5 - Geriatrics | The Internal Medicine Casebook: Real Patients, Real Answers

Editors: Schrier, Robert W.

Title: Internal Medicine Casebook, The: Real Patients, Real Answers, 3rd Edition

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Chapter 5

Geriatrics

Laurence Robbins

Dementia

What is the most common cause of primary dementia in the U.S. population?
What are the pathognomonic postmortem findings of Alzheimer's disease (AD)?
Can the children of patients with AD be genetically tested and told with assurance whether they will inherit the disease?
How can cognitive function be tested quickly and reliably?
Can the intellectual decline seen in patients with AD be halted or reversed with medications?

Discussion

What is the most common cause of primary dementia in the U.S. population?

AD is the most common cause of dementia in the U.S. population. Dementia currently affects approximately 4.5 million people in the United States and this number will grow to an estimated 10 million by 2050. As the most common etiology of dementia, it accounts for 70% or more of all
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dementia diagnoses. Advancing age remains the single greatest risk factor for AD. Currently, it afflicts approximately 2% of the population between 65 and 70 years of age, and approximately 30% of the population older than 80 years. The incidence of new disease is approximately 3% per year in community-dwelling elderly with an average age of 75. Acquired impairment of short-term memory is its hallmark with at least one of the following four symptoms as well: aphasia, apraxia, agnosia, and executive dysfunction. Aphasia may be fluent or nonfluent. Patients may have difficulty coming up with the correct word when trying to name objects, often substituting words that describe an object (e.g., when asked to name a watch, the patient with AD might say it's a thing you use to tell time ). Apraxia is the inability to carry out motor tasks in the absence of motor weakness (e.g., a patient is no longer able to knit although there is no weakness of hands or arms because they cannot reproduce the necessary motion to create a stitch). Agnosia is the inability to recognize sensory information (visual, auditory, etc.); it may include getting lost in familiar surroundings or failing to recognize familiar people. Executive dysfunction is the inability to complete a sequence of tasks in proper order. An example of executive dysfunction might include losing the ability to balance a checkbook. On a more basic level, it might affect the ability to get dressed (i.e., inability to put clothes on in the proper sequence).

Other causes of dementia are less common. The absence of clinical diagnostic criteria that unequivocally separate one cause of dementia from another obfuscates efforts to pinpoint the prevalence of any specific cause of dementia. Vascular dementia (VD) is arguably the second most common cause of dementia. Two features help distinguish VD from AD, clinically. Although AD primarily affects the gray matter of the temporal lobes, VD tends to include multiple small infarcts in the deep white matter of the brain. In VD, this distribution of ischemia leads to marked slowing in patient response time to questions and is more likely to produce focal neurologic motor and sensory findings, including gait disorders. Sparing of the motor cortex makes motor findings, including gait disorders, much less common in early AD than in VD.

Since first described in 1961, diffuse Lewy body dementia (DLBD) has received increasing attention as a more common cause of degenerative dementia than previously recognized. Although Lewy bodies are the hallmark of Parkinson's disease when found in the basal ganglia, particularly the substantia nigra, they may appear in cortical and subcortical areas as well. The astute clinician will suspect a diagnosis of DLBD when patients present with a triad of progressive but fluctuating cognitive decline, parkinsonism, and visual hallucinations (hallucinations are not typical early in the course of AD). Similarly, patients with a diagnosis of Parkinson's disease may initially appear cognitively intact but over time, usually well after the motor signs of Parkinson's disease have progressed, they develop progressive dementia. These latter patients have somewhat arbitrarily been diagnosed as having the dementia of
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Parkinson's disease to distinguish them from patients with DLBD who have the simultaneous onset of motor and cognitive dysfunction.

Frontotemporal dementias are a heterogeneous group of disorders that primarily affect the frontal and temporal areas of the brain. Most have nonspecific degenerative changes and not the Pick bodies that characterize Pick's disease, the first of these disorders to be specifically recognized. These patients most often come to medical attention for behavioral and speech problems (both fluent and nonfluent) rather than primarily for memory loss.

Besides VD, the non-AD causes of dementia are relatively uncommon, each accounting for less than 5% of all dementia. Other etiologies are even more rare, such as Creutzfeldt-Jakob disease, a prion-related disease that may affect as few as one in a million people in the United States. Other rare primary degenerative neurologic diseases causing dementia would include Huntington's chorea or progressive supranuclear palsy, each with its own relatively distinct set of clinical features.
What are the pathognomonic postmortem findings of AD?

Neurofibrillary tangles and neuritic plaques are postmortem findings pathognomonic for AD, and the diagnosis is certain only if the pathologist identifies a significant number of these lesions in the typical distribution (i.e., heavy concentrations in the hippocampus and surrounding areas of the temporal lobes). Ninety percent or more of patients with clinically diagnosed dementia of the Alzheimer's type have the diagnosis confirmed at postmortem examination. Plaques and neurofibrillary tangles are also found in the brains of healthy elderly subjects, but in much smaller numbers than in the elderly patients with AD. Depletion of cholinergic neurons is another pathologic hallmark, and maintenance or supplementation of cholinergic function has been the focus of several treatments of AD.

Other conditions that may be clinically confused with AD are associated with different pathologic findings. A multifocal loss of brain tissue secondary to ischemia is seen in the setting of multiinfarct dementia. Degeneration of the dopaminergic cells in the substantia nigra and Lewy bodies are found in patients with Parkinson's disease. Sometimes pathologists find cortical and subcortical neuronal loss associated with Lewy bodies outside the traditional distribution of these lesions in Parkinson's disease. This entity is now identified as DLBD and may represent the second most common cause of neurodegenerative dementia after AD.
Can the children of patients with AD be genetically tested and told with assurance whether they will inherit the disease?

The evidence for a hereditary predisposition of AD has led to genetic research that has identified several chromosomal abnormalities that increase the risk for developing AD. Researchers have identified defective genes in chromosomes 1, 14, and 21 that are linked to autosomal dominant inheritance patterns of AD in a small number of families. Afflicted patients in these families often have earlier onset of dementia, between 35 and 65 years of age, which is considerably earlier than the usual onset in patients with late-life AD typically
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beginning in the eighth decade or later. Late-life onset of AD occurs more often in patients who have the Apolipoprotein (Apo) E4 allele on chromosome 19. Three ApoE alleles have been described, namely ApoE2, ApoE3, and ApoE4. Although ApoE4 appears to increase the risk for development of late-onset AD, ApoE3 is the most commonly inherited allele and appears to confer neither a greater nor lesser risk of developing AD. ApoE2 is very rare (approximately 1% of the population) and may confer a slightly lower risk of AD. Not all individuals with an ApoE4 allele will develop AD and, conversely, AD occurs among many people who are homozygous for ApoE3. Therefore, genetic testing, with the exception of an autosomal dominant pattern inheritance of the disease, does not reliably predict an individual's risk of developing AD. Advancing age remains the single greatest risk for developing AD. The absence of consistent correlation between the presence or absence of currently known genetic markers and the risk of AD, and the absence of interventions that clearly delay or prevent the development of AD (see following text) suggest that genetic testing currently has little clinical utility.
How can cognitive function be tested quickly and reliably?

Numerous studies have shown that physicians overlook more than 50% of patients who have cognitive impairment. This is most often due to the clinician's failure to do formal mental status testing that would objectively identify these deficits. The Folstein Mini Mental Status Examination (MMSE) and similar brief mental status tests (e.g., the Pfeiffer and the Blessed Dementia Scales) are quick, reliable screening tools to assess cognitive function and may estimate the severity of mental status impairment. The MMSE measures orientation, memory, and attention as well as the status of written and spoken language and visuospatial skills. With a sensitivity of 87% and specificity of 82%, the MMSE results are reproducible when the test is administered either by a health care professional or by someone trained to administer the test. One of the best single-item screening tests is clock drawing. The inability to draw familiar, relatively simple objects may reflect apraxia, often an early sign of dementia. The examiner asks the patient to draw a clock face, fill in the numbers, and then draw the hour and minute hands indicating a time, such as 10 minutes past 2. Studies suggest that this simple test has a sensitivity and specificity similar to more elaborate screening tools like the MMSE.
Can the intellectual decline seen in patients with AD be halted or reversed with medications?

