Medical Clinics of N.A. Geriatric Medicine

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FORTHCOMING ISSUES November 2006 Antimicrobial Therapy Burke A. Cunha, MD, MACP, Guest Editor January 2007 Nanomedicine Chiming Wei, MD, PhD, Guest Editor March 2007 Acute Myocardial Infarction David Holmes, MD, and Mandeep Singh, MD, Guest Editors

RECENT ISSUES July 2006 Integrated Care for the Complex Medically Ill Frits J. Huyse, MD, PhD and Friedrich C. Stiefel, MD, PhD, Guest Editors May 2006 Emergencies in the Outpatient Setting: Part II Robert L. Rogers, MD and Joseph P. Martinez, MD, Guest Editors March 2006 Emergencies in the Outpatient Setting: Part I Robert L. Rogers, MD and Joseph P. Martinez, MD, Guest Editors

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GERIATRIC MEDICINE

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Preface Julie K. Gammack and John E. Morley Cognitive Impairment Seema Joshi and John E. Morley

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Cognitive impairment becomes increasingly more common with aging. The presence of delirium and dementia are missed often in older persons. There is increasing uncertainty about the role of acetylcholine esterase inhibitors in the management of dementia. It is important to treat the reversible causes of delirium and dementia.

Mood Disorders in the Elderly Mehret Gebretsadik, Sundeep Jayaprabhu, and George T. Grossberg

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Mood disorders in the elderly are common, underdiagnosed, and inadequately treated. Older adults suffer from a spectrum of depressive disorders that are commonly comorbid with other psychiatric or medical illnesses. Elderly people who have bipolar disorder pose a growing challenge relative to diagnosis and treatment. The approach to the treatment of these disorders is multifaceted and needs to be individualized with patients and caregivers. The three main modalities of treatment (pharmacotherapy, psychotherapy, and neuromodulation) are increasingly safe and effective for treating mood disorders in older adults.

Falls and Their Prevention in Elderly People: What Does the Evidence Show? Laurence Z. Rubenstein and Karen R. Josephson

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Falls are a common and complex geriatric syndrome that cause considerable mortality, morbidity, reduced functioning, and premature nursing home admissions. Falls have multiple precipitating causes and predisposing risk factors, which make their diagnosis, treatment, and particularly, prevention, a difficult clinical challenge. Nonetheless, much can be done to reduce the risk for falls VOLUME 90

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and to improve the quality of life for fall-prone individuals. This article provides an overview of the epidemiology of falls, their major causes and risk factors, the types of available fall-prevention interventions, and the evidence on the efficacy of these interventions.

Urinary Incontinence: Selected Current Concepts Margaret-Mary G. Wilson

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Urinary incontinence (UI) is highly prevalent in older adults and associated with excess comorbidity and increased mortality. Intensive screening and comprehensive clinical examination of all elders enables prompt detection, accurate classification, and appropriate treatment. Overactive bladder (OAB) is the most common cause of persistent incontinence in the older adult. As with other types of UI, behavior modification is first-line treatment of OAB. Although antimuscarinic agents have been shown to be highly effective in the treatment of OAB, limited data are available regarding the safety and tolerability of these agents in older adults. Patients who fail to respond to noninvasive treatment or those in whom surgery may be appropriate should be referred to the urologist for evaluation and further management.

Frailty John E. Morley, Matthew T. Haren, Yves Rolland, and Moon Jong Kim

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Frailty is a condition that now can be objectively defined by the Fried criteria. Frail people are at risk for rapid deterioration when exposed to stressful events. The causes of frailty are multifactorial and include sarcopenia, protein energy malnutrition, pain, and various disease processes, such as anemia, diabetes mellitus, depression, and congestive heart failure. At the pathophysiologic level, elevated proinflammatory cytokine, low vitamin D, and low testosterone levels (in men and possibly women) all play a role in the genesis of frailty.

Heart Disease and Aging Wilbert S. Aronow

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Coronary artery disease is the most common cause of death in older persons. Hypertension is present in nearly one third of older women and men. The prevalence of valvular aortic stenosis, aortic regurgitation, mitral regurgitation, and of mitral annual calcification increases with age in older men and in older women. Congestive heart failure (CHF) is the most common cause of hospitalization in persons aged 65 years and older. The prevalence and incidence of CHF increase with age; an increasing proportion of cases has normal left ventricular ejection fraction. The prevalence of chronic atrial fibrillation increases with age and is an independent predictor of new coronary events and thromboembolic stroke in older persons.

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Heart Failure in Older Adults Michael W. Rich

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Heart failure affects approximately 5 million Americans, half of whom are at least 75 years of age, and is the leading cause of hospital admission among older adults. Additionally, the prevalence of heart failure is increasing, largely owing to the aging of the population. Heart failure in older adults differs in many respects from heart failure that occurs during middle age, including an increased proportion of women, increasing prevalence of heart failure with preserved left ventricular systolic function, and a marked increase in the number of coexisting medical conditions. In light of these factors, this article reviews the epidemiology, pathophysiology, clinical features, and treatment of heart failure in older adults.

Nutritional Disorders in the Elderly Ian McPhee Chapman

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Undernutrition is common in older people and has serious adverse effects. Weight loss and low body weight are key markers. Correctable causes, such as depression, are common and should be sought. Structured efforts to encourage food intake, together with nutritional supplements often are of benefit. It is hoped that a better understanding of the underlying mechanisms will lead to targeted treatments. Overweight and obesity also are common in older people, and are associated with morbidity and impaired function. It probably is appropriate to recommend weight loss to obese older people who have associated comorbidities, particularly reduced mobility, but seldom, if ever, for increased weight alone.

Diabetes in the Elderly Graydon S. Meneilly

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We are approaching an epidemic of diabetes in the elderly. Diabetes and its complications have a significant impact on quality of life in this age group. Recent studies suggest that diabetes can be prevented in a large number of patients with appropriate interventions. It seems that diabetes in this age group is metabolically distinct. As a result, the approach to therapy in the elderly differs from that in younger patients. Unfortunately, we still have huge gaps in our understanding of the pathogenesis and treatment of diabetes in the aged, and further studies are needed urgently.

Assessment and Management of Chronic Pressure Ulcers in the Elderly Aime´e Dinorah Garcia and David R. Thomas

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The aging population is increasing the number of individuals at risk for pressure ulcer formation. Risk factors, such as immobility, poor nutrition, comorbidities, and aging skin, make the elderly more susceptible to pressure ulcer formation. The key to management is prevention, but once pressure ulcers occur, it is important to understand the principles of wound healing including debridement, CONTENTS

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bacterial management, moist wound healing, pressure relief, and nutritional support.

Elders with Epilepsy Nancy S. Collins, Rita A. Shapiro, and R. Eugene Ramsay

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Seizures and epilepsy are increasingly common in the growing numbers of elders worldwide. Provoked seizures need to be distinguished from epilepsy, as evaluation and management differ. Seizures in older adults are frequently under-recognized and have presentations that may be mistaken for other causes of altered mental status, such as dementia, transient ischemic attack, syncope, or stroke. Considering the medications taken for common comorbidities in elders, the pharmacokinetic profile of the newer antiepileptic medications (AEDs) has distinct advantages. After appropriate recognition, evaluation, and treatment, the prognosis of epilepsy in elders is good, with improved seizure control along with maintenance of functional status and quality of life.

The Older Cancer Patient Heidi K. White and Harvey J. Cohen

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Providing effective and tolerable cancer treatment for the growing number of older adult patients who have cancer requires an understanding of the role of aging, comorbidity, functional status, and frailty on treatment outcomes. The incorporation of comprehensive geriatric assessment (CGA) into the care of older patients who have cancer ensures that the cognitive, physical, and psychosocial strengths and limitations of individual patients are considered in the development of treatment plans. CGA also may improve outcomes by identifying and optimally treating comorbid conditions and functional impairments. Optimal treatment of the older adult patient who has cancer starts with careful delineation of goals through conversation. The treatment plan should be comprehensive and address cancer-specific treatment, symptom-specific treatment, supportive treatment modalities, and end-of-life care.

Palliative Care and Pain Management Laura J. Morrison and R. Sean Morrison

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Palliative care has largely evolved to address the significant suffering and deficiencies in care documented among persons living with advanced chronic illness, both those approaching the end of life and those earlier in their course. Clinicians caring for older adults need to recognize the critical role of geriatric palliative care in serving this population and develop expertise. This article examines five key domains of palliative care: communication, symptom management, coordination of care, psychosocial and spiritual realms, and grief and bereavement support. Specific attention is given to pain management and the approach to treating dyspnea, constipation, and nausea and vomiting, all common symptoms experienced by elders with potentially life-limiting illness. A xii

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patient case is discussed to illustrate the integral role palliative care often plays as a part of appropriate, routine medical care.

Andropause: A Quality-of-Life Issue in Older Males Matthew T. Haren, Moon Jong Kim, Syed H. Tariq, Gary A. Wittert, and John E. Morley

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Late-onset hypogonadism, also known as andropause, is common in older men. To make the diagnosis there is often a need to measure free or bioavailable testosterone. Testosterone replacement can lead to improved sexuality, increased muscle mass and strength, decreased fat mass, enhanced bone mineral density, better cognition, and improved function.

Aging and Sexuality Terrie B. Ginsberg

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Sexuality in the elderly has unique ramifications. With the aging process come changes and challenges faced by our senior citizens. Health issues, sexual myths, discrimination, indifference, and intolerance are all obstacles facing this group. Proactive measures taken by health care providers, including educating our society and educating our seniors, create a more comfortable and enjoyable environment for our seniors.

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Preface

Julie K. Gammack, MD John E. Morley, MB, BCh Guest Editors

For age is opportunity no less than youth itself, though in another dress, and as the evening twilight fades away, the sky is filled with stars, invisible by day. dHenry Wadsworth Longfellow, 1807–1882

At the start of the twentieth century there were 3.1 million people over the age of 65 years, representing 4.1% of the total population of the United States. By 2000, 34.9 million older people composed 12.6% of the total population. This growth in the elderly demographic has been particularly dramatic for the oldest old, with more than 4.5 million people currently over the age of 85 years. By the year 2030, one in five Americans will be older than 65. The number of individuals over 75 will triple and those over 85 will double in the same period. The United States, like most developed nations, is seeing a ‘‘squaring off’’ of the life expectancy curve, meaning individuals are living longer and dying at a greater frequency in the older years. At age 65, the average life expectancy is 19.1 years for females and 15.3 years for males [1]. Currently the average life expectancy for a 75-year-old individual is 11.3 years and for an 85-year-old it is 6.5 years. This then also means that older individuals are living longer with a greater number of chronic medical conditions. The care of these individuals is becoming increasingly complex; diseases that were rapidly fatal in the past have become chronic conditions that elders now ‘‘live with’’ rather than ‘‘die from.’’ As a result, the approach to care of the older adult has evolved to use a comprehensive, multidisciplinary method of assessment and 0025-7125/06/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.mcna.2006.06.004 medical.theclinics.com

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treatment. This process identifies and addresses medical as well as cognitive, functional, social, financial, and psychological impairments. Therapists, social workers, and nursing specialists work together with physicians to coordinate care for these most frail and challenging adults. As the population ages, the need for physicians well trained in the complex care needs of the aging adult has grown. It is unlikely that in the near future there will be a sufficient number of fellowship-trained geriatricians to personally care for all those older than age 65. It is thus necessary for all physicians, primary care providers and consultants, surgeons and specialists, to provide age-appropriate care across all areas of the health care setting. Just as one would not approach the care of an adolescent in the same manner as an infant, one does not approach the care of an older adult in the manner of a young adult. Chronologic age itself, however, is not the best marker for selecting evaluation and management strategies. Ageist views, such as ‘‘the patient is not a good candidate at this age,’’ continue to restrict healthy old individuals from receiving beneficial treatments. Functional status or the presence of frailty are better markers for decision-making and can be equally useful in reducing inappropriate treatments for individuals too impaired to tolerate traditional interventions. Despite living longer and with more chronic conditions, the population is living with less functional impairment. Over a 10-year period ending in 2003, the percent of individuals over age 65 with impairments declined in all activities of daily living. This was true for both men and women and across all age categories. Community-dwelling elders had the greatest decline in functional impairment, whereas institutionalized individuals had greater functional limitation in all activities of daily living [2]. Geriatrics brings together a multidisciplinary group of providers for the coordinated care of a complicated and challenging group of patients. As team leaders, geriatricians are called upon to be educators for institutions, health professionals, families, and the community, on the standards of quality care for older adults. As the economic, social, and political climate has changed in the United States, geriatricians promote policies and direct debates on care of the aging population. Lobbying for health care benefits and services is increasingly necessary as financial aspects of health care are politically determined by governmental agencies. Research in geriatric medicine is of growing importance in our understanding of the physiology and pathophysiology of aging. This work continues to demonstrate the differences between normal aging and disease. Scientists are breaking down barriers to understanding and treating conditions such as dementia, delirium, and frailty. Geriatricians are specifically trained to incorporate this research into a care plan designed to address the health care needs of the individual person. Geriatricians are the educators, researchers, and expert clinicians leading the medical profession through the changing economic, political, and medical environment in which our elders are living.

