyte balance, hydration, and nutrition.
When delirious patients become agitated, they may resist treatment, threaten staff, or place themselves in danger. Of equal importance, these patients have elevated circulating catecholamines, which causes an increase in heart rate, blood pressure, and ventilation. Hospital personnel must protect patient rights and apply the least restrictive intervention when dealing with an agitated patient (see Chapter 34). The use of mechanical restraints increases morbidity, especially if the restraints are applied for more than 4 days. A sitter, although expensive, can sometimes obviate the need for physical restraint. Specially designed beds can also reduce the need for restraints. The Health Care Financing Administration has recently introduced strict guidelines for the use of restraints in psychiatric settings.
When other methods fail to control agitated patients, chemical sedation is usually more effective and less dangerous than physical restraint. According to the practice parameters of the Society of Critical Care Medicine, haloperidol is the preferred agent for the treatment of delirium in the critically ill adult. Many clinicians prefer the atypical antipsychotic agents in elderly patients because of the lower incidence of extrapyramidal side effects. The U.S. Food and Drug Administration (USFDA) has issued a warning because of the risk of cardiac complications and type II diabetes accompanying these agents. Whether or not these warnings are meaningful during the short-term use of these agents in patients with delirium is unknown. One recent study, however, indicated that haloperidol and other high-potency neuroleptics had a higher risk in elderly patients than the atypical antipsychotic agents such as olanzapine or quetiapine. In emergencies, haloperidol should be administered intravenously for a painless, rapid, and reliable onset of action that occurs in about 11 minutes. The dose regimen can be adjusted every 30 minutes until the patient is under control. For mildly agitated patients, 1–2 mg may suffice. Severely agitated patients may do better with an initial dose of 4 mg. Every 30 minutes the dose is doubled until the patient’s behavior is contained. About 80% of patients will respond to less than 20 mg per day of intravenous haloperidol. This dose should be minimized in the elderly patient. Although intravenous haloperidol is safe, significant Q-T interval prolongation and “torsades de pointes” (an atypical rapid ventricular tachycardia) are possible complications of high-dose intravenous haloperidol therapy. Droperidol was used in similar fashion in the past, but is no longer available for this purpose because of the high frequency of “torsades de pointes”. Hypotension may occur rarely. Acute dystonic reactions occur in less than 1% of patients. Other extrapyramidal side effects, however, such as Parkinsonism and tardive dyskinesia, are very common with this agent.
Patients admitted to the intensive care unit are often anxious and in pain, conditions that make delirium worse. Anxiety and delirium may be difficult to distinguish from one another. The interplay between confusion and anxiety may cause patients to become agitated when they are encouraged to engage in stressful activities such as weaning from mechanical ventilation. Benzodiazepines, if carefully monitored, can help in these situations. If benzodiazepines are given intravenously, they can cause respiratory depression or hypotension, however, this class of drugs can be easily titrated when monitoring is appropriate. As a result, benzodiazepines are effective in the treatment of delirium in many patients. Neuroleptic agents such as haloperidol may act synergistically with benzodiazepines, resulting in control of agitation. The patient’s level of consciousness and respiratory drive are usually maintained but should be monitored. Once sedation has been achieved, intermittent administration of a neuroleptic agent in combination with a benzodiazepine can usually maintain control.
Physicians need to be aware of the side effects of benzodiazepines. Even when these medications are used as hypnotics, they may cause a decrease in the patient’s MMSE score. Note that benzodiazepines are also employed to produce amnesia for uncomfortable procedures such as colonoscopy or transesophageal echocardiography. A variety of factors, including reduction in hepatic metabolism, modify the pharmacokinetics of many benzodiazepines in elderly patients. Lorazepam and oxazepam may be less affected by hepatic factors and are therefore preferred. Midazolam has been used as an intravenous infusion in intensive care settings because it is safe and has a short half-life.
Barbiturates are highly effective sedatives, but they depress the respiratory and cardiovascular systems. Given the efficacy of benzodiazepines, barbiturates should probably be reserved for agitated patients who have special indications for these drugs. Etomidate and propofol should be avoided for long-term use in agitated patients because of potentially serious side effects.