Efforts to halt or at least delay the progression of cognitive decline in patients suspected of having AD is extremely challenging. First, the clinician must rule out potential reversible factors that may hasten a patient's deterioration. Depression is a common complication of AD. Left unrecognized, depression may lead to a loss of interest, and decrease in ability to concentrate and function in patients with AD. Treatment of depression can reverse some of the additional decline in intellectual function that occurs when depression is left untreated. Second, medication side effects can give the appearance of progression of AD. A large number of medications, including anticonvulsants, muscle
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relaxers, analgesics, and others, may be implicated. Psychoactive medications, particularly those with anticholinergic side effects such as tricyclic antidepressants, are notorious for causing reversible increased confusion and cognitive decline in patients with underlying dementia. The experienced physician will work methodically to reduce or eliminate medications that may exacerbate cognitive losses of patients with AD, recognizing that medications are the single most common cause of reversible cognitive impairment. In addition to reducing medications that may exacerbate cognitive decline, clinicians should rule out abnormalities such as B₁₂ deficiency, hypothyroidism, hypo- or hyperglycemia, hyponatremia, or other metabolic problems that may also hasten cognitive impairment. Finally, structural abnormalities such as subdural hematomas, normal pressure hydrocephalus, or brain tumors occasionally lead to reversible deterioration in memory and related intellectual function. The presence of focal neurologic signs and/or the presence of a gait disorder are not consistent with a diagnosis of AD and may trigger a request for a brain imaging study to rule out one of the three structural central nervous system problems noted in the preceding text that may present opportunities for intervention to reverse cognitive losses.

When patients with AD have no evidence of reversible contributors to their cognitive decline, therapies aimed at halting or reversing disease progression have been only modestly successful to date. Recognizing that cholinergic neuronal loss is a predominant pathologic finding in AD, investigators have focused on finding ways to enhance cerebral cholinergic activity. This effort led to the development of cholinesterase inhibitors that block the breakdown of acetylcholine in the brains of patients with AD. The U.S. Food and Drug Administration (FDA) has approved a total of five medications for the treatment of AD, four of which are cholinesterase inhibitors. The first of the cholinesterase inhibitors, namely tacrine (Cognex), is no longer used because it must be taken on an empty stomach four times a day and has been associated with gastrointestinal and hepatic toxicity. Donepezil (Aricept) was the second agent approved and can be taken once a day, usually at bedtime and has minimal gastrointestinal toxicity and no reported hepatotoxicity. The FDA also approved galantamine (Razadyne) and rivastigmine (Exelon) which are prescribed twice a day and may cause slightly more gastrointestinal upset but also have no apparent hepatotoxicity. More than 9,000 patients have now participated in randomized controlled trials of cholinesterase inhibitors lasting up to 1 year. All were pharmaceutical company sponsored and had strict criteria for participation that some experts suggest would have excluded 90% of patients with dementia. All of these studies showed modest slowing of progression on scales that measured cognitive function, behavior, and global function. This effect is equivalent to preventing progression of AD for a few months. In a modestly successful attempt to study longer-term effects of cholinesterase inhibitors in a more inclusive group of demented patients over several years, a group of British investigators reported their results in 2004 for a study entitled AD 2000. At the end of this 3-year study, they found no differences in clinically significant outcomes such as
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caregiver report of the patients' function, caregiver burnout, nursing home placement, or hospitalization. The study did demonstrate a persistent slowing of decline in cognitive tests that was equivalent to delaying disease progression for 3 months. The absence of a clinically significant benefit was disappointing. Memantine (Namenda) is the only other medication currently FDA approved for treatment of AD. This drug is a partial antagonist of the N-methyl D-aspartate (NMDA) receptor in the brain, an important mediator of glutamate activity. Experimental evidence suggested that excessive activity of the NMDA receptor may be associated with progression of AD and suppression of NMDA activity might slow the progression of the disease. In studies of approximately 1,000 patients, memantine has a similar effect as the cholinesterase inhibitors in slowing the deterioration of patient performance on several scales in studies lasting up to 1 year. Like the cholinesterase inhibitors, memantine has minimal toxicity but has not been subjected to long-term randomized trials to determine its effectiveness in slowing the clinical deterioration of AD.

Epidemiologic and small intervention studies have suggested that medications including estrogen, nonsteroidal antiinflammatory agents such as ibuprofen, vitamin E, selegiline (a monoamine oxidase inhibitor), ginkgo biloba, and others may slow the progression of AD. Unfortunately, none of these agents have proved effective to date in long-term, randomized studies. Therefore, none of these medications has received FDA approval in the prevention or treatment of AD.

In summary, no currently available medications for the treatment of AD have significant clinical impact on the prevention or progression of this disease. Improvement in cognition and function is most likely to occur when the clinician reduces or discontinues medication that can interfere with cognitive function, recognizes and treats depression, and corrects overlooked medical conditions (e.g., congestive heart failure, emphysema) or metabolic abnormalities (e.g., hyponatremia, hypoglycemia).

Case

An 80-year-old white man is brought to you by his 77-year-old wife because she is concerned about his memory. The patient's only medical problem is mild hypertension, treated with hydrochlorothiazide (12.5 mg daily). During the initial outpatient interview, his wife confides that approximately 2 years ago she began to notice he was becoming more forgetful and irritable. A retired schoolteacher, he had always been a little stubborn but increasing stubbornness is taxing his wife's patience. One year ago, the wife took over responsibilities for writing checks and paying bills when her husband fell behind in this responsibility and they began to receive overdue notices. Gradually, his interests and involvement in activities that he previously enjoyed have declined. He has begun to nap during the day and then stay up at night. Sometimes she has found him in the kitchen preparing dinner at 3:00 a.m. She has become afraid to leave him alone at home. Six months ago, he was involved in a minor motor vehicle accident and was charged with failure to yield the right-of-way, but has refused to stop driving despite several near-collisions since then.

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You find the patient to be a tall, well-dressed man with a friendly manner but little spontaneity. His blood pressure is 165/80 mm Hg; pulse, 75 beats per minute and regular; and respirations, 18 per minute. His temperature is 37 C (98.6 F). Findings during the physical examination, including a thorough neurologic examination, are normal except for bilateral grasp reflexes (involuntary grasping of the examiner's hand when the patient's palms are stroked by the examiner's fingers). He exhibits difficulty following simple commands. His Folstein MMSE score is 20/30 (normal, >23) and he is unaware of his errors. He scores 3/30 on the Geriatric Depression Scale (normal <15/30), suggesting that he is not depressed. When asked how things are at home, he hesitates and says, fine. On further questioning about his relationship with his wife, all he says is that his wife is a good woman. His self-assessment is that he is doing well for an old man. When asked about his memory, he says that it's good and he has no problems remembering important things. Laboratory evaluation reveals normal hematocrit and serum creatinine values. Liver function test results are normal. His vitamin B₁₂ level is 480 pg/mL (normal, 225 to 800 pg/mL); folate, at 10 ng/mL, and thyroid-stimulating hormone, at 3 IU/mL, were also normal. A rapid plasma reagin test (for syphilis) is nonreactive. A head computed tomography (CT) scan obtained at the time of his automobile accident 6 months ago reportedly showed cerebral atrophy, consistent with age.

Which aspect of this patient's presentation is most valuable in formulating a differential diagnosis?
On a CT scan or magnetic resonance imaging (MRI), what findings are most characteristic of AD or other causes of dementia?
For what potentially treatable cause of memory loss should this patient be screened?
Can anything be done to help his wife manage the behavior of her husband?