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This issue highlights the most recent data for evaluation and management of common medical conditions found in the older adult. The chapters are authored by some of the most well-known and respected geriatric medicine physicians in the United States. This review provides a guide for the practicing clinician who cares for older adults, using a syndrome-based and in some cases a disease-based approach. It is hoped that, as presented above, old age can represent a time of opportunity and wellness, with starry skies in the years of fading twilight. Julie K. Gammack, MD St. Louis University School of Medicine Division of Geriatric Medicine 1402 Grand Boulevard, M238 St. Louis, MO 63104 Geriatric Research, Education, and Clinical Center (GRECC) Jefferson Barracks Veterans Affairs Medical Center 915 North Grand Ave. St. Louis, MO 63106 E-mail address: [email protected] John E. Morley, MB, BCh St. Louis University School of Medicine Division of Geriatric Medicine 1402 Grand Boulevard, M238 St. Louis, MO 63104 Geriatric Research, Education, and Clinical Center (GRECC) Jefferson Barracks Veterans Affairs Medical Center 915 North Grand Ave. St. Louis, MO 63106 E-mail address: [email protected]

References [1] Life Expectancy National Center for Health Statistics. Trends in Health and Aging. http:// www.cdc.gov/nchs/agingact.htm. Accessed May 16, 2006. [2] Functional Status and Aging. National Center for Health Statistics, Trends in Health and Aging. http://www.cdc.gov/nchs/agingact.htm. Accessed May 16, 2006.

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Cognitive Impairment Seema Joshi, MB, BS, John E. Morley, MB, BCh* Division of Geriatric Medicine, Saint Louis University School of Medicine, 1402 South Grand Boulevard, M238, St. Louis, MO 63104, USA

The face of aging in the United States is changing dramatically and rapidly. The U.S. population that is aged 65 and older is expected to double in size within the next 25 years. By 2030, almost one out of every five Americansdsome 72 million peopledwill be 65 years or older. The age group of 85 years and older is the fastest growing segment of the U.S. population [1]. Cognitive decline has been associated with aging. Age affects memory as it does many other skills. The frequency of cognitive decline can be identified by the use of the word ‘‘senility.’’ Historically, the word ‘‘senility’’ has been used as a synonym for the loss of cognitive abilities in old age; however, senility just means the state of being old and now is considered to be a politically incorrect term [2]. Dementia is a common and disabling disorder in the elderly. Dementia has growing public health relevance because of the worldwide aging phenomenon that exists in developed and developing countries. It is estimated that 24.3 million people worldwide have dementia, with 4.6 million new cases of dementia every year (one new case every 7 seconds). The number of people affected will double every 20 years to reach 81.1 million by 2040 [3]. In a population-based study of people aged 75 and older, dementia and low scores on the Mini-Mental Status Examination (MMSE) were major determinants for the development of dependence and decline over 3 years [4]. In the Cache County Study, dementia was the strongest predictor of mortality, with a risk that was two to three times that of other life-shortening illnesses [5]. Normal cognitive aging Memory problems that are associated with normal aging tend to reflect a generalized decrease in the efficiency by which information is processed and retrieved. Memory for past events can be based on retrieval that is * Corresponding author. E-mail address: [email protected] (J.E. Morley). 0025-7125/06/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.mcna.2006.05.014 medical.theclinics.com

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accompanied by specific contextual details (recollection), or on the feeling that an event is old or new without the recovery of contextual details (familiarity). There is evidence that recollection is more dependent on the hippocampus, whereas familiarity is more dependent on the rhinal cortex, and that healthy aging has greater effects on recollection than on familiarity. With aging, there occurs a reduced functional connectivity within a hippocampal-retrosplenial/parietotemporal network but increased connectivity within a rhinal-frontal network. These findings indicate that older adults compensate for hippocampal deficits by relying more on the rhinal cortex, possibly through a top-down frontal modulation. This finding has important clinical implications because early Alzheimer’s disease (AD) impairs the hippocampus and the rhinal cortex [6]. Typically, short-term memory is well preserved unless there is high demand placed on processing resources. Older subjects, however, have greater difficulty than do younger subjects in manipulating the information that is being held in short-term memory (eg, arranging the digits in order or repeating the string of digits back in reverse order). With regard to long-term memory, age-related impairments in free recall of stories and word lists are evident by age 50 years. When structure is provided by the use of recognition testing or cueing, however, the age differences diminish, which suggests greater impairment of retrieval processes than of encoding or retention [7–10]. Several studies confirmed a strong negative relationship between age and performance on tests of learning and memory. Decades of research have yielded an abundance of empiric studies that demonstrate that older adults show decline in comparison with young adults across a variety of cognitive tasks [11,12]. Memory changes show a slow progressive impairment over the lifespan. Most of the decline occurs in the working memory (the ability to maintain information while processing other tasks) and episodic memory (storage and retrieval of information from long-term memory). Semantic memory (retrieval of concepts) and implicit memory (unconscious effects of memory) show only minor changes with aging [13]. Identifying memory problems Neurotransmitters and memory Originally, it was believed that the laying down and retrieval of memories was due predominantly to the action of a single neurotransmitter, acetylcholine [14]. This led to the development of the acetylcholinesterase inhibitors to treat cognitive impairment. The further recognition of the role of the glutamate-N-methyl-D-aspartate receptor led to the development of memantine [15]. More recently, it was recognized that several neuropeptides also play an important role in memory modulation. These include neuropeptide Y, orexin A, and the endogenous opioid peptides [16–19]. This has opened

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up a host of new potential drug therapies for cognitive impairment. It is important to recognize that all of these neurotransmitters, while enhancing memory at low doses, inhibit memory at high doses. This phenomenon (hormones) is characteristic of many physiologic systems. When a task is learned before a meal is ingested, it is recalled better at a later date [20]. This was shown to be due to the release of the gastrointestinal hormone cholecystokinin. Cholecystokinin stimulates the ascending fibers of the vagus, which, through relays in the midbrain and the amygdale, eventually leads to activation of neurons in the hippocampus [20–22]. Additionally, ghrelin, a hormone that is produced by the fundus of the stomach, has receptors in the hippocampus and enhances memory [23]. This gut– brain axis seems to play an important role in modulating foraging behavior in animals and possibly thoughts about food in humans (Fig. 1). Amyloid-b peptide is well known to inhibit memory [24,25] and produce oxidative damage [26]. It is considered by many investigators to be the primary trigger of AD. The SAMP8 mouse is an animal model of AD in which there is overproduction of amyloid-b protein, which is associated with poor acquisition and memory and increased oxidative damage [27–31]. In these animals, antibodies to amyloid-b protein improve memory and increase acetylcholine release [32,33]. Antibodies to amyloid-b protein recently were shown to enhance memory and acetylcholine release in transgenic mice that overproduce amyloid-b protein [34]. In SAMP8 mice an antisense to amyloid precursor protein reversed the memory deficits and decreased oxidative damage to the brain [35–37]. These studies suggest potentially exciting new ways to treat AD.

Fig. 1. Mechanisms by which food enhance cognition.

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Screening for memory problems Numerous studies have shown that physicians and family members often fail to recognize persons who are in the early stages of dementia [38]. For this reason, several standardized tests for recognizing dementia have been developed. Of these, the most widely used has become the MMSE. Unfortunately, the copyright on this test is now being enforced and one has to pay to use it. For this reason, the senior author and colleagues developed the St. Louis University Mental Status Examination, which has been validated (Fig. 2) [39,40]. Overall, it has better receiver operating characteristics than does the MMSE and it recognizes persons who have mild cognitive impairment (MCI), which the MMSE fails to identify. Mild cognitive impairment The term ‘‘mild cognitive impairment’’ was used previously to refer to people with mild difficulties on cognitive testing but it was not necessarily distinguishable from mild dementia. The term MCI is used now to refer to people with evidence of cognitive impairment on neuropsychologic testing who do not meet the criteria for dementia. MCI is the earliest clinical manifestation of AD [41,42]. There is limited data on the prevalence of MCI; however, slightly more is known about the prevalence of MCI. Depending on the study, prevalence ranges from 5% to 25% among community-dwelling populations [43–46] and between 6% and 85% in a clinical setting [47]. MCI is not benign and is associated with significant mortality and morbidity. Mortality for individuals who have MCI is twice as high as for people without impairment [48–51]. These individuals are at increased risk for progressing to dementia. Annual conversion rates vary from less than 5% to more than 35% per year compared with 1% to 7% per year for individuals who do not have MCI [52–55]. The progression of MCI to overt AD depends on the severity of cognitive impairment at baseline. Studies indicate that the lesser the severity of cognitive impairment, the slower is the rate of progression to AD [56]. A two- to threefold increased risk for nursing home placement has been seen with MCI; these individuals have greater difficulties managing financial affairs [49,57–59]. MCI is a heterogeneous condition. MCI has been classified into various subtypes (Box 1) [60]. In a study by Waite and colleagues [61], risk factors that predicted the progression of MCI to dementia included the presence of cognitive impairment, extrapyramidal signs, or vascular risk factors. The combination of two or more of these conditions increased the odds ratio to 5 to 12 times that of healthy individuals. MRI-based hippocampal volumetric measurement was sensitive to differentiating normal controls from patients who had very mild AD, even after controlling for age and sex. An association

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Fig. 2. St. Louis University Mental Status Examination. (From Banks WA, Morley JE. Memories are made of this: recent advances in understanding cognitive impairments and dementia. J Gerontol Med Sci 2003;58:316.)

between reductions in hippocampal volume and cognitive impairment was shown in nondemented elderly [62,63]. Reduced glucose metabolism in the temporoparietal region on positron emission tomography scan is a predictor of future progression of MCI to dementia [64–66]. APOE-34 genotyping was a predictor of conversion to dementia. APOE-34 may be a risk factor for the conversion of MCI to dementia only for amnestic MCI that appears at an early age, but not other MCI subtypes [67,68]. Elevated levels of tau protein

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Box 1. Characteristics that are used to classify mild cognitive impairment Cognitive features Amnestic MCI versus nonamnestic MCI MCI with memory impairment only versus MCI with multiple impaired cognitive domains Neurologic or clinical presentation MCI with or without parkinsonism or depression Etiology Vascular Depressed Parkinsonian Lewy body disease and related parkinsonian syndromes Normal pressure hydrocephalus Frontotemporal dementias Neuroimaging findings MCI with or without hippocampal atrophy Genetic features MCI with or without APOE-34 genotype Progression rate MCI converters to dementia compared with nonconverters in cerebrospinal fluid may be a potential biomarker for the conversion of MCI to dementia [69,70]. No drug is approved by the U.S. Food and Drug Administration (FDA) for the treatment of MCI. In a randomized control trial using donepezil, 10 mg/d for 24 weeks, no treatment benefit was found. Another study that compared donepezil and vitamin E with placebo for the rate of progression of MCI to clinically probable dementia showed no benefit of treatment for vitamin E. Rates of progression to dementia were similar between donepezil and placebo groups during a 3-year follow-up. The group that was treated with donepezil showed a slower rate of progression during the first year of treatment, but this effect disappeared by the second year [71,72]. Dementia Based on the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition (DSM-III-R) and Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria, the essential feature of dementia is impairment in short- and long-term memory, which is