Pain relief is important. Opiates are the cornerstone of analgesia, but they may also contribute to delirium. In acute settings, opiates with short half-lives are the most efficacious. The Society of Critical Care Medicine recommends morphine, however, the total daily dosage must be monitored carefully in situations in which as-needed dosing is permitted. Naloxone can reverse the effects of a morphine overdose, but the clinician must be aware of the 20-minute half-life of this antagonist. Morphine is contraindicated in patients who have renal failure. Meperidine has been associated with hallucinations and seizures and should not be given to patients with delirium.
The determination of the effective dosage of sedatives and analgesics in patients who have multiple organ system insufficiency requires careful planning and monitoring. Because the liver and kidney eliminate these drugs, organ system failure usually affects their distributive volume and clearance. The physician must assess the patient’s creatinine clearance and liver function. Malnourished patients may have reduced plasma binding. By reducing the size and frequency of doses, the physician can avoid toxic effects. In life-threatening delirium, consultation with the anesthesia service is recommended, and therapeutic paralysis with muscle relaxants and anesthetic agents can be considered.
Patients with delirium have longer hospital stays and higher mortality than lucid patients. About half of all patients with acute encephalopathies improve if they receive proper treatment. Of the remainder, half will die and half will prove to have early signs of dementia. The severity of the underlying illness determines whether the delirious person will live or die, and patients with the poorest cognitive status on admission have the poorest long-term outcome. Ideal management requires awareness of the causes of delirium and active preventive efforts. Very elderly patients and patients with sensory impairment are at highest risk. The alert physician who recognizes systemic illness early and avoids complicated drug regimens can help prevent delirium.
Dementia
Slow evolution of multiple cognitive deficits characterizes dementia. Usually dementia patients have prominent memory impairment, however, dementia has many presentations. Personality disturbance or impaired information processing may reflect the early stages of a dementing process. Occasionally, language disorders or visuospatial syndromes are the presenting features of dementia. Sometimes the clinical syndrome is specific for a particular underlying pathology, but often the presentation may reflect a variety of possible pathologies. DSM-IV categorizes dementias according to presumed etiology, but this categorization will undoubtedly continue to undergo substantial revision because of the explosion of knowledge emerging from dementia research. In this chapter, DSM-IV criteria are included wherever possible (see “DSM-IV Diagnostic Criteria” sections, where applicable), however, in some cases alternative classifications better express the growing field of knowledge (see “Essentials of Diagnosis” sections, where applicable).
Clinical diagnosis is ultimately an attempt to deduce the neuropathologic basis of the patient’s problem. Most dementias are associated with destruction or degeneration of brain structures. The autopsy shows whether the damage is the result of degenerative disease, vascular disease, infection, inflammation, tumors, hydrocephalus, or traumatic brain injury. Multiple causes for dementia are often apparent at an autopsy. Because the autopsy comes too late to help the patient or the family, the clinician must be knowledgeable about the pathology that is most likely to be associated with a given clinical presentation.
Clinical diagnosis is based on the patient’s history and mental status and on laboratory examination. Several basic tests are recommended in the evaluation of dementia. These include complete blood count with differential, electrolytes, liver function tests, blood urea nitrogen, creatinine, protein, albumin, glucose, vitamin B12, urinalysis, and thyroid function tests. A brain imaging study, either CT or magnetic resonance imaging (MRI), is virtually always required. CT generally gives less information than MRI. In a significant minority of cases, imaging does not clarify the diagnosis, but nonetheless provides comfort to the family and the clinician that “no stone has been unturned.” Imaging studies are recommended in some practice guidelines, including those of the American Academy of Neurology. Optional tests include sedimentation rate, blood gases, folate, HIV screen, syphilis serology, heavy metals screen, positron emission tomography (PET) or single photon emission computed tomography (SPECT) scanning. Genetic testing (for apolipoprotein E), cerebrospinal fluid (CSF) assays of tau, and neural thread protein are available but generally not recommended.