Case Discussion

Which aspect of this patient's presentation is most valuable in formulating a differential diagnosis?

An immediate clue to the patient's diagnosis is his presentation. His wife made the appointment because she is concerned about his memory, although the patient seems less aware of his deficits. This pattern is characteristic of dementia. If the patient had made the appointment himself and had come alone complaining about his memory or difficulty in concentration, this pattern would be more consistent with depression. When dementia is advanced, its diagnosis is obvious. Early on, however, the patient may hide or rationalize his deficits and his cognitive changes may be so subtle that they are more apparent at home than in the clinician's office. This is where the family's observations become extremely helpful. In this case, the patient's wife supplied many clues to her husband's dementia.

A normal physical examination is common in a patient with early AD. The first pathologic changes in AD occur mostly in the temporal and parietal lobes of the brain and spare the motor strip. Therefore, the first signs of disease are frequently limited to memory impairment, subtle personality changes (e.g., increased irritability or flattening of affect), aphasia, and apraxia. Gait disorder and motor findings are unusual.

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The only significant finding during this patient's neurologic examination, besides his abnormal mental status examination, was bilateral grasp reflexes. This response, the involuntary grasping of the examiner's fingers when the examiner strokes the patient's palm, is a primitive reflex that may appear with bilateral frontal lobe disease, which may occur in AD as well as other dementias.
On a CT scan or MRI, what findings are most characteristic of AD or other causes of dementia?

CT scanning or MRI may show evidence of temporal lobe atrophy in early AD. However, neuroimaging evidence of cerebral atrophy correlates more with advancing age than it does with mental status decline. CT scan or MRI findings of white matter disease consistent with multiinfarct dementia have been reported in patients with normal cognition. Conversely, MRI and CT scan fail to show abnormalities in 20% of patients who have clinically diagnosed AD. Therefore, it is not surprising that the patient's CT scan findings were normal for his age. If the dementia has gradually progressed for 2 or more years, if the mental status examination shows severe impairment, and if the patient has no focal neurologic findings or gait disorder, neuroimaging is extremely unlikely to reveal findings that will alter management.
For what potentially treatable cause of memory loss should this patient be screened?

The goal of the evaluation is to identify diseases that can be diagnosed confidently, or for which there is treatment that might reverse the cognitive deficits. Therefore, the physician should routinely take a careful history, complete a careful physical examination, and order a basic laboratory evaluation including a complete blood count, serum electrolytes, calcium, creatinine, thyroid-stimulating hormone, and vitamin B₁₂ level. The physician should order other tests, such as CT scan or MRI, based on the results of the history and physical examination. For example, if the patient has had a history of recent or sudden onset of cognitive impairment after head trauma, the possibility of a subdural hematoma would indicate the need for brain imaging. This is particularly true if the physical examination reveals a gait disorder or focal neurologic signs. The triad of dementia of recent onset, gait disorder, and urinary incontinence may suggest the diagnosis of normal pressure hydrocephalus, another potentially reversible cause of cognitive decline. This disorder is extremely rare, and, although some patients may experience improvement with ventricular shunting, postoperative complications (e.g., subdural hematoma, infection, and shunt obstruction) are very common. For the patient described in the preceding text, these diagnostic possibilities would not be likely.

Hypothyroidism and vitamin B₁₂ deficiency sufficient to affect neuronal function usually cause disturbances in attention and consciousness, and are diagnosed and treated long before dementia appears. Occasionally, however, a patient delays getting medical care until dementia is present, so all patients should be evaluated for these conditions.

Neurosyphilis is no longer a common cause of cognitive impairment. These patients usually have other neurologic findings, such as dorsal column disease manifest by loss of position and vibratory sensation, in addition to mental status decline.

A severely depressed patient may seem disoriented and perform poorly on tests of cognitive function. These deficits may be due to reversible changes that mimic
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the irreversible changes of dementia. Because the diagnosis of depression can be difficult and it is based on subtle findings in an elderly patient, many tools, such as the Geriatric Depression Scale, have been developed to aid in its diagnosis.

Unfortunately, the patient described here did not exhibit any of these potentially treatable abnormalities.
Can anything be done to help his wife manage the behavior of her husband?

Yes. There are ways to help the patient's wife manage her husband's behavior. Caring for a demented patient is a physically and emotionally exhausting job. As recommendations are made, the physician must consider not only the patient but also the caregiver. Allowing caregivers to vent emotions, acknowledging the difficulty of their task, telling them what to expect as the disease progresses, offering respite care, and referring them to support groups are small things that may help them cope better with the patient and his or her needs.

The treatment of behavioral problems is difficult, but can be effective. Regular exercise and limiting the number and duration of late afternoon or evening naps may help reduce the nocturnal insomnia that often complicates the management of demented elderly patients. Most sedatives and hypnotics, particularly the long-acting ones, should not be used because they may cause oversedation or a paradoxical increase in agitation, and may only worsen cognitive and behavioral deficits.

Delusions are common in dementia syndromes. In fact, approximately 50% of the patients with AD or multiinfarct dementia experience delusions. Agitation and combative behaviors can accompany these symptoms. The cautious use of low doses of haloperidol, or other antipsychotics, may be helpful in ameliorating these behaviors.

Suggested Readings

AD 2000 Collaborative Group. Long-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomized double-blind trial. Lancet 2004;363:2105.

Boustani M, Peterson B, Hanson L, etal. Screening for dementia in primary care: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 2003;138:927.

Inouye SK. Delirium in older persons. N Engl J Med 2006;354:11.

Kawas C. Early Alzheimer's disease. N Eng J Med 2003;349:1056.

Falls in the Elderly

How commonly do falls occur in the elderly?
How often does injury or death result from a fall?
What factors make the elderly more likely to fall?
What should the history and physical examination focus on in a patient who is having problems with falling?

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Discussion

How commonly do falls occur in the elderly?

Thirty percent of the elderly older than 65 years who live out in the community experience falls annually. Most patients are reluctant to tell their physician or family members of these falls, so this figure is probably an underestimate. Nearly 8% of individuals older than 70 years will visit an emergency room annually and one third of these will be hospitalized for an average of more than 1 week. Because a history of falls increases the risk of future falls (i.e., 60% chance with the first year after an index fall) and serious injury, physicians should routinely ask elderly patients if they have fallen and then intervene to reduce the risk of future falls.
How often does injury or death result from a fall?

Accidental injury is the sixth leading cause of death in people older than 65 years, and two thirds of these deaths are related to falls. Fractures occur in approximately 5% of falls, and the most common fracture sites are the spine, hip, humerus, wrist, and pelvis. Another 5% of falls cause soft tissue injuries, such as sprains, joint dislocations, and hematomas. Even in those cases in which no injury is evident, there are still consequences; a person who has fallen may become emotionally paralyzed by a fear of falling and begin to limit activities. Soon they become socially isolated and become even weaker as they are less active. Therefore, even when a fall does not cause significant structural damage, it may have a negative impact on a person's quality of life and independence. In nursing homes, 50% or more of the ambulatory residents fall each year, despite the presence of trained staff and careful observation of safety measures. Approximately 4% of all patients in nursing homes have traumatic bone fractures annually, including a 1% risk of hip fracture each year.
What factors make the elderly more likely to fall?

Frequently, multiple factors, rather than a single problem, contribute to an elderly patient's risk of falling. It is often best to divide these factors into two categories: intrinsic and extrinsic. Intrinsic factors are those related to aging and disease processes. These include changes in balance and gait, pain and stiffness due to arthritis, decreased muscle strength, dizziness, postural hypotension, sensory losses (hearing, vision, and proprioception), cognitive impairment, and syncope. Other intrinsic causes to consider are vertebrobasilar insufficiency, depression, hypothyroidism, mechanical foot problems, or cardiac arrhythmias.