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associated with impairment in abstract thinking, impaired judgment, other disturbances of higher cortical function, or personality change. The disturbance is severe enough to interfere significantly with work or social activities or relationships with others [73,74]. The American Academy of Neurology (AAN) recommends use of criteria that are elaborated in DSM-III-R and DSM-IV for the diagnosis of dementia [75]. Several studies have shown that diagnosis of dementia is missed frequently by physicians, and as many as 50% of demented patients are not diagnosed by their community physicians [76–79]. In a study by Ross and colleagues [80], 60% of subjects who were identified as having dementia using standard diagnostic criteria were not recognized by their family informants to have a memory problem, or were not reported by their family informants to have had a medical assessment for this problem. Dementia is a clinical diagnosis whose evaluation involves assessment of the presenting problem; history about the patient that is provided by an informant (someone who knows the patient, usually a family member); complete physical and neurologic examination; evaluation of cognitive, behavioral, and functional status; and laboratory and imaging studies [81–85]. The diagnosis of dementia does not require an extensive laboratory work-up [86]. The AAN practice parameter recommends structural neuroimaging, which may include CT or MRI, and screening for depression, vitamin B12 deficiency, and hypothyroidism. Based on these criteria the screening for syphilis without risk factors is not justified [75]. Venereal Disease Research Laboratory (VDRL) testing detects only 75% of the cases of tertiary syphilis, and cerebrospinal fluid–VDRL may be negative in 30% to 70% of patients who have neurosyphilis [87]. Screening evaluations are recommended to detect conditions such as subdural hematomas, cerebral infarcts, cerebral tumors, and normal pressure hydrocephalus [88]. There is no consensus regarding the routine neuroimaging of patients who have dementia. The Canadian Consensus Conference on Dementia provides a reasonable approach for performing a cranial CT in patients who have dementia [89]. There are several clearly reversible causes of dementia that are remembered by the mnemonic DEMENTIA: Drugs (any drug with anticholinergic activity) Emotionalddepression Metabolic (hypothyroid) Eyes and ears declining Normal pressure hydrocephalus Tumor or other space-occupying lesion Infection (syphilis, AIDS) Anemia (vitamin B12 or folate deficiency) The major syndromes with progressive dementia include AD, vascular dementia (VaD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD).

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Alzheimer’s disease AD was described originally at the dawn of the twentieth century separately by Alzheimer and by Fischer as a pathologic entity consisting of amyloid plaques and neurofibrillary tangles (NFTs). Epidemiologic studies indicate that AD is the most common cause of dementia worldwide. It is responsible for 75% of all dementias. It affects 5% of the population that is older than 65 years and 30% of patients that are older than 85 years [90]. The prevalence of AD in the United States has been projected to grow from 4.5 million individuals in 2000 to 15 million individuals by 2050 [91]. A useful model for the prevalence of AD is to consider the prevalence at age 60 to be 1%, and assume that the rate doubles every 5 years, which leads to a predicted prevalence of greater than 30% by the age 85 years [92]. The incidence rates for dementia vary widely; from ages 65 to 69 years the incidence ranges from 0.7 to 3.5 per 1000 per year, and it doubles approximately every 5 years [93]. AD is considered to be the third most expensive illness in the United States. The economic burden is estimated to be around $60 to $100 billion annually [2]. Major risk factors for AD include advanced age, family history, apolipoprotein E 3-4 allele, and mutations in chromosomes 21 (presenilin 1) and 14 and 1 (presenilin 2) [94]. Possible risk factors for AD include low educational attainment, female gender, depression, and brain injury [2]. Early-onset AD is the dominantly inherited familial AD and accounts for less than 1% of cases of AD. Age of onset between the fifth and sixth decades is characteristic of familial AD. It is associated with mutations in chromosomes 1, 14, and 21 [95]. The apolipoprotein E genotype contributes to the effect of family history on the risk for developing AD. Apolipoprotein E exists in three allelic forms: 3-2, 3-3, and 3-4. Homozygosity for 3-4 is associated with an increased risk for AD. In one study, homozygosity for 3-4 was associated with a 30-fold increased risk, and heterozygotes for 3-3 and 3-4 had a fourfold increase in risk. The 3-2 allele may confer a protective effect [96]. The diagnostic accuracy of clinically diagnosed AD may be as high as 90% [97]. Confirmatory diagnosis requires histopathologic evidence of senile plaques and NFTs on autopsy. Memory decline is the hallmark of cognitive change and is characterized by a storage deficit with rapid forgetting and poor delayed memory [98,99]. Diagnostic criteria for AD have been published by the Clinical Practice Committee of the American Geriatrics Society and AAN [75,100]. The number of NFTs, neuronal loss, and cognitive dysfunction are correlated in AD [101]. The location of senile plaques correlates less well with cognitive decline than do measures of neuronal loss and NFT number [102]. AD is progressive in nature and results in disability, dependency, and increased mortality. The average duration of the illness is around 8 years [103]. In one study, the median survival from the time of diagnosis was 4.2 and 5.7 years in men and women, respectively [104].

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The first claim of the efficacy of tacrine hydrochloride in AD was shown in a controlled trial in 1986 [105]. In 1993, tacrine hydrochloride was the first drug to be approved for the symptomatic treatment of AD. Since then cholinesterase inhibitors (ChEIs) have been approved by the FDA for the treatment of mild to moderate AD. Cognitive improvement in patients who had mild to moderate AD was demonstrated for each of the approved ChEIs in several large, multicentered, double-blind, randomized, placebo-controlled clinical trials [106–114]. Clinical trials demonstrated efficacy with small improvements in cognitive and global functions in mild to moderate disease with the duration of benefit persisting as long as 36 months for some patients [115,116]. The AD2000 trial that was conducted in the United Kingdom showed no benefit for donepezil versus placebo for institutionalization, progression of disability, costs for health and social services, or caregiver measures of distress. The study did show small improvements in cognition and activities of daily living; however, these benefits did not reduce the cost of caring for the patients who had AD [117]. Memantine has been approved for the treatment of moderate to severe dementia. It seems to be beneficial alone or in combination with donepezil [118]. Several older nootropics, such as piracetam and Hydergine, have been less well studied but may be useful agents [119]. An increased risk for all-cause mortality was seen with vitamin E supplementation in a recent meta-analysis [120]. Based on current data, it would be prudent to avoid high-dose vitamin E supplementation. Estrogen replacement therapy has not been shown to reduce the risk for AD and may be harmful. The Women’s Health Initiative Memory Study showed no protection against cognitive decline, and subsequent studies showed increased risk for cerebrovascular disease, breast cancer, thrombophlebitis, cognitive decline, and dementia [121–124]. There is preliminary evidence that testosterone may improve some aspects of visuospatial memory in men who have AD [30,31]. Consumption of fish and intake of omega-3 polyunsaturated fatty acids have been associated with a reduced risk for cognitive decline [125]. Leisure-time physical activity at midlife is associated with a decreased risk for dementia and AD later in life. Regular physical activity may reduce the risk or delay the onset of dementia and AD, especially among genetically susceptible individuals [126]. The role of Gingko biloba as a memory aide is uncertain at present. Atypical antipsychotics are used frequently for the treatment of behavioral symptoms that are associated with advanced AD. The FDA issued a public health advisory on April 11, 2005 for increased mortality associated with the use of atypical antipsychotic drugs [127]. Vascular dementia Vascular disease in the brain is prevalent among individuals who have incident dementia. Cerebral ischemia has long been implicated in the development of dementia. The term ‘‘multi-infarct dementia’’ was coined

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in the 1970s to reflect the role of discrete cerebral infarcts and strokes in the development of dementia [128]. Vascular risk factors and cerebrovascular disease are common in the elderly; therefore, one is faced with the problem of discerning whether cerebrovascular disease is the sole cause or a concomitant or complicating factor in the diagnosis of dementia. In a study done by Lobo and colleagues [129], out of 382 autopsies that were done on patients who had dementia only 3% had pure VaD. There is marked heterogeneity of the VaD syndrome; it has various clinicopathologic subtypes that include hemorrhagic, ischemic, or a combination of the two. The ischemic form may be subdivided into large vessel, small vessel, or strategic infarcts. The diagnosis of VaD requires the presence of dementia and cerebrovascular lesions and a temporal association between the two [130]. The presence of scattered white matter changes on cerebral imaging in a person who has gradually progressing dementia is not sufficient to consider cerebrovascular disease as the sole cause of the dementia. Cerebrovascular lesions seem to contribute to the expression of dementia in men who have subclinical AD [131]. The typical cognitive pattern in VaD includes prominent frontal/executive dysfunction with less language impairment. Unilateral motor or sensory dysfunction can be seen in 90% of cases of pathologically verified VaD [132]. The prevention of cerebrovascular disease may reduce the occurrence of dementia, especially in individuals who have subclinical AD. The efficacy of ChEIs has been reported in VaD alone or coexisting with AD [133,134]. Dementia with Lewy bodies DLB, which was believed to be uncommon previously, is now considered the second most common type of neurodegenerative dementia in older adults. It accounts for 10% to 15% of cases of dementia at autopsy [135]. It is a clinically defined syndrome. Based on consensus clinical criteria, the diagnosis of DLB requires progressive cognitive decline; however, prominent or persistent memory impairment may not occur in the early stages but is evident with progression of disease. The core clinical features that are required for the diagnosis include fluctuating cognition, recurrent visual hallucinations, and spontaneous features of parkinsonism [136]. The diagnosis of this disorder is particularly significant because of its responsiveness to ChEIs and its extreme sensitivity to the side effects of neuroleptic drugs [137–139]. The pathologic hallmark of DLB is the presence of Lewy bodies. a-Synuclein is a normal synaptic protein that has been implicated in vesicle production. In an aggregated and insoluble form it constitutes the main component of the fibrils that are a major constituent of the Lewy bodies in DLB [140]. Neuroimaging investigations may be helpful in supporting the clinical diagnosis of DLB. Changes that are associated with DLB include preservation of hippocampal and medial temporal lobe volume on MRI and occipital hypoperfusion on single proton emission computed tomography [141,142].

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Frontotemporal dementia FTD is being recognized increasingly as an important cause of dementia [143]. It is defined as a clinical syndrome that is characterized by profound changes in personality and social conduct, and is associated with circumscribed degeneration of the prefrontal and anterior temporal cortex. The core clinical features include an insidious onset and gradual progression with early decline in social interpersonal conduct, impairment in regulation of personal conduct, emotional blunting, and loss of insight [144]. FTD can be subdivided into three main syndromes: frontal variant FTD, in which behavioral and judgment changes are most prominent; progressive nonfluent aphasia; and semantic dementia, which is characterized by fluent aphasia with a loss of word knowledge. The four major pathologic types of FTD are Microvacuolation without neuronal inclusions Microvacuolation with ubiquitinated rounded intraneuronal inclusions and dystrophic neuritis Transcortical gliosis with tau-reactive rounded intraneuronal inclusions (Pick’s bodies) and (usually) swollen achromatic neurons (Pick’s cells) Microvacuolation and tau-positive NFTs or Pick-like bodies in neurons, and sometimes tangles in glial cells of the cerebral cortical white matter [145] Patients who have FTD show deficiencies in the serotonin and dopamine neurotransmitter systems, whereas the acetylcholine system seems to be mostly intact. Antidepressant treatment significantly improves behavioral symptoms in FTD, but most studies are small and uncontrolled. Serotonergic treatments seem to improve the behavioral, but not the cognitive, symptoms of FTD [145]. The pharmacologic treatment of FTD is limited and results of clinical trials with selective serotonin reuptake inhibitors have been equivocal [146,147]. Thus, the management of patients who have FTD involves social, psychiatric, and community support; provision of respite care to reduce caregiver burden; and ultimately, residential care. Prion disease Prions are proteinaceous materials that lead to altered mental status in persons with a genetic predisposition. The first of these diseases was described in New Guinea tribespeople who ate the brains of their departed family members. This disease was called Juru, and was shown to be due to a transmissible factor. Jakob-Creutzfeld disease occurs in persons who received growth hormone that was extracted from human pituitaries. Bovine spongiform encephalopathy (Mad Cow Disease) occurs in persons who are exposed to neural tissue from infected cows.