CT and MRI scans are especially important in excluding focal lesions or conditions such as hydrocephalus, subdural hematoma, silent strokes, or brain tumors. The physician must be careful not to over-interpret findings. EEG was previously used more commonly in the evaluation of dementia, however, EEG slowing is difficult to interpret. Intermittent slowing is not related to MRI change or to decline in neuropsychological function. Runs of intermittent slowing increase in frequency with advancing age, but such episodes are brief and infrequent. Focal slow waves sometimes occur in temporal and frontal areas without significance. When any of these changes become prominent, pathology is usually present. Older people in good health may have an average occipital frequency that is a full cycle slower than young adults, however, they do not show EEG dominant frequencies below 8 hertz.
Occasionally, a dementia evaluation leads to the diagnosis of a treatable illness and permits curative treatment, especially when the dementia has toxic or metabolic etiologies. More commonly the physician establishes a plausible explanation of the clinical findings and suggests palliative care. Because families come to physicians for a diagnosis and a prognosis, the physician’s explanation should include statements about what is likely to happen to the patient. The family needs an interpretation of the observed behavior and suggestions about ways to deal with it. The physician gives the family some understanding of what is happening and helps them in planning for future decline in the patient’s status. The psychiatrist often manages the troubling behavior that occurs toward the end of many dementing illnesses. The psychiatrist also recognizes the needs of the caregiver and makes suitable suggestions to help the caregiver relinquish part of the burden.
Dementia of the Alzheimer’s type (AD), frontotemporal dementia (FTD), and diffuse Lewy body disease are primary degenerative processes occurring within the CNS. These syndromes are progressive and lead inevitably to severe disability and death. Other degenerative dementias are associated with diseases that affect other neurological systems; these include Huntington’s disease, Parkinson’s disease (PD), progressive supranuclear palsy, corticobasal degeneration, and multiple system atrophy.
The most widely applied criteria for the clinical definition of AD are those of the National Institute of Neurological and Communicative Disorders and Stroke and those of the AD and Related Disorders Association. The diagnosis of probable AD requires the presence of dementia established by clinical examination, documented by standardized mental status assessment, and confirmed by neuropsychological tests. These tests must demonstrate deficits in two or more areas of cognition, with progressive worsening of memory and other cognitive functions in the absence of delirium. The onset must be between ages 40 and 90 years, and there must be no other brain disease that could account for the clinical observations (this implies a work-up, including the blood studies and brain imaging tests discussed above). The disorder must also be progressive and associated with disability in routine activities. Supportive features include family history, specific progressive deficits in cognitive functions, and laboratory data such as PET or SPECT scans. PET ligands that bind to amyloid, such as the Pittsburgh Compound, may provide more accurate AD diagnosis in the future.
AD is the most common form of dementia, accounting for over half of all dementias. Oddly enough, just 25 years ago, many textbooks considered AD to be rare, likely because the disease was confined to “presenile” cases, younger than age 65. We now know that the neuropathology of presenile and senile dementia is the same. There has been a veritable explosion in research in AD.
Although memory problems dominate the early stages of the disorder, AD affects cognition, mood, and behavior. Cognitive impairment affects daily life because patients are unable to perform normal activities of daily living. Behavioral manifestations of the disease such as temper outbursts, screaming, agitation, and severe personality changes are more troubling than the cognitive difficulties. No two patients with AD are exactly alike when it comes to the behavioral manifestations of the disorder. Only recently has this aspect of the disease received substantial attention.
AD is the most common type of progressive dementia. This degenerative disease reaches 20% prevalence in 80-year-olds, as much as 48% prevalence in one study of community-dwelling elderly people over age 85, and afflicts over four million Americans. It is projected to affect 8–14 million by the year 2030. The disease affects women more often than men. The economic impact of AD has been estimated at over $100 billion annually.
In general, AD represents an imbalance between neuronal injury and repair. Factors contributing to injury may include free radical formation, vascular insufficiency, inflammation, head trauma, hypoglycemia, and aggregated β-amyloid protein. Factors contributing to ineffective repair may include the presence of the apolipoprotein E (ApoE) E4 gene, altered synthesis of amyloid precursor protein, and hypothyroidism. Some researchers hypothesize that β-amyloid causes chronic inflammation. AD also involves formation of tau-containing neurofibrillary tangles; most researchers feel that the tau protein changes (see below) are a secondary phenomenon in AD, though they may be primary in FTD and other diseases. Ultimately, the deficit of key neurotransmitters, especially acetylcholine, plays a major role in the cognitive symptoms.