Patients tend to attribute their falls to extrinsic factors, such as tripping over obstacles, but, with advancing age, it becomes less likely that extrinsic factors alone are at fault. Indeed, most falls in frail elderly occur during routine activities of daily living. For example, a one out of four falls occurs when the patient is climbing or descending stairs. However, certain extrinsic factors such as medication side effects (e.g., orthostasis, dizziness, imbalance) are common. Similarly, falling may be the first clue to suggest a diagnosis of occult alcoholism, leading to poor balance and subsequent falls. Other extrinsic factors that may contribute to falls include inadequate lighting, slippery floors, loose
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throw rugs, exposed electrical cords, items out of reach (so that patients stand on unstable chairs or other supports and lose their balance more easily), lack of assistive devices such as bathroom rails to steady themselves when they are using the tub or shower, too high a bed (so that falls from the bed more likely result in significant injury), unsafe stairs, and poorly fitting shoes. Identifying and eliminating or reducing extrinsic factors require a comprehensive review of the patient's living situation, as well as findings on physical examination. An occupational therapist or other members of a home care team may complete a home safety evaluation, identify hazards, and correct them and thereby reduce the risk of subsequent falls.
What should the history and physical examination focus on in a patient who is having problems with falling?

A careful history of the falling episodes should be obtained. This includes the frequency of falls, the patient's activity at the time of the fall, where they occur, and associated symptoms such as loss of consciousness. It is important to get information from anyone who may have witnessed the fall and can provide a more detailed description of the circumstances. For example, if the falls are associated with dizziness and consistently occur 30 to 60 minutes after a meal, postprandial orthostatic hypotension may be suspected. Ask carefully about drug usage, including over-the-counter medications as even drugs such as diphenhydramine (Benadryl), a common ingredient in over-the-counter sleep aids, have anticholinergic properties that may contribute to poor balance and subsequent falls. Physical examination must include comprehensive vital signs, including pulse and blood pressure, taken lying and standing, to identify orthostatic hypotension that often contributes to fall risk. On neurologic examination, visual acuity and peripheral vision, strength, and cerebellar, sensory, and mental status must be assessed, looking for impaired vision, weakness, ataxia, neuropathy, or dementia. A useful screening test for balance, strength, mobility, and endurance is the get-up-and-go test. The examiner asks the patient to get up from a chair (without using his or her hands to push up from the chair), walk approximately 15 to 20 feet, turn around, walk back to the chair, and sit down, again without using their arms to lower themselves into the chair. The get-up-and-go test takes very little time and reveals much about the patient's gait and safety. Beyond screening laboratory tests such as a complete blood count or chemistry panel, vitamin B₁₂ and thyroid-stimulating hormone levels should be measured if there is evidence of a peripheral neuropathy or of diffuse muscular weakness. Other tests such as visual acuity, assessment of vestibular function (e.g., electronystagmography), ambulatory cardiac monitoring, or CT scanning should be done only if there are clinical clues to specific disorders that may cause falls (i.e., vertigo, syncope, or focal neurologic findings).

Case

An 86-year-old man is seen because of a history of frequent falls, reported by his wife. She reports that he falls at least three times per week, usually without injury. However, he has required two trips to the emergency room in the last 3 months where he required

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suturing of lacerations received in the falls. These falls are not accompanied by loss of consciousness, palpitations, or seizure activity. His medical history is remarkable for mild dementia, severe degenerative joint disease with chronic low back pain, decreased hearing and vision, benign familial tremor, and urinary incontinence (related to his dementia). His current medications include calcium supplementation, propranolol (40 mg three times a day), an over-the-counter sleep medication that contains 50 mg of diphenhydramine which he takes nightly for chronic insomnia, and acetaminophen as needed. His wife reports that he has a cane and a walker but rarely uses them.

Physical examination reveals a pleasant, thin, demented man. His temperature is 37 C (98.6 F); respirations 20 per minute; pulse, 55 beats per minute; and supine blood pressure 105/70 mm Hg. On standing, his pulse rate remains at 55 beats per minute but his blood pressure drops to 85/65 mm Hg and, when asked, he says he feels woozy. Cardiac examination findings are unremarkable; the rhythm is regular and there are no murmurs or gallops. His gait is somewhat ataxic. His cranial nerves are intact and there is no nystagmus. He has a fine tremor in both hands when they are held in extension, but he has normal tone and strength in all extremities. Sensory examination is intact. Finger-to-nose and heel-to-shin testing demonstrates no dysmetria. His posture is stooped and his wide-based gait is unsteady. He walks by holding on to the office furniture. Laboratory tests consisting of complete blood count and electrolyte and creatinine measurements yield unremarkable findings.

What problems are contributing to this patient's falls?
What diagnostic tests may be the most helpful in this patient?
What intervention, or interventions, would you institute to decrease this patient's risk of falling?

Case Discussion

What problems are contributing to this patient's falls?

The history and physical examination findings suggest a number of factors contributing to this patient's falls. Degenerative joint disease increases the risk of falls in a number of ways. First, stiffness and change in posture affect balance and, second, joint pain experienced while walking may discourage activity and exercise, which, in turn, contributes to decreased muscle tone and balance and an increased risk of falling. This vicious cycle may foster a fear of falling and the eventual cessation of walking. Dementia may be associated with poor judgment, which also adds to the risk of falling. For example, without supervision, a demented patient may try to maintain his balance by grasping an unstable chair or other object that cannot support his or her weight. Even if a demented patient has a cane or a walker, he or she may not remember to use it. The patient's caregiver needs to be educated about the need for the frequent verbal cueing of demented patients (e.g., reminding them to use assistive devices or not to grasp unstable objects for balance). The physician must always review the nature of the patient's medication to determine if side effects may be contributing to fall risk. In this case, the patient is taking a -adrenergic blocker (propranolol) for the treatment of tremor, which may be
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causing bradycardia, and this, in turn, may contribute to the patient's weakness and risk of falling. Orthostatic hypotension caused by various medications is a frequent source of fall risk. Antihypertensive medications and anticholinergic medications (e.g., his diphenhydramine or tricyclic antidepressants, such as amitriptyline) are two classes of medications that frequently cause orthostatic hypotension. Sedative medications not only alter the level of consciousness but may also blunt postural reflexes. Cardiac dysrhythmias are responsible for 25% to 35% of all syncopal episodes, and they account for 2% to 10% of falls. However, in this patient, who has no history of cardiac disease or loss of consciousness, a dysrhythmia is an unlikely contributor to his falls.
What diagnostic tests may be the most helpful in this patient?

Because sensory deficits and untreated medical problems may contribute to the risk of falls and may have correctable etiologies, evaluation should include a comprehensive assessment for these problems. Ophthalmologic evaluation of his poor vision may identify a reversible problem such as cataracts. With better vision, the patient may be able to navigate more safely and thereby reduce his fall risk. Correction of hearing loss, although not directly related to vestibular function, may help in improving gait stability and reducing falls. Impairment of sensation in the distal extremities, particularly loss of position sensation, suggesting dorsal spinal track disease should trigger a search for treatable causes of peripheral neuropathy such as diabetes or B₁₂ deficiency.

This patient's urinary urgency may contribute to his falls when he tries to race to the bathroom. Checking for a urinary tract infection or treating symptomatic prostatic hypertrophy may reduce urge symptoms and reduce the risk of falling.