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Diagnosis of the causes of dementia At Saint Louis University, the authors and colleagues have developed a simplified approach to the diagnosis of dementia: Is the patient sad? Then diagnose and treat depression. Exclude other reversible dementias (use the DEMENTIA mnemonic). If there is no loss of function, diagnose MCI. If cognitive defect is of abrupt onset, shows stepwise deterioration, and the person has other evidence of vascular disease (eg, hypertension, angina, carotid bruit) diagnose VaD If there are early behavioral disturbances of parkinsonism diagnose Lewy body or FTD. In all other cases, diagnose AD. Acute confusional states Older persons are particularly vulnerable to developing delirium when they become sick. Often, delirium is not diagnosed by physicians [148]. This is because agitated and hallucinatory delirium is recognized easily, whereas the more common type, which is characterized by fluctuating levels of attention, is much harder to recognize. New-onset falls in older persons often are due to delirium. Diseases that lead to increased cytokine release commonly result in the development of delirium [149]. The common causes of delirium are remembered by the mnemonic, DELIRIUMS [150]. Drugs Emotional (acute psychotic and depressive episodes) Low oxygen states (anemia, pulmonary embolus, myocardial infarction, stroke) Infection Retention of urine and feces Ictal states, especially partial complex seizures Undernutrition and dehydration Metabolic (organ failure, thyroid disease, vitamin B12 deficiency) Subdural hematoma Classically, delirium leads to increased length of hospitalization, functional deterioration, and mortality [151,152]. At Saint Louis University the authors and colleagues have shown that the development of a delirium ICU can reverse these trends [153]. Summary As populations continue to age, the prevalence of dementia is expected to increase. AD is by far the most common cause of dementia. The clinical course of dementia represents the challenges that this disease presents. There are no truly effective therapies for treating dementia, and the cost

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effectiveness of ChEIs has been challenged; however, there has been an explosion of information about AD. Evidence-based practice parameters for diagnosis and management of dementia have been developed. There has been an increased interest in the possible prodromal states of dementia, such as MCI. The concept of MCI has risen in prominence in recent years; it is speculated that initiation of therapies early in the course of disease may be needed for them to be effective. Considering the enormous burdens that AD places on individuals and society, disease-modifying treatments for AD are needed desperately. There are promising avenues for the development of potentially disease-modifying therapies for this devastating disease. References [1] Dramatic changes in US aging highlighted in new census. Washington DC: National Institutes of Health; 2006. [2] Geldmacher DS. Contemporary diagnosis and management of Alzheimer’s dementia. Newton (PA): Handbooks in Health Care Co.; 2003. [3] Ferri CP, Prince M, Brayne C, et al. Global prevalence of dementia: a Delphi consensus study. Lancet 2005;366:2112–7. [4] Aguero-Torres H, Fratiglioni L, Guo Z, et al. Dementia is the major cause of functional dependence in the elderly: 3-year follow-up data from a population-based study. Am J Public Health 1998;88(10):1452–6. [5] Tschanz JT, Corcoran C, Skoog I, et al. Dementia: the leading predictor of death in a defined elderly population: the Cache County Study. Neurology 2004;62(7):1156–62. [6] Daselaar SM, Fleck MS, Dobbins IG, et al. Effects of healthy aging on hippocampal and rhinal memory functions: an event-related fMRI study. Cereb Cortex, in press. [7] Craik FIM. Age differences in remembering. In: Squire LR, Butters N, editors. Neuropsychology of memory. New York: Guilford; 1984. p. 3–12. [8] Albert MS, Duffy FH, Naeser MA. Nonlinear changes in cognition and their neurophysiologic correlates. Can J Psychol 1987;41:141–57. [9] Craik FIM, Byrd M, Swanson JM. Patterns of memory loss in three elderly samples. Psychol Aging 1987;2:79–86. [10] Albert MS. Cognitive function. In: Albert MS, Moss MB, editors. Geriatric neuropsychology. New York: Guilford; 1988. p. 33–53. [11] Craik FIM, Rabinowitz JC. Age differences in the acquisition and use of verbal information. In: Bouma H, Bouwhuis DG, editors. Attention and performance. Hillsdale (NJ): Erlbaum; 1984. p. 471–99. [12] Zacks RT, Hasher L, Li KZH. Human memory. In: Salthouse TA, Craik FIM, editors. Handbook of aging and cognition. 2nd edition. Mahwah (NJ): Erlbaum; 2000. p. 293–357. [13] Flood JF, Morley JE. Age-related memory changes in learning, memory and memory processing. In: Morley JE, Armbrecht HJ, Coe RM, et al, editors. The science of geriatrics. New York: Springer Publishing Company; 2000. p. 503–13. [14] Flood JF, Morley JE. Pharmacological enhancement of long-term memory retention in old mice. J Gerontol 1990;45:B101–4. [15] Flood JF, Morley JE, Lanthorn TH. Effect on memory processing by D-cycloserine, an agonist of the NMDA/glycine receptor. Eur J Pharmacol 1992;221:249–54. [16] Morley JE, Flood JF. Neuropeptide Y and memory processing. Ann N Y Acad Sci 1990; 611:226–31. [17] Flood JF, Baker ML, Hernandez EN, et al. Modulation of memory processing by neuropeptide Y varies with brain injection site. Brain Res 1989;503:73–82.

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Med Clin N Am 90 (2006) 789–805

Mood Disorders in the Elderly Mehret Gebretsadik, MD, Sundeep Jayaprabhu, MD, George T. Grossberg, MD* Saint Louis University School of Medicine, Department of Psychiatry, 1221 South Grand Boulevard, Saint Louis, MO 63104, USA

Introduction There is wide variability in the estimated frequency of mood disorders, particularly depressive illnesses, in the elderly because of the source of the sample, threshold of diagnosis, method of assessment, and experience of the rater. Regardless, late-life mood disorders are underreported and inadequately treated. The prevalence of depression in the elderly is lowest for those who live in the community, whereas it increases dramatically in the chronically ill, hospitalized patients, and long-term care residents [1–3]. In addition to sociodemographic factors, medical comorbidities play a significant role in late-life depression [4–7]. Moreover, suicide is markedly increased in the elderly, as is mortality from other causes [8]. It is estimated that 2% of community elderly and 9% of the chronically ill are depressed compared with 6% of the general adult population [1]. The figure increases dramatically to 36% for geriatric inpatients and even more for inpatients who have had stroke or myocardial infarction and patients who have cancer (39%–47%) [1,2]. Depression estimates for nursing home residents range from 29%–52.4% [9]. Although a significant portion of these patients have major depressive disorder, most have dysthymia, adjustment disorder with depressed mood, depression attributable to medical conditions, or other subsyndromal depressive symptoms. Mood disorders in the elderly are major causes of suffering and play a significant role in morbidity of this age group of frail patients [4,10,11]. Risk factors for late-life depression include female sex; social isolation; widowed, divorced, or separated marital status; lower socioeconomic status; comorbid medical

* Corresponding author. E-mail address: [email protected] (G.T. Grossberg). 0025-7125/06/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.mcna.2006.05.015 medical.theclinics.com

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conditions; uncontrolled pain; insomnia; family and past history of depression; functional impairment; and cognitive impairment [12,13]. Clinical features and diagnostic workup Major depressive disorders Major depressive disorders (MDD) in the elderly can be classified into two categories. Early-life onset is the occurrence of depression before the age of 65, and late-life onset is depression after the age of 65. A specific cause for either type of depression has not been isolated. It seems the cause of depression is multifactorial and includes biologic, psychologic, and sociologic aspects. No single gene or single biologic event has been associated with late-life depression, although there does appear to be an increased risk with a family history of depression. Cerebrovascular disease, which is more common among the elderly, seems to play a large role in late-onset depression and has led to the ‘‘vascular depression hypothesis’’ [14]. Magnetic resonance imaging of the brain in patients who have vascular depression shows extensive microvascular ischemic changes that are believed to disrupt circuits involved in regulation of mood. Systolic hypertension and diabetes are risk factors for these vascular changes. Vascular depression is characterized by functional impairment, apathy and anhedonia, and an absence of a family history of depression [15]. In comparison to nonvascular depression, vascular depression has more psychomotor retardation, greater cognitive impairment, greater lack of insight, less guilty feelings, and less agitation [14]. Germane to the topic of vascular depression is the correlation between depression and stroke. The risk seems to be greatest within the first 2 years following a cerebrovascular accident, when major depression develops in about 20% and minor depression in another 20% of patients [16,17]. If left untreated, depression following a stroke seems to last approximately 8 to 9 months according to some studies [14]. The risk for depression increases the closer the vascular insult is to the frontal pole and if the left cerebral cortex is affected. Subcortical infarcts in the thalamus and caudate also increase the risk for depression [16,17]. Myocardial infarctions and cancers also are associated with depression. It is common for depression to present in patients who have neuropsychiatric disorders, such as Alzheimer disease or Parkinson disease. Depression increases morbidity, particularly cognitive impairment, in these neuropsychiatric disorders [18]. The criteria for depressive disorders according to the diagnostic criteria from the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) of the American Psychiatric Association should be able to identify many of the presentations of depressive disorders among the elderly. Nevertheless, the elderly are a unique patient population and illness

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among this group may present differently than during younger adulthood. This difference can be true especially with regard to mood disorders. The mental status exam remains the gold standard for diagnosis of depressive disorders among all age groups [24,25]. In the elderly, MDD may present with anxiety, somatic complaints, or cognitive impairment as the chief presentation. Generalized anxiety or panic symptoms may accompany depression in the elderly. The patient may present with palpitations, restlessness, fatigability, tremor, body aches or pains, dyspnea, nausea or vomiting, dizziness, diaphoresis, faintness, paresthesia, frequent urination, insomnia, or facial flushing. Many of these symptoms have the potential to be attributed to medical causes rather than psychiatric ones. Somatic symptoms may be particularly troublesome because the physician may face more difficulty diagnosing depression. The patient may focus complaints on physical problems rather than openly address depression, or may admit to feeling depressed but only as a result of physical complaints. Comorbid psychotic symptoms are common among the elderly, present in 3.6% of community-dwelling elderly patients who have depression and in 20% to 45% of hospitalized elderly patients who have depression. Psychotic symptoms often involve delusions that are persecutory, guilty, nihilistic, or somatic in nature. Depression may at times present with cognitive impairment and look like dementia. This unique presentation is referred to as pseudodementia or the dementia syndrome of depression, recognizing that a geriatric patient with a clinically significant depression may show objective evidence of memory and cognitive changes secondary to the mood disorder. Once the mood disorder is treated, however, the cognitive changes disappear. The presence of late-life minor depression may be more common than latelife MDD [26]. Minor depression is defined as having two to four of the nine depressive symptoms described above. Although less severe than MDD, minor depression still carries with it functional impairment. Furthermore, minor depression may be a predisposing state for the development of MDD [27,28]. The essential ingredients for a diagnosis of MDD include a careful history and a thorough neurologic and medical evaluation. A review of the patient’s medications, including prescribed, over-the-counter, and supplements, is vital to identify agents that may contribute to mood change in the elderly. A consideration of social factors, life changes, and the presence of comorbid neurologic or medical symptoms is paramount. Initial or screening laboratory tests include an electrolyte panel, fasting serum glucose level, liver function tests, creatinine level, complete blood count, thyroid-stimulating hormone level, vitamin B12 and folic acid levels, electrocardiography, chest radiography, urinalysis, and a urine drug screen and serum drug screen if warranted. Consider further neurologic testing or imaging if warranted by the neurologic exam. As mentioned previously, however, the MRI may prove useful in visualizing changes secondary to a vascular depression.