Plaques and tangles identify the illness at the microscopic level. Amyloid plaques occur in vast numbers in severe cases. Amyloid plaques were first recognized in 1892. PAS or Congo Red stains identify these structures. β-Amyloid peptide, which is concentrated in senile plaques, has been linked to AD. The β-amyloid protein, in the form of pleated sheets, appears early in the brain and in blood vessels in AD. Some studies suggest that β-amyloid is toxic to mature neurons in the brains of Alzheimer’s patients. Neurons in these areas begin to develop neurofibrillary tangles. Amyloid plaques and neurofibrillary tangles gradually accumulate in the frontal, temporal, and parietal lobes. The density of plaques determines postmortem diagnosis. Amyloid binding can now be imaged in PET studies, using the Pittsburgh compound and other ligands. The number of neurons and synapses is reduced. This is particularly true of acetylcholine-cholinergic-containing neurons in the basal nucleus of Meynert, which project to wide areas of the cerebral cortex. PET studies demonstrate a reduction in acetyl cholinesterase and decreased binding of cholinergic ligands. Hirano bodies and granulovacuolar degeneration occur in the hippocampus and represent further degeneration.
Neocortical neurofibrillary tangles are extremely rare in normal individuals, however, neuropil threads and neurofibrillary tangles appear at the onset of dementia. These intracytoplasmic filaments displace the nucleus and the cellular organelles. Neurofibrillary tangles contain an abnormally phosphorylated protein named tau. The abnormal phosphorylation of tau protein probably causes defective construction of microtubules and neurofilaments. The neurofibrillary tangles in brains affected by AD abnormally express Alz-50, a protein antigen commonly found in fetal brain neurons. Neural thread protein is present in the long axonal processes that emerge from the nerve cell body and is found in association with neurofibrillary tangles. This protein may be involved in neural repair and regeneration.
Neurons bearing neurofibrillary tangles often project to brain regions that are rich in senile plaques containing β-amyloid. These plaques are found in areas innervated by cholinergic neurons. Cholinergic neurons in the hippocampus and the basal nucleus of Meynert degenerate early in AD, causing impairment of cortical and hippocampal neurotransmission and cognitive difficulty. The affected cortical areas become anatomically disconnected. One of the earliest areas to be disconnected is the hippocampus, which explains why memory disorder is one of the early manifestations of AD. As time goes on, there is a loss of communication between other cortical zones and subsequent loss of higher cognitive abilities.
These basal forebrain cholinergic projections not only mediate cognitive function but also mediate brain responses to emotionally relevant stimuli. In the late stages of AD, a wide range of behavioral changes occur, including psychosis, agitation, depression, anxiety, sleep disturbance, appetite change, and altered sexual behavior. These changes are mediated by cholinergic degeneration and by degeneration in other neural systems. Serotonergic neurons and noradrenergic neurons degenerate as the disease progresses. Degeneration of these systems also contributes to some of the later cognitive and behavioral manifestations of the disorder. Because dopaminergic neurons are relatively immune to degeneration in AD, the performance of well-learned motor behaviors is preserved well into the late stages of the disease.
AD has demonstrated genetic diversity. Chromosome 21 has been implicated for many years because it is well known that patients with Down syndrome are very likely to develop the histological features of AD. Genetic mutations usually cause familial, autosomal dominantly transmitted, early-onset AD. Several mutations of the amyloid precursor protein gene on chromosome 21 have been described. These mutations increase the production of an abnormal amyloid that has been associated with neurotoxicity. Another form of early-onset disease has been localized to a variety of defects on chromosome 14. These mutations are associated with presenilin 1 and account for the majority of familial Alzheimer’s cases. A mutation on chromosome 1 is associated with presenilin 2. Both of these mutations also cause increased production of amyloid, in that the presenilins are now known to be secretase enzymes involved in the formation of beta-amyloid peptide, a 40–42 amino acid peptide, from the amyloid precursor protein.