More sophisticated and expensive tests, such as electroencephalography, Holter monitoring, and CT scanning of the head, may be performed in patients who have falls but should be done selectively, based on the patient's history and physical examination findings. Because this patient has no evidence of seizure activity, an electroencephalogram is unlikely to be revealing. Likewise, the diagnostic yield of 24-hour ambulatory cardiac monitoring would probably be very low, given the lack of cardiac symptoms, and is unnecessary for this patient. If he had any focal neurologic deficits, a gait disorder, or changes in cognition, an imaging study of the brain (i.e., CT scan or MRI) might be helpful in ruling out a subdural hematoma, a stroke, a brain tumor, or normal pressure hydrocephalus (characterized by a triad of cognitive impairment, gait disorder, and urinary incontinence). If the patient has evidence of upper motor neuron disease (e.g., hyperreflexia, plantar flexor or Babinski's response, increased muscle tone) and no evidence of cranial nerve or cortical signs (e.g., memory impairment, aphasia, etc.), then cervical myelopathy may be the etiology of the patient's poor balance and imaging of the neck should be considered, particularly if the patient is considered to be a candidate for surgical correction of spinal cord impingement. Because this patient is ataxic and has mild dementia and urinary incontinence, an imaging study of his brain would help rule out a potentially treatable cause of his gait disorder and falls, such as normal pressure hydrocephalus.

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What intervention, or interventions, would you institute to decrease this patient's risk of falling?

Careful scrutiny of this patient's medication list may reveal opportunities to reduce or eliminate medications that contribute to his risk of falling. Propranolol may reduce his tremor modestly but the lowering of his blood pressure and pulse may be contributing to his fall risk. If the diphenhydramine is causing him to be more cognitively impaired, then he is also more likely to have an increased risk of falls as well. Eric Larson etal. noted that patients whose cognitive impairment was in part due to medication side effects were also three times more likely to fall than those whose cognitive impairment was due to other causes. A trial period of reducing or stopping the propranolol and diphenhydramine should be considered to see if the patient's confusion, dizziness, and orthostasis resolve and his balance improves.

Even when a physician fails to identify specific, reversible etiologies of a patient's risk for falling, several interventions may help in reducing the risk of subsequent falls and injury. A patient who is elderly and has many medical problems is often expected to be frail and weak. However, even the frail elderly may improve their strength and balance by participating in a regular exercise program. Evidence has emerged that modest resistance training, in addition to aerobic conditioning, may further help in increasing muscle mass and balance, and reduce the risk of falls. Referral to a physical therapist may lead to a balance and strengthening program that may reduce the risk of falls. However, if a physical therapist is not available, studies have shown that enrollment in a group fitness program may have the same benefits as individual therapy. In one study, elderly patients randomized to participate in the ancient martial art of Tai Chi had impressive reduction in fall risk compared with those who did not participate. Therefore, regular exercise through a variety of options may help in reducing the risk of falling.

Most falls among the elderly occur in the home setting. Approximately one third of falls are related to accidents or environmental factors. A home safety assessment, usually completed by a physical or occupational therapist, may identify preventable extrinsic causes of falls such as throw rugs that slip when stepped on, poor lighting, wearing of unsupportive or slippery footwear, storage of commonly used items in out of reach places, etc. Because a single visit may identify and eliminate many of these risks, a home safety assessment is likely to be a cost-effective intervention to reduce the risk of falling.

Recent data also suggests that increasing the intake of vitamin D may not only increase bone density (and thereby reduce risk of fracture) but also reduce the likelihood that falls will occur. The mechanism is not well defined, but may, in part, be related to the positive effects of vitamin D on muscle strength. The optimal dose of supplemental vitamin D that should be prescribed is not clear, but 800 IU daily appears to be safe and adequate.

Finally, patients, their families, and their physicians may be faced with the continued occurrence of falls despite comprehensive, multifactorial interventions to prevent them. The choices are not easy ones. Allowing the patient to continue to
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ambulate will incur a risk of future falls. Restricting a patient's mobility may reduce the risk of falls but at the cost of increasing weakness, disuse atrophy, loss of independence, and a sense of despair. Although any injury that occurs during a fall is significant, hip fractures clearly carry the greatest morbidity and mortality. Studies of specially designed hip pads suggest that if elderly individuals can be persuaded to wear them, the risk of hip fracture, if they do fall, is reduced.

Suggested Readings

Bischoff-Ferrari HA, Dawson-Hughes B, Willett C, etal. Effect of Vitamin D on falls: a metanalysis. JAMA 2004;291:1999.

Kannus P, Parkkari J, Niemi S, etal. Prevention of hip fracture in elderly people with use of a hip protector. N Eng J Med 2000;343:1506.

King MD, Tinetti ME. Falls in community-dwelling older persons. J Am Geriatr Soc 1995;43:1146.

Tinetti ME. Preventing falls in elderly persons. N Eng J Med 2003;348:42.

Tinetti ME, Williams CS. Falls, injuries due to falls, and the risk of admission to a nursing home. N Eng J Med 1997;337:1279.

Urinary Incontinence

How common is urinary incontinence in the elderly?
What are the normal changes in bladder physiology that occur with aging?
How is incontinence classified, and what are the characteristics of the different types?
Of what does the differential diagnosis of transient urinary incontinence consist?

Discussion

How common is urinary incontinence in the elderly?

Urinary incontinence, the involuntary loss of urine, affects 10 million Americans. Of people older than 65 years, 5% of men and 25% of women have problems with incontinence. In 1987 alone, the direct cost of the problem was more than $10 billion. Incontinence adds $3 to $12 per day to the cost of nursing home care, and 50% to 90% of all nursing home residents experience some incontinence.

Besides the significant expense caused, incontinence is a source of many medical complications, such as rashes, pressure ulcers, catheterization, urinary tract infections, falls, and fractures. There are also social consequences, such as embarrassment, isolation, and depression. It also adds to caregiver stress.
What are the normal changes in bladder physiology that occur with aging?

Bladder capacity and compliance decline with aging, as does the ability to postpone voiding. There are also more frequent uninhibited bladder
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contractions and an increase in the residual volume of urine. Because of an age-related decrease in the glomerular filtration rate and a delay in the excretion of a water load, approximately two thirds of fluid is excreted in the evening rather than during the day. This leads to nocturnal urinary frequency and the risk of nocturnal urinary incontinence.

There are also sex-specific changes. Estrogen deficiency in women leads to weakened sphincter tone and changes in the position of the bladder neck. The urethral length shortens and the maximal urethral closure pressures decline. In men, prostatic enlargement can potentially block urine outflow. All of these changes predispose elderly patients to incontinence. The encouraging news is that 50% of the cases are transient and two thirds of the remaining cases can be either cured or markedly alleviated with therapy.
How is incontinence classified, and what are the characteristics of the different types?

Urge incontinence is the most common type of incontinence in the elderly, accounting for approximately 80% of cases. Afflicted patients often describe a sudden uncontrollable urge to void that may not allow them time to reach the bathroom. The urge is caused by contraction of the bladder's detrusor muscle, which forces moderate to large volumes of urine out through the urethra. Central nervous system diseases (e.g., stroke, AD, Parkinson's disease, a primary brain tumor, or metastatic disease) and primary disease of the bladder (e.g., carcinoma, the effects of radiation treatment, or bladder outlet obstruction) may be associated with urge incontinence.

Stress incontinence is particularly common in elderly women. In pure stress incontinence, leakage occurs with increases in pressure caused by coughing, sneezing, laughing, or lifting; only a small amount of urine leaks out after a delay of 5 to 15 seconds. The source of the problem in women is usually urethral hypermobility due to laxity of the pelvic floor musculature caused by childbearing. In men, stress incontinence is less common but may occur if the urethral sphincter is damaged during transurethral or radical prostatectomy.

Overflow incontinence is caused either by outlet obstruction or by an atonic bladder (i.e., ineffective detrusor contraction due to myogenic or neurologic causes). Leakage of small amounts of urine may occur throughout the day and night. Patients may also describe urinary hesitancy and a feeling of incomplete emptying. On abdominal examination, a distended bladder may be palpated even after the patient has attempted to void.

Reflex incontinence is usually due to a suprasacral spinal cord lesion. As the bladder distends, contraction occurs. Leakage is not associated with stress and there is no warning before the onset of urination. Incontinence episodes are of moderate volume and occur frequently.