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Bipolar affective disorder Bipolar affective disorder (BAD) typically is diagnosed in adolescence to adulthood, and little is known about the initial presentation of this illness in the elderly, or late-onset BAD. Much of current understanding of presentation and management of BAD in the elderly is extrapolation from what is known from research on adolescent and adult patients, or early-onset BAD. There is evidence, however, that late onset of BAD in the elderly is more commonly refractory to treatment, more likely to have psychotic features, more likely to be associated with cerebrovascular disease, less likely to have a family history of mood disorder, and less likely to have the social stressors of separation or divorce [19,20]. Increased age-related changes found on neuroimaging in late-onset BAD may account for the increased cognitive deficits found among late-onset BAD patients [21,22]. A higher incidence among women than men of up to two times has been reported also [23]. The prognosis for late-onset BAD generally is worse than that for early-onset BAD and is associated with a higher mortality [21]. The diagnosis of BAD in the elderly follows the DSM-IV-TR criteria. Bipolar disorder rarely presents for the first time in an elderly patient. In fact, a first episode presentation of mania in patients older than 65 should alarm the clinician to identify possible psychologic, structural, or metabolic causes. Side effects from medications and behavioral sequelae of dementia are some of the more common causes in the differential. A presentation with a loss of sensorium or awareness or cognitive impairment as the prominent symptom should especially alert the clinician to consider a workup for metabolic or structural causes.

Management of mood disorders in the elderly Treatment of mood disorders in older adults usually requires a combination of approaches, including pharmacotherapy, psychotherapy, and less frequently neuromodulation (Fig. 1). Pharmacotherapy When considering pharmacotherapy for MDD and bipolar disorder, there are at least four considerations: (1) response versus remission, (2) safety, (3) length of treatment, and (4) compliance. Controlled trials relative to the use of antidepressants in the treatment of late-life depression are scarce. As of 2003, only four placebo-controlled trails and six comparative trials had been conducted. The results of these studies are mixed and there is no single agent that is clearly more effective than any other. Many pharmacotherapy trials for MDD in the elderly also show a robust placebo response.

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1. Diagnosis of major depression; rule out bipolar disorder if possible. 2. Initiate SSRI or other newer antidepressant therapy with adequate trial being 6-8, or up to 12 weeks 3. If SSRI/newer antidepressant efficacious and with tolerable side effects, continue for 12 months. Consider indefinite treatment. 4. If SSRI/newer antidepressant ineffective or side effect noted, consider trial with another SSRI or switching class to Bupropion, Venlafaxine, Mirtazapine or Duloxetine 5. If second SSRI or other newer antidepressants ineffective or side effects noted, consider referral to a geriatric psychiatrist for TCA or MAOI therapy or augmentation/combination therapies.

6. If TCA or MAOI ineffective or side effects noted, depression is considered treatment-resistant; consider other modalities of treatment such as ECT, VNS, rTMS or DBS.

Fig. 1. Algorithm for the treatment of major depression in the elderly.

Monamine oxidase inhibitors Monamine oxidase inhibitors (MAOIs) are the first generation of drugs developed to treat depression. They are used rarely now because of the risk for side effects. Hypertension is a feared complication of this medication when combined with a list of foods and drinks containing high levels of tyramine, including certain alcoholic drinks, cheeses, and fermented foods. With tyramine restriction, the MAOIs can cause hypotension, which may lead to falls in the elderly. As of this writing, the Food and Drug Administration (FDA) has approved an MAOI, selegiline, in the form of a transdermal patch, which may prove to be safer and easier to use than current MAOIs. Overall, MAOIs are used mainly for refractory depression. Tricyclic antidepressants Tricyclic antidepressants (TCAs) are also one of the first classes of medication approved to treat depression. TCAs are similar to MAOIs. Once used extensively for depression, this class is used less since the advent of newer antidepressants. The TCAs are not well tolerated by the elderly secondary to anticholinergic, orthostatic, and sedative side effects. TCAs also carry a potential risk for cardiotoxicity, convulsions, coma, and death in overdose.

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Selective serotonin reuptake inhibitors According to pharmacotherapy guidelines developed by the Prevention of Suicide in Primary Care Elderly: Collaborative Trial group relative to safety and efficacy, the selective serotonin reuptake inhibitors (SSRIs) are the first choice in treating the elderly who have depression [29]. The most significant reason for the preferred use of SSRIs over TCAs is their safer side-effect profile, especially in the setting of an overdose. Also, older patients often tolerate side effects of SSRIs better than those of TCAs. Studies show that most antidepressants are effective in the elderly. So, the selection is largely based on the drug’s side-effect profile and potential interaction with other medications. Table 1 provides the names, initial dose, usual dosage range, and potential side effects of various antidepressants in the elderly. It generally is recommended to initiate doses at half the initial dose recommended for younger adults and titrate up slowly to the optimal dose. If adverse effects do occur, one should consider decreasing dosage if the medication is effective or discontinuing the medication if the adverse event is severe or intolerable. If the side effect of the SSRI is minor, one should consider trying another SSRI versus changing to another class of antidepressant. If the side effect is severe, consider switching to another class of antidepressants. An adequate trial of medication is at least 6 weeks at the recommended dosage. If depressive symptoms resolve, continuation of antidepressant therapy for 12 months is recommended to prevent relapse. In older adults with a history of two or more episodes of MDD, long-term indefinite treatment should be considered at the same dose that showed efficacy. Further guidelines for long-term maintenance have not been adequately established. Mood stabilizers Lithium has been the treatment of choice for mania in the past. It has been well documented that lithium decreases the risk for suicide [30–33]. Fewer physicians are using lithium, however, secondary to its narrow therapeutic index, need for close monitoring of levels especially in the setting of renal dysfunction or dehydration, and more common neurotoxicity in the geriatric population. Several other mood stabilizers are effective for the treatment of bipolar disorder. Each carries different advantages and disadvantages and risks for side effects. To date, there have been no randomized, double-blind, placebo-controlled trials looking at the use of anticonvulsants or mood stabilizers in older patients who have BAD. These medications are discussed further in Table 2. Atypical antipsychotics If psychosis is present with any of the mood disorders, one should consider the use of an atypical antipsychotic along with the appropriate class of medication for that particular mood disorder. Many of the atypical antipsychotics are also gaining FDA approval for the treatment of acute mania. Extrapyramidal side effects, sedation, orthostasis, and anticholinergicity are

Table 1 Antidepressant guidelines for MDD in the elderly Antidepressant

Nortriptyline

Initial dosage (mg/d)

Usual range (mg/d)

Comments

10 5–10 5–10 50 10 25

20–40 10–20 10–40 100–300 10–40 50–150

SE: GI symptoms, sexual dysfunction d-isomer of citalopram; SE: GI symptoms, sexual dysfunction SE: GI symptoms, sexual dysfunction, insomnia SE: GI symptoms, sexual dysfunction, anticholinergic SE: GI symptoms, sexual dysfunction, anticholinergic SE: GI symptoms, sexual dysfunction

75–100 7.5–15 25 50–75 20–30

150–300 15–60 150–300 75–300 30–60

SE: SE: SE: SE: SE:

10–25

75–150

10–25

50–150

Agitation, seizures Sedation, increased appetite, bone marrow toxicity Sedation, orthostasis GI symptoms, hypertension nausea; indicated also for diabetic neuropathic pain

SE: Cardiac conduction abnormality, anticholinergic, orthostasis; fatal in overdose; therapeutic windowdcheck serum level to guide dosing SE: Sedation, cardiac conduction abnormality, anticholinergic, orthostasis; fatal in overdose; therapeutic windowdcheck serum level to guide dosing

MOOD DISORDERS IN THE ELDERLY

Selective serotonin reuptake inhibitors Citalopram Escitalopram Fluoxetine Fluvoxamine Paroxetine Sertraline Miscellaneous Bupropion Mirtazapine Trazodone Venlafaxine Duloxetine Tricyclic antidepressants Desipramine

It is generally accepted to initiate doses at half the initial dose or less of that recommended for younger adults and titrate up slowly to the optimal dose. Abbreviations: GI, gastrointestinal; SE, potential side effects. 795

796

Table 2 Bipolar disorder in the elderly: therapeutic agents Medication

Initial dosage (mg/day) Usual dosage range (mg/day) Comments

Atypical antipsychotics Aripiprazole 2.5–5 Clozapine 12.5–25 Olanzapine 2.5–5

5–15 25–50 5–10 100–300

Risperidone Ziprasidone

0.25–0.5 20–40

0.5–1.5 80–160

Mood stabilizers Carbamazepine

100–200

400–800

Lamotrigine Lithium

25 150–300

50–150 600–1200

Oxcarbazepine

100

300–600

Topiramate Valproate

25 125–250

500–1500

Optimal serum level of 4–12 mg/mL; numerous drug–drug interactions; risk of agranulocytosis; periodic cbc Slow titration as risk of Stevens-Johnson syndrome with rapid increases Acute 1–1.5 mmol/L; maintenance 0.5–1 mmol/L; monitor renal and thyroid function; tremor; monitor fluid intake Stevens-Johnson syndrome and toxic epidermal necrolysis (rare); hyponatremia; sedation at high doses; no blood work required May cause cognitive impairment and weight loss Therapeutic range at 50–100 mg/mL; drug–drug interactions; sedation at high doses; thrombocytopenia; elevated liver function tests

It is generally accepted to initiate doses at half the initial dose recommended for younger adults and titrate up slowly over several weeks to the optimal dose. Abbreviations: EPS, extrapyramidal side effects; IM, intramuscular; WBC, white blood cell count.

et al

12.5–25

GEBRETSADIK

Quetiapine

Partial D2 agonist; not sedating; low EPS risk Agranulocytosis; weekly wbc; increased anticholinergic Possible adverse metabolic effects: weight, glucose and lipids; IM formulation available Low potency; often used in low doses for irritability; somnolence at low doses; orthostasis at high doses High potency; EPS at high doses Give with meals as absorption doubles with food; no controlled geriatric studies

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side effects associated with various atypical antipsychotics. Table 2 also illustrates this class of medications used for the treatment of psychosis and BAD with dosages, side effect profile, and possible advantages and disadvantages. Once again, it is recommended that initiation of pharmacotherapy for geriatric patients begin at half or less of the dose recommended for younger adults and increase slowly. The dosing for atypical antipsychotics when treating psychosis in the context of a mood disorder is generally on the lower end of the spectrum of usual daily dosages, and treatment should be reevaluated periodically after resolution of symptoms. It is important to note the recent black box warning placed on atypical antipsychotics by the FDA for a relative increased mortality in off-label use in patients who have psychosis and behavioral problems in the setting of dementia. Out of 17 trials examined, 15 were found to show increased rates of death associated with aripiprazole, olanzapine, quetiapine, and risperidone. No controlled geriatric studies had been completed on clozapine and ziprasidone at that time, but the FDA has mandated that these drugs also carry the new warning, believing that it may be a class effect. Further investigations as to the specific cause of death found either cardiovascular events or upper respiratory infections to be mainly responsible [34]. Comorbidity Pharmacotherapy may be complicated when there are comorbid psychiatric disorders. Anxiety disorder, for example, is a common occurrence. Benzodiazepines often are used to alleviate anxiety symptoms and often are successful. In the geriatric population, however, the use of benzodiazepines can be more complicated than in the adult population because these drugs may cause falls, cognitive impairment, oversedation, depression, toxicity, and abuse. If needed, benzodiazepines with a short half-life are preferred in the geriatric population for this reason. Judicious use with monitoring of patients for side effects with gradual discontinuation after anxiety symptoms resolve is recommended. Alcohol or substance abuse or dependence may lead to depressive symptoms, which usually resolve within weeks to months if the patient maintains sobriety and no other stressors exist. If the depressive symptoms are moderate or severe, however, aggressive treatment of depressive symptoms is recommended. Psychotherapy Psychotherapy with the elderly is underused and has been slow to develop, both theoretically and operationally. Moreover, the dominance of biologic models in geriatric psychiatry and neuropsychology has tilted toward brain-based rather than psych-based explanations for most illnesses and despairs in later life. In most instances, neuroimaging and charting of deficits takes priority over any meaningful psychotherapeutic exploration and intervention based on patients’ existential fears and psychosocial dysfunction.