The ApoE E4 allele is associated with the risk of late-onset familial and sporadic forms of AD. ApoE; a plasma protein involved in the transport of cholesterol is encoded by a gene on chromosome 19. Disease risk increases in proportion to the number of ApoE E4 alleles. The population that is positive for ApoE E4 has a lower age at onset. The ApoE E2 allele may offer some protection. Although patients with the ApoE E4 allele may be more likely to have AD, a full diagnostic evaluation including imaging, laboratory tests, and neuropsychological evaluation is still indicated when the clinical situation warrants. It is premature to regard ApoE testing as a screening tool for AD, and it is not recommended for presymptomatic screening in family members of patients with AD. Another gene, SORL1, has recently been described as a marker for sporadic AD.
A subjective sense of memory loss appears first, followed by loss of memory detail and temporal relationships. All areas of memory function deteriorate including encoding, retrieval, and consolidation. Patients forget landmarks in their lives less often than other events. Amnesia for names and specific nouns is the earliest language abnormality in AD, and a mild anomic aphasia is often found in patients with early AD. Agnosia (failure to recognize or identify objects), more severe aphasia (language disturbance), apraxia, and visuospatial-topographical impairments such as getting lost while walking or driving occur later in the disease.
In the early stages of AD, a subjective memory deficit is difficult to distinguish from benign forgetfulness. Considerable research has examined patients with impaired memory but otherwise normal cognitive function, a disorder called “mild cognitive impairment.” These patients are more likely to develop AD over time than age-matched controls. Deficits in memory, language, concept formation, and visual spatial praxis evolve slowly. Later, patients with AD become passive, coarse, and less spontaneous. Many become depressed, and depression may worsen the patient’s cognitive function. Depressed Alzheimer’s patients often exhibit degeneration of the locus coeruleus or substantia nigra.
More than half of patients with mild Alzheimer’s patients present with at least one psychiatric symptom, and one-third present with two or more symptoms. After the initial stage of the disease, patients enter a stage of global cognitive deterioration. Denial or loss of self-awareness replaces anxiety, and cognitive deficits are noticeable to family and friends. In the final stages, patients become aimless, abulic (unable to make decisions), aphasic, and restless. At this stage, abnormal neurologic reflexes, such as the snout, palmomental, and grasp reflexes, are common.
The clinical assessment and staging of AD have always been difficult. The MMSE is often used but sometimes seriously underestimates cognitive impairment. The Standardized MMSE has better reliability than the MMSE. The Blessed Dementia Scale uses collateral sources and correlates well with postmortem pathology. The interrater reliability of the Blessed Dementia Scale is low.
The Extended Scale for Dementia is a rating scale designed to distinguish the intellectual function of dementia patients from normal seniors. The Neurobehavioral Cognitive Status Examination (NCSE) is a tool that assesses a patient’s cognitive abilities in a short amount of time. This instrument uses independent tests to estimate functioning within five major cognitive ability areas: language, constructions, memory, calculations, and reasoning. The Mattis Dementia Rating Scale (DRS) is useful in staging dementia. Both the NCSE and the DRS are sensitive, but they are more time consuming than the MMSE. In most clinical practices, the MMSE is used for assessment of dementia and for following the patient’s progress, and common recommendations for drug therapy are based on the MMSE score.
Comprehensive scales combine clinical judgment, objective data, and specific rating criteria. The Reisberg Brief Cognitive Rating Scale and the Global Deterioration Scale are brief comprehensive scales. The Clinical Dementia Rating Scale (CDR) is a more extensive instrument that includes subject interview, collateral interview, brief neuropsychological assessment, and interview impression. Patients with a CDR score of 0.5 are likely to have “very mild” AD. The CDR has a complicated scoring algorithm and is best reserved for research.
The Alzheimer’s disease Assessment: Cognitive (ADAS COG) and the Behavioral Pathology in AD (Behave-AD) instruments are used in clinical drug trials to determine pharmacologic efficacy in cognitive areas or behavioral areas, respectively.