Functional incontinence is due to a problem unrelated to the urinary tract. Examples are impaired mobility or metabolic problems such as hyperglycemia or mild renal insufficiency. This diagnosis can be made only by taking a very careful history and after excluding the previously listed causes. Functional incontinence may result from the use of iatrogenic drugs that impair cognition or from imposed limitations on mobility, such as restraints.

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Because urinary incontinence in the elderly is often multifactorial, all potentially contributing risk factors should be carefully reviewed to determine its cause.
Of what does the differential diagnosis of transient urinary incontinence consist?

An acute change in a patient's mental status (delirium) or a mood disorder (depression) may contribute to functional incontinence, such as the patient who is too confused to find a bathroom or too despondent to care about personal hygiene. End-stage dementia may render a patient incapable of recognizing the urge to void.

Urinary tract infection may lead to irritation of the detrusor muscle and therefore cause urinary frequency and urgency. Similarly, inflammation caused by atrophic urethritis or vaginitis may contribute to increased urge.

Medications may foster urinary incontinence in a variety of ways. Sedatives depress the level of consciousness, leading to a functional incontinence. Diuretics increase the urine volume, which then increases urinary frequency. A larger urine volume may then trigger more frequent episodes of bladder spasm and augment the risk of urge incontinence. Anticholinergic medications, such as antihistamines, tricyclic antidepressants, and antipsychotics, inhibit detrusor contractions and lead to overflow incontinence. Calcium channel blockers (e.g., nifedipine, verapamil, and diltiazem) may similarly decrease detrusor contractility and worsen overflow incontinence.

Endocrine conditions such as hyperglycemia and hypercalcemia cause urinary frequency and, like diuretics, increase urine volumes, and hence the risk of incontinence. Restricted mobility due to severe arthritis, stroke, cardiac disease, or any other debilitating condition may simply prevent a patient from reaching the bathroom in time (i.e., functional incontinence). Finally, stool impaction may contribute to pelvic nerve compression, leading to an atonic bladder and overflow incontinence.

Case

A 73-year-old mother of six is brought to your office by her daughter to establish her mother's primary care in town. The patient has come to live with her daughter after her husband died 6 months ago. The patient's children are concerned that she is depressed and report she is not getting out of her house except when she has a doctor's appointment. Her past medical history is remarkable for hypertension (for which she takes hydrochlorothiazide daily) and some arthritis in her knees. She has undergone no surgical procedures. She denies any other problems, but, when specifically asked, she admits to having urinary incontinence for several years, which has been worse during the past few weeks. She describes getting the urge to void almost every hour and, if she does not get to the bathroom in a matter of minutes, she has started to lose enough urine such that she now needs to wear adult pads. When asked if she loses urine when she coughs or laughs, she confirms that this has occurred for many years. She says that she has not reported this embarrassing problem to her previous physicians because they never asked, and has attributed it to just getting old. She and her husband had stopped having sex because she was afraid that it would make her incontinence worse.

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Physical examination reveals a healthy-appearing elderly woman whose vital signs are normal, including her blood pressure, which is 130/76 mm Hg. Her examination findings are unremarkable except for her pelvis, which exhibits atrophic mucosa and a grade III cystocele (bladder and urethra protruding). She is asked to cough and a small amount of urine leaks from the urethra. The rectal findings are normal and there is good rectal tone. Neurologic findings are normal, including a normal anal wink (suggesting intact sphincter), and there are no lumbosacral neurologic findings. Laboratory evaluation reveals normal electrolyte and creatinine values and a random blood glucose level of 240 mg/dL. Urinalysis, with urine obtained by catheterization, reveals 5 to 10 white blood cells per high-power field, no epithelial cells, 2+ bacteria, and 3+ glucose.

Of what does the differential diagnosis of this patient's incontinence consist?
What conservative treatments could you try in this patient?
If these measures help but do not eliminate her incontinence completely, what would be the next step in treatment?
How would the emphasis of your evaluation differ for a male patient?

Case Discussion

Of what does the differential diagnosis of this patient's incontinence consist?

This patient describes symptoms of the most common type of incontinence in the elderly, namely, urge incontinence. She has a history of six vaginal deliveries and also has corresponding symptoms of stress incontinence, with suggestive findings discovered on examination (i.e., urine leaks when she laughs). The urinalysis findings are abnormal, indicating a possible urinary tract infection that could be exacerbating her symptoms of urgency and frequency. It may explain the worsening of symptoms in the past few weeks. An elevated blood glucose level may foster an osmotic diuresis that increases urine volumes and thereby adds to the risk of incontinence.

Fear of leaving her home and the consequent social isolation may have been precipitated by her incontinence because patients prone to urge incontinence often limit their activities to avoid embarrassing accidents. On visual inspection, she was found to have an atrophic mucosa, which may suggest estrogen deficiency. Similar atrophy may occur in the urethral mucosa, which in turn reduces urethral sphincter competence.

She is on a diuretic, which may also exacerbate her incontinence. Her blood pressure may respond either to another agent or to diet alone, with weight reduction and sodium restriction. She also has arthritis in her knees, which limits her ability to get to the bathroom in time. It may be that the bathroom is farther from the bedroom in her daughter's home, and this could contribute to the recent worsening of symptoms. A simple rearrangement of her bedroom furniture may put her bed closer to the toilet and reduce the risk of nocturnal incontinence by shortening the distance she needs to travel to the bathroom.
What conservative treatments could you try in this patient?

First, the easily reversible causes need to be eliminated. A careful evaluation, including a pelvic examination, must precede any treatment. It would be reasonable
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to have her urine cultured and to treat her for a urinary tract infection, to see if the urgency dissipates. If she has no contraindications to estrogen replacement, such treatment could be given orally or topically to alleviate the atrophic urethritis. Her diuretic medication could be discontinued and replaced with a different agent, if weight loss and sodium reduction fail to control her blood pressure. If the distance from the bedroom to the bathroom is a source of nocturnal incontinence, getting the patient a bedside commode can alleviate the problem. Treatment of her diabetes, either with diet, oral agents, or insulin, will help decrease the urine volume. In general, it is reasonable to counsel all patients complaining of incontinence to refrain from drinking too much fluid before going out or near bedtime.
If these measures help but do not eliminate her incontinence completely, what would be the next step in treatment?

The patient has symptoms of both urge and stress incontinence. However, the possibility of overflow incontinence should also be assessed. This is done by catheterizing the patient after she has voided to see if there is urinary retention (>100 mL), which would indicate possible overflow incontinence. Neither stress nor urge incontinence alone should cause a high postvoid residual volume. Behavioral techniques are very effective in alleviating both urge and stress incontinence. Because the uninhibited bladder spasms associated with urge incontinence are brief, the patient should be instructed to sit calmly and allow the urge to pass. Jumping up to go to the bathroom only accentuates abdominal pressure during the contraction and makes the leakage of urine more likely. Behavior modification alone can considerably ease the patient's urge incontinence. Women with stress incontinence may reduce loss of urine by performing exercises that strengthen the pelvic floor muscles. To teach patients these exercises (Kegel exercises), ask the patient to feel the muscles she uses to stop her stream of urine or a bowel movement. She must contract these muscles without also contracting the abdominal muscles 10 to 15 times, three times a day. This practice must be continued to remain effective. If the incontinence persists even after diligent exercising for several weeks or months, the patient should be referred to a gynecologist for consideration of surgical correction of pelvic floor laxity.
How would the emphasis of your evaluation differ for a male patient?

Overflow incontinence associated with bladder outlet obstruction resulting from benign prostatic hypertrophy is an important cause of incontinence, unique to men. Therefore, men should be asked carefully about urinary frequency and hesitancy, a decrease in the force of the urine stream, and if they experience a sensation of incomplete emptying. It is more important to evaluate the postvoid residual volume early in the workup of a man. A low residual volume does not absolutely rule out obstruction because of the intermittent nature of such an obstruction. However, if the volume is greater than approximately 250 mL, the diagnosis of bladder outlet obstruction is very likely. Most urologists perform cystoscopy before prostatic surgery to confirm the diagnosis and rule out detrusor flaccidity in men with large postvoid residual urine volumes. If the patient has a flaccid bladder, the urologist may be reluctant to perform prostate surgery because such patients are likely to continue to require either permanent or intermittent postoperative catheterization.