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Despite negative stereotypes about the treatability of older adults and alternative paucity of psychotherapy theory that can speak to later life, an evidence and practice base exists to suggest that cognitive-behavioral therapy (CBT), interpersonal therapy (IPT), systemic (family) therapy, psychoeducation, and cognitive analytical therapy (CAT) or psychodynamic therapies can help a range of psychiatric illness, including mood disorders [35]. Psychotherapy alone or in combination with other modalities of treatment is effective in treating late-life mood disorders depending on the severity and nature of the illness and patient characteristics. The duration and the choice of therapy depend on several factors, including disease severity, presence of a support system, individual patient variability, and use of combination treatment modalities. Cognitive behavioral therapy CBT is a structured, goal-directed, problem-focused, and time-limited approach focusing simultaneously on the environment, behavior, and cognition. Patients learn how their thoughts contribute to symptoms of their affect and how to change these thoughts. Increased cognitive awareness is combined with specific behavioral techniques. It is the form of psychotherapy most often used with depressed older adults and has shown to be highly effective with patients who have depression in hospital and community settings and in individual and group formats [9,35,36]. CBT also seems to be of benefit in the management of bipolar disorder in lowering rate of relapse, improving medication compliance, and decreasing hospitalizations [35,37,38]. Interpersonal therapy IPT is a practical, focused, brief, and manual-based therapy applicable in the treatment of depression in older adults in acute phase and in relapse prevention. It focuses on disturbance of patients’ current relationships in the domains of role transition, role dispute, abnormal grief, and interpersonal deficit. The aim is improving communication, expressing affect, and supporting renegotiated roles in relationships, with the effect of symptom reduction and improvement in functionality [35,39–41]. Interpersonal therapy has shown clear benefit in depressed older adults [39,41]. Systems (family) therapy Systems (family) therapy attempts to correct distorted communications and relationships as a means of helping the entire family or system, including the identified patient. Depressive illness in late life is sometimes complicated by enmeshed and ‘‘high expressed emotion’’ family or systemic relationships. It is indicated if at least some part of the system (crucial members of the family) can be engaged in it. Controlled outcome studies of family therapies for depression suggest that the addition of problem-centered, family-based interventions may improve family function and enhance patient recovery from depressive symptoms [35].

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Cognitive analytical therapy or brief dynamic therapy CAT or brief dynamic therapy represents a modern integration of analytic and cognitive therapy traditions to offer a brief, structured, and collaborative therapeutic experience in a coherent way of linking the past and present. It realizes that later life can be a time when coping mechanisms are challenged by losses, disability, and changes in social role, which then can easily resurface pre-existing trauma and low self-esteem to produce affect deregulation and interpersonal difficulty. Patients who have personality disorders and past traumatic experiences living in highly dysfunctional relationship or isolation can get help from a dynamic or CAT approach [35,39,40]. Psychoeducation Psychoeducation provides patients and families with information about their diagnosis, its treatment, how to recognize signs of relapse, relapse prevention, and strategies to cope with the reality of prolonged emotional or behavioral difficulties. It can be a component of, or an adjunct to, other forms of therapy and may be directed toward the patient or the patient’s family. The main goal is to reduce distress, confusion, and anxiety within the patient or the patient’s family to facilitate treatment compliance and reduce the risk for relapse. In combination with primary treatments, psychoeducation is particularly helpful for patients and the families of patients who have bipolar disorder [35,42]. Neuromodulationdanother approach to mood disorders Apart from its psychopharmacotherapeutic approach, psychiatry has been using electroconvulsive therapy (ECT) as its sole device-based alternative for the treatment of a range of psychiatric disorders, including mood disorders, for almost 7 decades. The approval of vagus nerve stimulation (VNS) by the FDA in 2005 for treatment-resistant depression not only increased the options of these classes of treatment modalities in psychiatry but also opened a new paradigm in the understanding of mental illnesses. Other similar device-based brain stimulating methods, such as repetitive transcranial magnetic stimulation (rTMS) and deep brain stimulation (DBS) are evolving and have shown promising results to join this group of alternative strategies [43,44]. These device-based treatment strategies have a common target of modulating the neural circuitry of mood, unlike the neuronal synapse-based pharmacotherapeutic approaches. The various aspects of these modalities are compared in Table 3 [43–45]. It is another potentially exciting opportunity for the treatment of elderly patients who have mood disorders who are not responding to or tolerating pharmacotherapy. ECT has already been proven to be one. Electroconvulsive therapy ECT has remained an important and effective treatment of selected serious neuropsychiatric illnesses, including severe mood disorders. Since its

800

Table 3 Comparison of various neuromodulatory treatments for depression rTMS

DBS

Type of stimulus

Scalp electrical

Vagus nerve pulsated electrical

Site of stimulus

Unilateral or bilateral hemisphere Strong

Left vagus nerve Accepted

Pulsated magnetic field Left and right prefrontal cortex Possible for depression

Other indications

Mania, catatonia, NMS, schizoaffective, Parkinson

Refractory epilepsy, possible rapid cycling mania, bulimia

Deep brain, pulsated electrical Subgenual cingulate region Strong in treatment for refractory depression (limited data) Movement disorders, epilepsy

Session duration Sessions per course Length of treatment Common side effects

30 min 6–12 2–4 wk Memory impairment, headache, confusion, myalgias

Implant 60 min; office 30 min 6–12 month trial Minimum 3 mo Hoarseness (25%–50%), occasional dyspnea, neck discomfort

Effiacy

Possibly mania, OCD, schizophrenia, PTSD, catatonia, pain 10–30 min 15–20 3–4 wk Headache, dizziness, slight seizure risk

? ? ? Surgical risks, temporary weakness in the limbs, possible changes in cognitive function or infection at the site of implantation

Abbreviations: NMS, neuroleptic malignant syndrome; OCD, obsessive-compulsive disorder; PTSD, posttraumatic stress disorder. Adapted from O’Reardon JP, Peshek AD, Romero R, et al. Neuromodulation and transcranial magnetic stimulation. Psychiatry 2006;3(1):30–40, Table 1.

et al

VNS

GEBRETSADIK

ECT

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introduction in 1938 it has evolved into a sophisticated procedure with a proven track record of safety. It is used most commonly in the treatment of major depressive disorders, typically when patients fail to respond to or tolerate antidepressant medications, or when we do not have the luxury of time for the antidepressants to work. It also is used effectively in bipolar disorder in depressed, mixed, or manic states. ECT as first line of treatment has response rates in the 80% to 90% range, whereas patients who have failed to respond to an adequate trail of one or more antidepressants may respond in the range of 50% to 60% [46]. The response to ECT usually is faster than with medications, and it should be considered early or as first line when rapid and definitive response is urgent, as in agitated, psychotic, actively suicidal patients or patients whose medical condition is seriously compromised because of severe depression [46]. Elderly patients tend to have higher rates of medication intolerance, medical complications, and psychotic depression, thus resulting in earlier referral to ECT. ECT is given as unilateral or bilateral electrical stimulation under general anesthesia with a titrating dose for a total of 6 to 12 initial treatments two to three times each week [46]. For patients who relapse after their first course of ECT and for treatment-resistant depression, maintenance treatment for up to 6 months in a tapering manner is indicated to prevent relapse. The absolute contraindications for ECT are increased intracranial pressure and recent myocardial infarction. ECT is safe and has a mortality rate of 0.01%, most of which is related to cardiac complications [46]. Common side effects include acute confusion, anterograde amnesia, and retrograde amnesia. Acute confusion is related to the induction of seizure and anesthetic agents. It usually resolves in an hour but may take longer in the elderly. Anterograde amnesia usually resolves in 1 to 3 weeks after treatment, whereas retrograde amnesia, the most serious and rare of the three, takes a longer time to resolve. Patients are maintained on antidepressant medication after ECT to prevent relapse and maintain remission. Vagus nerve stimulation VNS initially was used and finally approved for treatment-refractory epilepsy in 1997. Noticing its mood-brightening effect on epilepsy patients, anatomic afferent connections of the left vagus nerve to the CNS and to structures relevant to mood regulation lead to studies being conducted to determine its effectiveness for depression [47]. Many of these studies demonstrated its long-term benefit for treatment-resistant depression, which resulted in its FDA approval in 2005 for the same indication [48–51]. So far studies have failed to show its effectiveness as monotherapy or in the acute setting [49,52]. VNS may be more promising as a long-term maintenance treatment to sustain remission than as an initial treatment to bring someone out of depression. Under general anesthesia, a pulse generator is implanted in the left chest wall and a wire threaded into the neck and around the left vagus nerve. The

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stimulator, similar to a cardiac pacemaker, is programmed through an external handheld device. This procedure is safe (the only common adverse effect is hoarseness) and causes fewer side effects than antidepressant medications and ECT [47,51]. Performing a surgical procedure under general anesthesia is a disadvantage as is the one-time high cost. Its safety and low side-effect profile makes it a good modality for selected elderly patients, although there is no adequate controlled data in this age group [43]. Repetitive transcranial magnetic stimulation rTMS uses an electric coil to generate a magnetic field that stimulates the cerebral cortex. It is well tolerated by patients and, in contrast to ECT, does not require the use of anesthesia and does not appear to cause cognitive impairment [44,53]. Randomized, controlled, and meta-analytic studies of rTMS have produced conflicting results [45,54–58]. A subsequent randomized trial of rTMS in 60 patients who had treatment-resistant depression did show a significantly higher rate of response in two active treatment groups (high-frequency left-sided rTMS and low-frequency stimulation to the right prefrontal cortex) compared with placebo; the absolute benefit, however, appeared to be relatively small [55]. rTMS seems most promising as an alternative to antidepressant medication or as something to offer patients w ho have depression who have not responded to medication before going on to ECT [43]. Once its benefit is established this is another safe and potential treatment option in the geriatric group. One study showed no significant benefit for treatment-resistant depression in the elderly, however [56]. rTMS is not FDA approved at the present time. Deep brain stimulation DBS is an FDA-approved treatment of refractory Parkinson disease and other movement disorders. Stimulating electrodes (w1 mm in diameter) are implanted stereotactically, through a scalp burr hole and under MRI visualization, into the subgenual cingulate region (Brodmann area 25), one lead on each side. The leads are connected to pulse generators placed in the chest. The stimulators are programmed using telemetry. Electrodes are directed to this metabolically overactive region in treatment-resistant depression. The high-frequency stimulation in DBS is believed to work by inhibiting neuronal activity. Patients selected for this procedure are severely and chronically ill and have not responded to any of the available treatment modalities, including, in most instances, ECT. Mayberg and colleagues published the results from their first 6 patients in March 2005, which demonstrated a remarkable outcome [59]. Five of the 6 patients experienced substantial respite from their depressive symptoms, and 4 remained well after 6 months of treatment. So far, fewer than 20 patients who have depression worldwide have undergone DBS [43]. Given its invasiveness and the need for more data, DBS would be reserved for patients who have