The Consortium to Establish a Registry for Alzheimer’s disease Criteria (CERAD) examination includes general physical and neurologic examinations as well as laboratory tests. Specified neuropsychological tests and a depression scale are also administered.
Although CT scans reveal atrophy in Alzheimer’s patients as a group, atrophy alone does not reliably predict AD in individual patients. Atrophy can be quantified using appropriate ratios and progresses on serial evaluation, but this information adds little to the patient’s clinical care.
MRI region-of-interest techniques reveal reduced brain volume and higher CSF volume in patients with AD. AD may be associated with enlarged CSF spaces or atypical signal intensity in the medial temporal lobes. These findings imply that advancing AD is associated with increased brain water, where either the atrophy leads to an increase in CSF spaces, or there are associated ischemic changes in the deep cerebral white matter. Finally, volumetric studies may show hippocampal sclerosis in the brains of Alzheimer’s patients. Hippocampal atrophy may be relatively specific to AD and may be useful for early detection and differential diagnosis.
31P–nuclear magnetic resonance (NMR) spectroscopy profiles may be helpful in the evaluation of AD. 31P NMR profiles of AD patients show elevated ratios of phosphomonoesterase to phosphodiesters in the temporoparietal region.
In the early stage of dementia, functional brain imaging (i.e., PET and SPECT scans) is more sensitive than structural brain imaging (i.e., MRI and CT scan). PET scans reveal changes in temporoparietal metabolism that differentiate patients with AD from the normal elderly. PET scans reveal the following abnormalities in AD: (1) reductions in whole-brain metabolism (paralleling dementia severity), (2) hypometabolism in the association cortex exceeding that in the primary sensorimotor cortex, and (3) metabolic asymmetry in suitable cortical areas accompanying neuropsychological deficits. In AD metabolic deficits start in the parietal cortex. Frontal metabolism decreases as dementia progresses. AD spares the primary motor cortex, sensory cortex, and basal ganglia.
SPECT scans can reveal information about regional brain function at a much lower cost and degree of complexity than PET scans, but the spatial resolution is not as good. In more advanced AD cases, SPECT scans reveal decreased perfusion in the bilateral temporoparietal regions.
EEG abnormalities are not common early in AD, but they develop as the disease progresses. Diffuse slow wave abnormalities occur first in the left temporal regions and become more frequent and longer as the disease progresses. EEG abnormalities that occur early in dementia suggest a coexisting delirium. Because dementia often presents first in association with delirium, infectious, toxic, or metabolic disturbances should be considered if the EEG slowing is severe.
Evoked potentials are an EEG technology that average many signals following a specific stimulus. In AD, the auditory P300 amplitude in the posterior parietal regions is suppressed on evoked potential maps. Other studies have not demonstrated clinically useful abnormalities of the P300 component in dementia. Compared to control subjects, AD patients show longer P100 latencies of pattern-reversal visual evoked potentials. The flash P100 distinguishes them only marginally. The long-latency auditory evoked potential helps differentiate between cortical and subcortical dementias. Patients with subcortical dementias exhibit prolonged latencies.
Clinicians have traditionally used a battery of laboratory tests to differentiate AD from a variety of medical conditions that cause memory impairment. These tests include complete blood count, comprehensive metabolic panel, thyroid function tests, and vitamin B12. In appropriate cases, the erythrocyte sedimentation rate, serological tests for syphilis, and even a lumbar puncture may be indicated. In many cases, a careful history and bedside mental status examination can reliably diagnose presumed AD and distinguish it from other forms of dementia. A detailed drug history is necessary because drugs, especially those with anticholinergic properties, can cause Alzheimer-like symptomatology. A normal neurologic examination is entirely consistent with AD. Neurologic abnormalities are much more common in other dementing illnesses. The relationship between AD and depression is complex and is discussed later in this chapter.
Memory loss is common in nondemented seniors. Many of these patients become terrified that they have AD and seek medical help. Physicians have difficulty distinguishing normal age-associated memory loss, benign forgetfulness, and early AD.