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Urge incontinence is also an important diagnosis in male patients. It often coexists with obstruction because a distended bladder is more prone to contractions. Therefore, men treated for symptoms of outlet obstruction must also be asked about symptoms of urgency that may require additional treatment to prevent continued urinary incontinence after surgical correction of urinary tract obstruction.

Suggested Readings

Consensus Conference. Urinary incontinence in adults. JAMA 1989;261:2685.

Fantl JA, Newman DK, Colling J, etal. Urinary incontinence in adults: acute and chronic management. U.S. Department of Health and Human Services, Agency for Health Care Policy and Research. Rockville, MD, U.S. Government Printing Office, 1996.

McDowell BJ, Burgio KL, Dombrowski M, etal. An interdisciplinary approach to the assessment and behavioral treatment of urinary incontinence in geriatric outpatients. J Am Geriatr Soc 1991;40:370.

Medication Use in the Elderly

What is polypharmacy, and is it a significant problem in the elderly? If so, why?
Why do elderly patients experience an increased incidence of adverse drug reactions (ADRs)?
Name several ways in which ADRs might be associated with each of the following in elderly patients: new medications, the long-term use of drugs, and the sudden cessation of medications.

Discussion

What is polypharmacy, and is it a significant problem in the elderly? If so, why?

Polypharmacy is the concurrent use of many medications. Although this term is most often used to refer to the use of too many medications, some patients with multiple medical problems may be appropriately receiving several prescription medications. Because medications are a common cause of reversible problems in the elderly (e.g., drug-induced confusion and orthostatic hypotension), each medication prescribed for an elderly person must be carefully scrutinized to determine whether the benefits outweigh the adverse effects of the drug. Because the adverse effects frequently outweigh the benefits, it has been said of good geriatricians that they stop more medications than they start.

Polypharmacy is a serious problem in the elderly. An average elderly person takes two to five prescription medications as well as three to four over-the-counter drugs. Although elderly Americans (older than 65 years) constitute 12% of the U.S. population, they consume approximately 25% of
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all prescription medications. They are therefore not only exposed to more drugs but also to more potential adverse drug effects. Indeed, older people have three to seven times more ADRs than younger patients, and the frequency of ADRs correlates with the number of medications used.
Why do elderly patients experience an increased incidence of ADRs?

The management of drug therapy in the elderly differs from that in younger patients, and the resulting higher incidence of polypharmacy in the elderly population increases the risk of drug drug interactions. These interactions may result from the altered absorption, excretion, or protein binding of the drugs involved. In addition, unanticipated drug effects may occur if one drug enhances or interferes with the hepatic metabolism of another. Such interactions may result in either toxic or subtherapeutic drug levels.

Comorbidity adds to the incidence of ADRs because the signs and symptoms of a preexisting disease may be worsened by the effects of medications given to treat another disorder. This can result either from the worsening of an underlying disease process by the offending drug (e.g., the use of ₂-blockers in patients with chronic obstructive pulmonary disease or congestive heart failure) or because the signs and symptoms of the drug's side effects mirror and, therefore, intensify those of the underlying disease process. An example of this is the urinary retention caused by anticholinergic medications (e.g., tricyclic antidepressants and diphenhydramine) in a patient with an enlarged prostate. The retention occurs because the enlarged prostate obstructs the urine flow and the anticholinergic medication weakens detrusor contraction.

Elderly patients often have less physiologic reserve and therefore handle physiologic stress less successfully than younger patients. The amount of physiologic reserve varies among elderly patients and even among different organ systems in the same individual. Sometimes physicians obtain baseline measurements to assess a patient's reserve. For example, the creatinine clearance may suggest how much kidney reserve is left. Therefore, the risk of ADRs may be minimized by the careful evaluation of an individual elderly patient's renal function before prescribing potentially toxic medications. Sometimes, simply reducing the dosage may confer an adequate therapeutic effect without producing toxicity. Those elderly patients with better reserve who are capable of more normal metabolism of medications may need the same dosage as younger patients to obtain a therapeutic effect. In summary, therapy must be individualized to obtain the optimum effect from medication while avoiding toxicity.

Age-related physiologic changes in the elderly include a decline in lean muscle mass and total body water content, with an increased proportion of total body fat. These changes affect drug disposition in the following manner: less total body water translates into a smaller volume of distribution for water-soluble medications, resulting in higher-than-anticipated serum concentrations. Because adipose tissue is often proportionately greater in older patients, the volume of distribution for fat-soluble medications increases,
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prolonging the elimination period. Another physiologic change of great importance is a decline in renal function with age, occurring in approximately 65% of elderly people. For the elderly, the serum creatinine concentration alone is an unreliable indicator of kidney function because it depends on the amount of muscle mass, which decreases with advancing age. Instead, creatinine clearance is a more accurate estimate of renal function in the elderly. Age-related physiologic changes in hepatic metabolism and protein binding usually have less impact on drug metabolism than the decline in renal function.
Name several ways in which ADRs might be associated with each of the following in elderly patients: new medications, the long-term use of drugs, and the sudden cessation of medications.

New medications may elicit ADRs by producing predictable side effects, especially if the side effects exacerbate preexisting disease-related symptoms. For example, preexisting postural hypotension can be worsened by tricyclic antidepressants. New medications can also cause adverse effects if the dosages prescribed are not appropriate for the elderly, leading to drug intoxication. For example, digoxin toxicity may occur if the physician fails to adjust the dosage to accommodate renal impairment. When new medications are added to an already complicated medical regimen, this may also foster noncompliance, either because of patient frustration about having to take so many pills or because of confusion over complicated dosing schedules. New medications can precipitate ADRs when they become involved in drug drug interactions, as previously discussed. Finally, patients may not tolerate new medications for idiosyncratic reasons, thereby emphasizing the need for physicians to maintain vigilance in detecting an ADR. Contributing to this is the fact that drug side effects may not be recognized as such by patients because they ascribe their symptoms to old age.

The long-term use of medications may be associated with an ADR when a patient's renal, hepatic, or nutritional status changes without a concomitant dose adjustment. For instance, a drug dose tolerated for many years may become toxic as renal clearance declines. In addition, ADRs result when new medications adversely affect the pharmacokinetics of medications that elderly patients have otherwise tolerated for years. An example of such interactions is the digoxin toxicity that occurs secondary to decreased clearance after the addition of verapamil to a medical regimen.

Changes in compliance can result in ADRs. Noncompliance is a common geriatric problem, with estimates ranging from 26% to 59% for the geriatric population, and polypharmacy increases the incidence of noncompliance. Compliance can be improved when physicians regularly ask their patients in a nonjudgmental manner about their medication use, simplify the medical regimen, and remind elderly patients about the need for each medication. Other factors that influence compliance include cognitive, financial, and functional changes.

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ADRs can also occur when a patient is hospitalized and started on a medical regimen that the physician incorrectly assumed was being followed at home. If the patient has been taking fewer pills than actually prescribed, this enforced compliance may precipitate toxicity although the dosing schedule may seem correct.

Finally, many drugs commonly used in the elderly are associated with withdrawal syndromes. Of particular importance are the psychotropic drugs, such as the benzodiazepines, antipsychotics, and antidepressants. Drug withdrawal syndromes may occur if these medications are discontinued abruptly or tapered too quickly, and should be considered as a potential source of a marked change in an elderly patient's behavior. Drug withdrawal may occur even when therapeutic and not necessarily high doses are abruptly discontinued. Unfortunately, drug withdrawal frequently goes unrecognized, leading to potentially preventable adverse complications. Agitation and delirium are among the more common symptoms associated with withdrawal from some psychotropic drugs. For this reason, it is important to consider drug withdrawal as a possible cause of any unexplained delirium.