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depression who are severely impaired and have been refractory to all other treatment modalities [43]. Summary Mood disorders in the elderly are a growing source of morbidity and mortality. Unfortunately, mood disorders in later life frequently are not diagnosed and treated. Appropriate, prompt diagnosis and treatment of latelife mood disorders can significantly improve the quality of life of patients and families and may prove life saving. Current treatments can help most older adults with mood disorders. Future treatments are promising, particularly for those with treatment-resistant depression. References [1] Hybels CF, Blazer DG. Epidemiology of late life mental disorders. Clin Geriatr Med 2003; 19(4):663–96. [2] Burke WJ, Wengel SP. Late life mood disorders. Clin Geriatr Med 2003;19(4):777–97. [3] Gurland BJ. Epidemiology of psychiatric disorders. In: Sadavoy J, Jarvik LF, Grossberg GT, et al, editors. Comprehensive textbook of geriatric psychiatry. 3rd edition. New York: W.W. Norton and Company; 2004. p. 3–37. [4] Rovner BW, German PS, Brant LJ, et al. Depression and mortality in nursing homes. JAMA 1991;265(8):993–6. [5] von Ammon Cavanaugh S, Furlanetto LM, Creech SD, et al. Medical illness, past depression, and present depression: a predictive triad for in-hospital mortality. Am J Psychiatry 2001;158(1):43–8. [6] Frasure-Smith N, Lesperance F, Juneau M, et al. Gender, depression, and one-year prognosis after myocardial infarction. Psychosom Med 1999;61(1):26–37. [7] Holly C, Murrell SA, Mast BT. Psychosocial and vascular risk factors for depression in the elderly. Am J Geriatr Psychiatry 2006;14(1):84–90. [8] Bruce ML, Ten Have TR, Reynolds CF 3rd, et al. Reducing suicidal ideation and depressive symptoms in depressed older primary care patients: a randomized controlled trial. JAMA 2004;291(9):1081–91. [9] Alexopoulos GS. Late life mood disorders. In: Sadavoy J, Jarvik LF, Grossberg GT, et al, editors. Comprehensive Textbook of Geriatric Psychiatry, 3rd edition. New York: W.W. Norton and Company; 2004. p. 609–53. [10] Reynolds CF 3rd, Dew MA, Frank E, et al. Effects of age at onset of first lifetime episode of recurrent major depression on treatment response and illness course in elderly patients. Am J Psychiatry 1998;155(6):795–9. [11] Birrer RB, Vemuri SP. Depression in later life: a diagnostic and therapeutic challenge. Am Fam Physician 2004;69:2375–82. [12] Cole MG, Dendukuri N. Risk factors for depression among elderly community subjects: a systematic review and meta-analysis. Am J Psychiatry 2003;160(6):1147–56. [13] Boswell EB, Stoudemire A. Major depression in the primary care setting. Am J Med 1996; 101:3S–9S. [14] Conway CR, Steffens DC. Geriatric depression: further evidence for the ‘vascular depression’ hypothesis. Curr Opin Psychiatry 1999;12(4):463–70. [15] Alexopoulos GS, Meyers BS, Young RC, et al. ‘Vascular depression’ hypothesis. Arch Gen Psychiatry 1997;54:915–22. [16] Pohjasvaara T, Leppavuori A, Siira I, et al. Frequency and clinical determinants of poststroke depression. Stroke 1998;29(11):2311–7.

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[17] Morris PL, Robinson RG, Raphael B. Prevalance and course of depressive disorders in hospitalized stroke patients. Int J Psychiatry Med 1990;20(4):349–64. [18] Lapid MI, Rummans TA. Evaluation and management of geriatric depression in primary care. Mayo Clin Proc 2003;78:1423–9. [19] Wylie M, Mulsant B, Pollock B, et al. Age at onset in geriatric bipolar disorder: effects on clinical presentation and treatment outcomes in an inpatient sample. Am J Geriatr Psychiatry 1999;7(1):77–83. [20] Young R, Klerman G. Mania in late life: focus on age at onset. Am J Psychiatry 1992;149: 867–76. [21] Shulman K, Herrmann N. The nature and management of mania in old age. Psychiatr Ann 2000;30:473–80. [22] Steffens C, Krishnan R. Structural neuroimaging and mood disorders: recent findings, implications for classification, and future directions. Soc Biol Psychiatry 1998;43: 705–12. [23] Sajatovic M, Bingham R, Campbell E, et al. Bipolar disorder in older adult inpatients. J Nerv Ment Dis 2005;193(6):417–9. [24] Diagnostic and Statistical Manual of Mental Disorders. 4th edition, text revision. Washington D.C: American Psychiatric Association; 2000. p. 168–71. [25] Raj A. Depression in the elderly: tailoring medical therapy to their special needs. Postgrad Med 2004;115(6):26–42. [26] Lyness JM, King DA, Cox C, et al. The importance of subsyndromal depression in older primary care patients: prevalence and associated functional disability. J Am Geriatr Soc 1999; 47:647–52. [27] Lebowitz BD, Pearson JL, Schneider LS, et al. Diagnosis and treatment of depression in late life: consensus statement update. JAMA 1997;278:1186–90. [28] Raue PJ, Alexopoulos GS, Bruce ML, et al. The systematic assessment of depressed elderly primary care patients. Int J Geriatr Psychiatry 2001;16:560–9. [29] Mulsant BH, Alexopoulos GS, Reynolds CF 3rd, et al. PROSPECT Study Group. Pharmacological treatment of depression in older primary care patients: the PROSPECT algorithm. Int J Geriatr Psychiatry 2001;16(6):585–92. [30] Baldessarini RJ, Tondo L, Hennen J. Treating the suicidal patient with bipolar disorder: reducing suicide risk with lithium. Ann N Y Acad Sci 2001;932:24–38. [31] Tondo L, Hennen J, Baldessarini RJ. Lower suicide risk with long-term lithium treatment in major affective illness: a meta-analysis. Acta Psychiatr Scand 2001;104:163–72. [32] Bowden CL. The ability of lithium and other mood stabilizers to decrease suicide risk and prevent relapse. Curr Psychiatry Rep 2000;2:490–4. [33] Bruce ML, Ten Have TR, Reynolds CF 3rd, et al. Reducing suicidal ideation and depressive symptoms in depressed older primary care patients: a randomized controlled trial. JAMA 2004;291(9):1081–91. [34] Rosack J. FDA orders new warning on atypical antipsychotics. Psychiatr News 2005;40(9):1. [35] Hepple J. Psychotherapies with older people: an overview. Adv Psychiatr Treat 2004;10: 371–7. [36] Dobson KS. A meta analysis of the efficacy of cognitive behavioral therapy in depression. J Consult Clin Psychol 1989;57(3):414–9. [37] Lam DH, Watkins ER, Hayward P, et al. A randomized controlled study of cognitive therapy for relapse prevention for bipolar affective disorder: outcome of the first year. Arch Gen Psychiatry 2003;60(2):145–52. [38] Scott J, Garland A, Moorhead S. A pilot study of cognitive therapy in bipolar disorders. Psychol Med 2001;31(3):459–67. [39] Hollon SD, Thase ME, Markowitz JC. Treatment and prevention of depression. Psychological Science in the Public Interest 2002;3:39–77. [40] Hollon SD. Psychotherapy research with older populations. Am J Geriatr Psychiatry 2003; 11(1):7–8.

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[41] Miller MD, Frank E, Cornes C, et al. The value of maintenance interpersonal psychotherapy (IPT) in older adults with different IPT Foci. Am J Geriatr Psychiatry 2003;11:97–102. [42] Seltzer A, Roncari I, Garfinkel P. Effect of patient education on medication compliance. Can J Psychiatry 1980;25(8):638–45. [43] Brown WA. Brain stimulation methods for treating depression. Appl Neurology 2006;2(2). Available at: http://www.appneurology.com/article/printableArticle.jhtml/?articleId=181500920 &printableArticle=true. [44] Schlaeper T, Kosel M. Novel physical treatments for major depression: vagus nerve stimulation, transcranial magnetic stimulation and magnetic seizure therapy. Curr Opin Psychiatry 2004;17(1):15–20. [45] O’Reardon JP, Peshek AD, Romero R, et al. Neuromodulation and transcranial magnetic stimulation. Psychiatry 2006;3(1):30–40. [46] Greenberg RM, Keller CH. Electroconvulsive therapy: a selected review. Am J Geriatr Psychiatry 2005;13(4):268–81. [47] George MS, Sackeim HA, Rush AJ, et al. Vagus nerve stimulation: a new tool for brain research and therapy. Biol Psychiatry 2000;47:287–95. [48] Nahas Z, Marangell LB, Husain MM, et al. Two year outcome of vagus nerve stimulation (VNS) for treatment of major depressive episodes. J Clin Psychiatry 2005;66(9):1097–104. [49] Bender KJ. Study expands on vagus nerve stimulation for depression. Psychiatric Times [serial online]. 2001;18(4). Available at: http://www.psychiatrictimes.com/p0104vagus.html. Accessed August 2006. [50] Rosenbaum JF, Heninger G. Vagus nerve stimulation for treatment resistant depression. Biol Psychiatry 2000;47(4):273–5. [51] Rush AJ, George MS, Sackeim HA, et al. Vagus nerve stimulation (VNS) for treatmentresistant depression: a multicenter study. Biol Psychiatry 2000;47(4):276–86. [52] Rush AJ, Marangell LB, Sackeim HA, et al. Vagus nerve stimulation for treatment-resistant depression: a randomized, controlled acute phase trial. Biol Psychiatry 2005;58(5):347–54. [53] Martis B, Alam D, Dowd SM, et al. Neurocognitive effects of repetitive transcranial magnetic stimulation in severe major depression. Clin Neurophysiol 2003;114(6):1125–32. [54] Ebmeier KP, Lappin JM. Electromagnetic stimulation in psychiatry. Adv Psychiatr Treat 2001;7:181–8. [55] Fitzgerald PB, Brown TL, Marston NA, et al. Transcranial magnetic stimulation in the treatment of depression: a double blind, placebo-controlled trial. Arch Gen Psychiatry 2003; 60(10):1002–8. [56] Mosimann UP, Schmitt W, Greenberg BD, et al. Repetitive transcranial magnetic stimulation: a putative add-on treatment for major depression in elderly patients. Psychiatry Res 2004;126(2):123–33. [57] Fabre I, Galinowski A, Oppenheim C, et al. Antidepressant efficacy and cognitive effects of repetitive transcranial magnetic stimulation in vascular depression: an open trial. Int J Geriatr Psychiatry 2004;19(9):833–42. [58] Couturier JL. Efficacy of rapid-rate repetitive transcranial magnetic stimulation in the treatment of depression: a systematic review and meta-analysis. J Psychiatry Neurosci 2005;30(2): 83–90. [59] Mayberg HS, Lozano AM, Voon V, et al. Deep brain stimulation for treatment-resistant Depression. Neuron 2005;45:651–60.

Med Clin N Am 90 (2006) 807–824

Falls and Their Prevention in Elderly People: What Does the Evidence Show? Laurence Z. Rubenstein, MD, MPHa,b,*, Karen R. Josephson, MPHb a

Department of Medicine, David Geffen School of Medicine at UCLA, 10945 Le Conte Ave., Los Angeles, CA, 90095, USA b Geriatric Research Education & Clinical Center (GRECC), VA Sepu´lveda Ambulatory Care Center & Nursing Home, 16111 Plummer Street, North Hills, CA 91343, USA

Falls are a common and complex geriatric syndrome that cause considerable mortality, morbidity, reduced functioning, and premature nursing home admissions. Falls have multiple precipitating causes and predisposing risk factors, which make their diagnosis, treatment, and prevention a difficult clinical challenge. A fall may be the first indicator of an acute problem (infection, postural hypotension, cardiac arrhythmia), may stem from a chronic disease (parkinsonism, dementia, diabetic neuropathy), or simply may be a marker for the progression of ‘‘normal’’ age-related changes in vision, gait, and strength. Moreover, most falls that are experienced by older persons have multifactorial and interacting predisposing and precipitating causes (eg, a trip over an electrical cord contributed to by a gait disorder and poor vision). Fig. 1 provides the complex relationship between selected risk factors, underlying causes, precipitating events, and falls. Identifying effective interventions to prevent falls and fall-related injuries among older adults is a major area of research and policy development in geriatrics. Several published clinical guidelines review the evidence for fall prevention strategies and provide recommendations for assessment and intervention. In the past few years there has been a major increase in the number of randomized controlled trials that have evaluated various fall prevention interventions. Meta-analysis of these trials has provided more evidence on efficacy. These clinical guidelines and the extensive fall prevention literature provide much needed insight into the difficult clinical challenge of fall prevention. This article provides a brief overview of the * Corresponding author. Geriatric Research Education & Clinical Center (GRECC), VA Sepu´lveda Ambulatory Care Center & Nursing Home, North Hills, CA 91343. E-mail address: [email protected] (L.Z. Rubenstein). 0025-7125/06/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.mcna.2006.05.013 medical.theclinics.com

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Intrinsic Risk Factors Gait & balance impairment Peripheral neuropathy Vestibular dysfunction Muscle weakness Vision impairment Medical illness Precipitating Causes Advanced age • Trips & slips Impaired ADL • Drop attack Orthostasis • Syncope Dementia • Dizziness Drugs

• • • • • • • • • • •

FALL

Extrinsic Risk Factors

• Environmental hazards • Poor footwear • Restraints

Fig. 1. The multifactorial and interacting causes of falls.

epidemiology of falls, their major causes and risk factors, the types of available fall prevention interventions, and a review of the latest evidence on the efficacy of these interventions.