Benign senile forgetfulness is a condition that occurs when effects of aging on memory are greater than expected. Elderly patients with benign forgetfulness forget unimportant details. This contrasts with Alzheimer’s patients, who forget events randomly. Seniors who experience benign senile forgetfulness have trouble remembering recent information; typically, Alzheimer’s patients have difficulty with recent and remote memory. The most important aspect of the treatment of benign senile forgetfulness is reassurance, but cognitive retraining can sometimes be helpful. When the memory loss is clearly more than normal for age, the diagnosis should be “mild cognitive impairment” (MCI). As mentioned earlier, this condition is not as benign, in that almost half of patients with MCI progress to AD over a 3–4-year period. Drug treatment for patients with MCI is the subject of active research, but no specific recommendation exists, as yet. Treatment should be considered when the cognitive disorder becomes disabling, or by common insurance company guidelines, when the MMSE drops below 24.
Although AD can be diagnosed accurately in clinical settings, inaccuracy of diagnosis continues to plague clinical care. AD is over-diagnosed. Patients with FTD, PD, diffuse Lewy body disease, or even metabolic conditions mistakenly receive the diagnosis of AD. Unfortunately, even patients taking multiple medications and those who have delirium may receive the diagnosis of AD.
The aim of pharmacotherapy in AD is as follows: (1) to prevent the disease in asymptomatic individuals, (2) to alter the natural course of the disease in those already diagnosed, and (3) to enhance patients’ cognition and memory. As yet, no treatment has been shown to be effective in preventing the disease, though general health measures such as exercise, healthy diet, treatment of hypertension and hyperlipidemia, and avoidance of tobacco and excessive alcohol are all suggested to delay or prevent the disease. Treatment to enhance memory in Alzheimer’s patients has focused on improving cholinergic activity. Cholinergic enhancement can occur through the administration of acetylcholine precursors, choline esterase inhibitors, and combinations of AChE with precursors, muscarinic agonists, nicotinic agonists, or drugs facilitating AChE release. To date, only cholinesterase inhibitors have proved effective in clinical trials.
Early attempts to treat dementia with ergoloid mesylates were of limited benefit. In some studies, ergoloid mesylates were more effective than placebo. The dose-response relation suggests that the effective dosage may be higher than currently approved. Unfortunately, the original clinical trial designs were flawed, leaving their benefit unproved.
Attempts to enhance acetylcholine transmission with precursors such as lecithin and choline failed to show benefit in AD. Cholinomimetic substances such as arecoline were more successful but have had limited use because of adverse side effects, short half-life, and narrow dose range. Physostigmine, an acetylcholinesterase inhibitor, has limited benefit because of its short half-life and significant side effects.
The first acetylcholinesterase inhibitor approved for use in mild to moderate AD was tetrahydroaminoacridine (Tacrine). Tacrine frequently causes adverse side effects, particularly gastrointestinal hyperactivity. Elevation of liver transaminase is another significant side effect. Of the patients who take tacrine, 25% will experience elevations (up to three times the normal) in alanine amino transferase levels. For these reasons, tacrine is rarely used currently.
Second-generation cholinesterase inhibitors such as donepezil are more specific for CNS acetylcholinesterase than for peripheral acetylcholinesterase. These drugs do not have the limitations associated with tacrine. Donepezil has the additional advantage of daily dosing. It does not cause significant hepatotoxicity. Donepizil has an orally dissolving tablet form and has been approved for mild, moderate, and severe AD. Rivastigmine is a cholinesterase inhibitor that has a relative specificity for both acetylcholinesterase and butyrylcholinesterase, an effect shared only with tacrine. There is evidence that butyrylcholinesterase is present at high concentrations in the brains of patients with AD, but the relevance of this factor to its clinical effect is unknown. The drug has more gastrointestinal side effects than donepizil. It is given twice daily at doses of 1.5, 3, 4.5, and finally 6 mg, with dose advances made every four weeks. A last cholinesterase agent, galantamine, has similar effects on the acetylcholinesterase enzyme, but may also increase presynaptic release of acetylcholine. This agent is available in both twice daily and extended release preparations. The daily doses are 8, 16, and 24 mg. The gastrointestinal side effects of this agent are intermediate between those of donepizil and rivastigmine, but individual patients may tolerate one better than another.