Case

An 81-year-old man who was admitted to the hospital 2 days ago for the evaluation of epigastric burning in conjunction with hemoccult-positive stools and anemia suddenly exhibits confusion. He has undergone endoscopy and was found to have gastritis. His hematocrit reading has remained stable and discharge planning is in progress. His abdominal symptoms have been alleviated with the addition of the H₂ blocker, cimetidine.

His past medical history is limited, and he is vague when answering questions about it. His daughter has reported that he has dementia. No other medical problems have been identified. The patient denied alcohol or tobacco use on admission. The medications he was taking before admission are unknown, but he is currently being given cimetidine (400 mg orally twice daily) and diphenhydramine (25 mg orally at night, as needed) for insomnia. He has no known drug allergies.

The patient is a widowed, retired plumber who lives alone. His family history is noncontributory and a review of systems is significant for insomnia.

The nurses relate that the patient was well during the day, but became progressively confused during the evening. He is found to be disoriented and irritable, with his mental status fluctuating between agitation, with perceptual distortions and visual hallucinations, and hypersomnolence.

Physical examination reveals the following findings: blood pressure, 140/80 mm Hg; temperature, 98.6 F (37.0 C); pulse, 80 beats per minute; and respirations, 16 per minute. There are no orthostatic changes.

The patient is unable to cooperate fully with mental status testing but is noted to be disoriented to time and place and appears anxious. He is flushed. Head, eye, ear, nose, and throat findings, as well as the cardiac, pulmonary, and abdominal findings are unremarkable. Neurologic examination reveals nonfocal findings. His cranial nerves are intact and there

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is no asterixis. His reflexes are 2+ and symmetric. His motor ability is scored as 5/5 and symmetric. His sensation is intact to light touch, although other sensory modalities cannot be tested. His toes are downgoing bilaterally and he has no cerebellar abnormalities.

You correctly ascertain that the patient's current behavior cannot simply be due to worsening of his underlying dementia but is consistent with delirium. To exclude metabolic, infectious, traumatic, or neurologic causes, the following data are obtained: white blood cell count, 6,000 cells/mm³ with a normal differential; hematocrit, 35% and stable compared with admission; platelets, 350 10³/mm³; sodium, 140 mEq/L; chloride, 105 mEq/L; creatinine, 0.9 mg/dL; potassium, 4.0 mEq/L; CO₂, 27 mEq/L; blood urea nitrogen, 12 mg/dL; glucose, 125 mg/dL; calcium, 9.0 mg/dL; arterial blood gases, normal; aspartate aminotransferase, 20 U/L (normal range, 14 to 30 IU/L); alkaline phosphatase, 175 IU/L (normal range, 30 to 110 IU/L); total bilirubin, 0.4 mg/dL; thyroid-stimulating hormone, 4 U/mL (normal range, 0.5 to 5 U/mL); vitamin B₁₂, 600 pg/mL (normal range, 225 to 800 pg/mL); and rapid plasma reagin, nonreactive.

No pyuria is found on urinalysis and blood specimens are sent for culture. A chest radiograph and electrocardiogram are normal, as is a CT scan of the head, which shows no evidence of hemorrhage.

The diphenhydramine is discontinued and the patient's daughter is called and told of her father's condition. She reports that on entering her father's apartment that evening, she discovered a half-empty bottle of lorazepam (a benzodiazepine) that she had not known he was taking.

Which of the patient's symptoms are consistent with delirium?
Is the presentation of benzodiazepine withdrawal in elderly patients different from that in younger patients?
How could this withdrawal syndrome have been prevented?
Are there other drugs cited in the case that can cause confusion? If so, how?

Case Discussion

Which of the patient's symptoms are consistent with delirium?

The symptoms that are consistent with delirium in this patient, which may reflect benzodiazepine withdrawal, include fluctuations in consciousness, anxiety, confusion, irritability, perceptual disturbances, and hallucinations. Because drug withdrawal is frequently unrecognized, physicians should consider the possibility of withdrawal in any geriatric patient who exhibits an abrupt alteration in behavior and cognition, particularly when other systemic causes have been excluded. Physicians must also maintain a high index of suspicion for alcohol withdrawal in both elderly men and women. Finally, as exemplified in this patient, communication with family, friends, and caregivers may provide valuable information about otherwise unreported psychoactive drug use or abuse.

Lorazepam is an intermediate-acting benzodiazepine, with an onset of withdrawal symptoms typically occurring in the first 24 to 72 hours after discontinuation,
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which is consistent with this patient's clinical picture. Rarely, withdrawal symptoms may be delayed for up to 2 weeks in patients taking longer-acting benzodiazepines, such as diazepam and flurazepam. The age-related increase in the proportion of total body fat of geriatric patients may provide a larger volume of distribution for fat-soluble benzodiazepines, thereby lengthening the elimination period and postponing the onset of withdrawal symptoms.
Is the presentation of benzodiazepine withdrawal in elderly patients different from that in younger patients?

The clinical manifestations of benzodiazepine withdrawal in the elderly frequently differ from those seen in younger patients. The difference in the clinical manifestations of withdrawal in elderly patients is in general due to comorbidity stemming from other diseases and impaired homeostatic reserve. In some cases, these factors result in more severe and even life-threatening withdrawal symptoms. Benzodiazepine withdrawal is associated with increased autonomic nervous system activity. In younger patients, this manifests as tachycardia, mild hypertension, and diaphoresis. In elderly patients with limited physiologic reserve, the increased autonomic nervous system activity may precipitate severe cardiovascular complications. In other situations, comorbidity or impaired homeostatic reserve, or both, may result in more subtle withdrawal symptoms in elderly patients. Health care professionals may mistakenly attribute changes in mental status to worsening dementia. In geriatric patients, abrupt and isolated confusion is sometimes the only clue to benzodiazepine withdrawal.
How could this withdrawal syndrome have been prevented?

This patient's benzodiazepine withdrawal might have been prevented, first, by finding out whether he is taking a medication associated with a withdrawal syndrome. When admitting elderly patients with cognitive impairment, it is important to communicate with the primary caregiver because this frequently provides vitally important information. Second, if benzodiazepines are to be discontinued, the dose should be gradually tapered by 10% to 20% per week.
Are there other drugs cited in the case that can cause confusion? If so, how?

The patient was started on two new medications during his hospitalization cimetidine and diphenhydramine. Both of these drugs can cause confusion in elderly patients, and drug-induced delirium is more common in patients with preexisting dementia (an example of a drug disease interaction).

Cimetidine, an H₂ blocker, can produce a host of systemic effects and may participate in drug drug interactions because of its ability to decrease the metabolism of medications that are eliminated by the liver. Cimetidine also rarely causes central nervous system symptoms such as confusion and hallucinations. The mechanism responsible for cimetidine-mediated mental status changes is unknown.

Diphenhydramine is frequently used to promote sleep, but is actually a poor choice for frail, elderly patients. Of particular concern are its potential anticholinergic side effects, which include dry mouth, urinary retention, constipation, blurred vision, and confusion. Geriatric patients may be more sensitive to anticholinergic side effects than younger people because of age-related changes in acetylcholine neurotransmission.

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Suggested Readings

Ahronheim JC. Handbook of prescribing medications for geriatric patients. Boston: Little, Brown and Company, 1992:1 12,96 100,347 348.

Beers MH. Polypharmacy and appropriate prescribing. In: Beck JC, ed. Geriatric review syllabus, 1991 1992 ed. New York: American Geriatric Society, 1991:218.

Gerber JG, Brass EP. Drug use in the elderly. In: Jahnigen DW, Schrier RW, eds. Geriatric medicine, 2nd ed. Cambridge, MA: Blackwell Science, 1996.