New delivery mechanisms for the anticholenesterase medications have made them more tolerable. Galantamine is available in an extended release formulation. Rivastigmine will be available in a patch formulation that provided similar efficacy to that achieved at the highest doses of the capsule with three times fewer reports of nausea and vomiting.
Muscarinic M1 receptors are relatively intact in AD, despite the degeneration of presynaptic cholinergic innervation. Several muscarinic agonists have been studied in clinical trials, but none has been approved, to date. Finally, stimulation of nicotinic receptors may have a protective effect in AD.
The newest drug to be USFDA approved for AD is memantine, an antagonist at the NMDA receptor. The exact mechanism of action of this drug is not known; the NMDA effect could represent a neuroprotective effect on “excitotoxicity” of glutamate on surviving neurons, but this drug appears to have other beneficial effects on learning and memory. It has been approved for moderate to advanced AD, that is, patients with MMSE <20.
Treatment of behavioral complications of AD is problematic. Depression should always be treated, usually with an SSRI agent. Anxiety can be helped with trazodone at bedtime, but benzodiazepines tend to worsen the memory loss and may cause paradoxical agitation. Valproic acid has been found helpful in some, but not all studies. Both donepezil and memantine appear to ameliorate behavioral disturbances in patients with AD. The same therapeutic considerations discussed under delirium are relevant in the treatment of psychosis in AD. Atypical antipsychotic agents are not greatly effective and have a black box warning. In general, we recommend low doses of olanzapine, risperidone, aripiprazole or quetiapine, with increases in dosage or shifting to another agent if symptoms persist. In the CATIE trial, the benefit for those taking active drug compared to placebo, was small. While antipsychotic medications were more often associated with distressing adverse effects. Patients and families must be warned of the potential risks of these agents.
Therapeutic strategies intended to slow progression of AD have not been very successful. Early studies suggested that the incidence of AD was reduced in postmenopausal women taking estrogen, but the Women’s Health Initiative studies found the opposite: postmenopausal estrogen and progesterone hormone replacement therapy appears associated with a higher incidence of cognitive deficits and dementia. Use of non-steroidal anti-inflammatory drugs has been inversely associated with incidence of dementia in population studies, but a therapeutic use of these agents in AD has not been proved. The Cox II inhibitor refoxicib (Vioxx) was taken off the market because of increased cardiovascular events, and one of the two studies with this finding involved patients with AD. Antioxidants such as vitamin E and selegiline have shown a beneficial effect in some studies, but several recent studies have failed to establish any role for these agents. In particular, a study of mild cognitive impairment showed a limited benefit for donepizil, but none whatsoever for Vitamin E. Nicotine may have protective properties, but the toxic effect of the drug on other body systems currently precludes its use as treatment. Attempts to treat AD with nerve growth factor have been limited by the inability of the substance to cross the blood–brain barrier.
Treatments to reduce the deposition of amyloid protein in the brain have not proved effective as yet, but this field has great promise. A trial of a vaccine against amyloid had to be stopped because of the development of an encephalitis in about 10% of the recipients; one case, studied at autopsy, had little remaining amyloid staining. More selective vaccines and passive immunity with monoclonal antibodies against amyloid are currently in testing. An experimental drug called Alzhemed represents another attempt to reduce amyloid deposition; this clinical trial is still in progress. In general, AD is a very active area of clinical research.
An early-onset form of AD occurs in some people in their 40s, 50s, or 60s. A prolonged, indolent, subtle deterioration in mental function characterizes the clinical course of illness. From the time of clinical diagnosis the course is variable, but survival is possible up to 20 years from clinical recognition. Early-onset cases tend to progress more rapidly. Ultimately, functional performance declines. The patient’s ability to drive becomes impaired, and he or she becomes unable to manage personal finances or to produce a complete meal. In general, studies suggest that patients with a MMSE score below 20 are probably not safe drivers. Later, impairment of language and inability to recognize familiar people lead to agitation, restlessness, and wandering. Hallucinations and other disruptive behaviors may make management difficult. In the final stages of the disease, the patient is generally mute and completely devoid of comprehension. Death most often results from a comorbid illness such as pneumonia.
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