Epidemiology Falls are extremely common among older adults. Each year about one out of three people older than age 65 years who is living in the community falls; this rate increases with advanced age and is higher among people who are living in institutional settings. Falls cause considerable mortality and morbidity. About three fourths of deaths that are due to falls in the United States occur in the 13% of the population that is aged 65 and older [1]. Fallrelated mortality increases dramatically with advancing age, especially in populations older than age 70 years. The estimated 1% of fallers who sustain a hip fracture have a 20% to 30% mortality within 1 year of the fracture [2]. The propensity for fall-related injury in elderly persons is due to a high prevalence of clinical diseases (eg, osteoporosis) and age-related physiologic changes (eg, slowed protective reflexes) that make even a mild fall particularly dangerous. Although most falls produce no serious injury, between 5% and 10% of community-dwelling older persons who fall each year do sustain a serious injury, such as a fracture, head injury, or serious laceration [3,4]. Fall-related injuries often are associated with considerable long-term morbidity. Among community-dwelling fallers with hip fractures, between 25% and 75% do not recover their prefracture level of function in ambulation or activities of daily living [2].

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In addition to death and physical injuries, falls can produce other serious consequences. Repeated falls are a common reason for the admission of previously independent elderly persons to long-term care institutions. Fear of falling also has been recognized as a negative consequence of falls. Surveys have reported that between 30% and 73% of older persons who have fallen acknowledge a fear of falling [5–7]. This postfall anxiety syndrome can result in self-imposed activity restrictions among home-living [6,8] and institutionalized elderly fallers [9]. Loss of confidence in the ability to ambulate safely can result in further functional decline [10], depression, feelings of helplessness, and social isolation.

Causes and risk factors Table 1 summarizes the major causes of falls and their relative frequencies as reported in 12 studies: six were conducted among institutionalized populations and six were conducted among community-living populations [11]. Although the accuracy of these findings is limited by several factors (including differences in classification methods, patient recall, and the multifactorial nature of many falls), these data provide useful general information about the reasons for falls among older adults. So-called ‘‘accidents,’’ or falls that are triggered by environmental hazards, make up the largest fall cause category, and account for 25% to 45% in most series. In actuality, few ‘‘accidental falls’’ result from environmental hazards alone, but rather are the result of interactions between hazards or hazardous activities and increased individual susceptibility from accumulated effects of age and disease. For instance, age-associated changes in posture control, muscle strength, and step height can impair a person’s ability to avoid a fall after an unexpected trip or while reaching or bending. These types of falls are more common in community-living populations, probably because of the greater attention to creating hazard-free environments in institutions. The other major fall causes are related more directly to age-related changes or specific diseases. Overall, frail, high-risk populations tend to have more of these medical-related falls than do healthier populations. Because a single specific cause for falling often cannot be identified and because falls are usually multifactorial in their origin, many investigators have performed epidemiologic case-control studies to identify specific risk factors. A risk factor is defined as a characteristic that is found significantly more often in individuals who subsequently experience an adverse event than in individuals who do not experience the event. Although there are some differences in risk factors between community-living and institutionalized populations, most overlap. An analysis of the 16 fall risk factor studies that reported quantitative risk data summarized the relative risks of falls for persons with each risk factor [11]. Eight of these studies were conducted in community-dwelling populations and 8 were conducted in nursing home

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Table 1 Causes of falls in older persons: summary of 12 large studies Cause

Mean (%)a

Rangeb

Accident and environment related Gait and balance disorders or weakness Dizziness and vertigo Drop attack Confusion Postural hypotension Visual disorder Syncope Other specified causesc Unknown

31 17 13 9 5 3 2 0.3 15 5

1–53 4–39 0–30 0–52 0–14 0–24 0–5 0–3 2–39 0–21

Summary of 12 studies [11,26–36]. a Mean percent calculated from the 3628 reported falls. b Ranges indicate the percentage reported in each of the 12 studies. c This category includes arthritis, acute illness, drugs, alcohol, pain, epilepsy, and falling from bed.

populations. The ranks and mean relative risk data for the most commonly reported risk factors are listed in Table 2. Some of these are involved directly in causing falls (eg, weakness, gait and balance disorder), whereas others are more markers of other underlying causes (eg, previous falls, assistive device, age O80 years). Among these studies, leg weakness (detected by functional testing or manual muscle examination) was identified as the most potent risk factor associated with falls, and increased the odds of falling, on average, by more Table 2 Risk Factors for falls identified in 16 studies examining multiple risk factors: results of univariate analysis Risk factor

Significant/totala

Mean RR-ORb

Range

Lower extremity weakness History of falls Gait deficit Balance deficit Use assistive device Visual deficit Arthritis Impaired ADL Depression Cognitive impairment Age O80 y

10/11 12/13 10/12 8/11 8/8 6/12 3/7 8/9 3/6 4/11 5/8

4.4 3.0 2.9 2.9 2.6 2.5 2.4 2.3 2.2 1.8 1.7

1.5–10.3 1.7–7.0 1.3–5.6 1.6–5.4 1.2–4.6 1.6–3.5 1.9–2.9 1.5–3.1 1.7–2.5 1.0–2.3 1.1–2.5

a Number of studies with significant odds ratio or relative risk ratio in univariate analysis/ total number of studies that included each factor. b Relative risk ratio (RR) calculated for prospective studies. Odds ratio (OR) calculated for retrospective studies. Data from Rubenstein LZ, Josephson KR. The epidemiology of falls and syncope. Clin Geriatr Med 2002;18:141–58.

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than four times (4.4; range, 1.5–10.3). A recent meta-analysis that examined the relationship between muscle weakness and falls among purely prospective studies reported that leg weakness had a combined odds ratio of 1.76 for any fall and 3.06 for recurrent falls [12]. In addition to having a strong association with falls, leg weakness is common in older persons. As a group, healthy older people score 20% to 40% lower on strength tests than do young adults [13], and the prevalence of detectable leg weakness ranges from 57% among residents of an intermediate-care facility [14] to more than 80% among residents of a skilled nursing facility [15]. Weakness often stems from deconditioning that is due to limited physical activity or prolonged bed rest together with chronic debilitating medical conditions, such as heart failure, stroke, or pulmonary disease. Individuals who have fallen have a threefold increased risk of falling again. Although recurrent falls in an individual frequently are due to the same underlying cause (eg, gait disorder, orthostatic hypotension), they also can be an indication of disease progression (eg, parkinsonism, dementia) or a new acute problem (eg, infection, dehydration). Gait and balance disorders also are common among older adults, and affect between 20% and 50% of people who are older than 65 years [16,17]. Among nursing home populations, nearly three quarters of residents require assistance with ambulation or are completely unable to ambulate [18]. Gait and balance impairments were a significant risk factor for falls, and were associated with about a threefold increased risk for falling; the use of an assistive device for ambulation was associated with a 2.6-fold increased risk for falling. Visual impairment increases the risk for falling about 2.5 times. At least 18% of noninstitutionalized persons who are 70 years and older have substantial visual impairment [19]. The primary causes include cataracts, glaucoma, and macular degeneration. Arthritis, the most common chronic condition in persons 70 years and older in the United States [19], increases the risk for falling about 2.4 times. The relationship between arthritis and falls most likely is related to the gait impairment and weakness that often are associated with arthritis. Functional impairment, usually indicated by the inability to perform basic activities of daily living (ADLs; eg, dressing, bathing, eating), doubles the risk for falling. In the community, ADL impairment affects 20% of persons who are older than age 70 [19]. In the nursing home setting, the prevalence of functional impairment is much higher; 96% of nursing home residents require assistance with bathing and 45% require assistance with eating [18]. Depression is associated with about a twofold increased risk for falling. Although the relationship between depression and falls is not well studied, depression may result in inattention to the environment, or cause more risk-taking behaviors. Conversely, it may be a reaction to previous fallrelated morbidity and not be an actual causative risk at all. Additionally, psychotropic medications increase fall risk [20,21]. Common risk factors

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have been identified for depression and falls (ie, poor self-rated health, cognitive impairment, functional impairment, slow gait speed) [22]. Mild depressive symptoms occur in close to one quarter of the older population, and about 5% of this population suffers major depression [23]. Cognitive impairment almost doubles the risk for falling. In a recent study among residents of 59 nursing homes, the unadjusted fall rate for residents who had dementia was 4.05 falls per year compared with 2.33 falls per year for residents who did not have dementia (P ! .0001; adjusted relative risk, 1.74) [24]. Confusion and cognitive impairment are cited frequently as causes of falls, and may reflect an underlying systemic or metabolic process (eg, electrolyte imbalance, fever), as well as a dementing illness. Dementia can increase falls by impairing judgment, visuospatial perception, and orientation ability. Falls also occur when demented residents wander, attempt to get out of wheelchairs, or climb over bed side rails. Cognitive impairment affects between 5% and 15% of persons who are older than age 65, and the prevalence increases with age and among institutionalized populations. The risk for falls also is nearly double for individuals who are older than the age of 80. This is probably due to the increasing prevalence of multiple risk factors associated with age. The relationship between medication use and falls also has been examined in many studies. A meta-analysis [20,21] found a significantly increased risk from psychotropic medication (odds ratio [OR], 1.7), class 1a antiarrhythmic medications (OR, 1.6), digoxin (OR, 1.2), and diuretics (OR, 1.1). Several studies also showed a strong relationship between the use of three or more medications and the risk for falls [15,15–26]. Although the sizes of these odds ratios are not as large as those for the previous set of risk factors, they are statistically and clinically significant. Several of the studies (see Table 2) used multivariate analysis to understand better the possible interactions between the individual risk factors and to rank their relative importance. The risk factors and relative ranks that emerged from these analyses were similar to the univariate factors, although the size of risk was altered for some of them. Muscle weakness remained the dominant risk factor with a fourfold increased risk for falls (range, 3.0–5.9), and balance deficits and history of falls still were associated with about a threefold increased risk for falls. Cognitive impairment, age greater than 80 years, and visual impairments increased in magnitude to about a threefold increased risk, whereas gait deficits declined to a twofold increased risk for falls in the multivariate analyses [11]. Many other case-control studies have examined the relationship between falls and single possible risk factors in isolation. For example, several studies examined the relationship of leg strength alone and fall status without exploring other possibly confounding risk factors. Gehlsen and Whaley [27] reported that healthy older persons with a history of falling had significantly weaker leg strength than did nonfallers. Whipple and colleagues [28]

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examined knee and ankle strength, and reported that weakness at both joints was significantly more common among institutionalized fallers than nonfallers. They also performed gait analysis of 49 nursing home patients, and found that fallers had significantly slower gait speed and shorter stride length than did nonfallers [29]. Studenski and colleagues [30] found that outpatients with impaired mobility had a significantly higher rate of recurrent falls over a 6-month period. Other studies have compared measures of dynamic balance in older fallers and nonfallers. Deficit in the ability to control lateral stability was associated with an increased risk for falling in a healthy ambulatory population [31]. Other single-variable risk factor studies documented significant relationships between falls and single leg stance [32], postprandial hypotension [33], impaired depth perception [34], musculoskeletal pain [35], and foot problems [36], to name only a few. Probably as important as identifying risk factors for falling per se is identifying risk factors for injurious falls, because most falls do not result in injury. Risk factors that are associated with injurious falls have been identified by several research groups [29,37–39]. Among community-living populations, risk factors that were identified as increasing the likelihood of an injurious fall include having a previous fall with a fracture, being Caucasian, having impaired cognitive function, and having impaired balance. A survey of elderly Medicaid enrollees revealed that the risk for hip fracture increased twofold for community-living elderly persons and nursing home residents who were taking psychotropic medications [40]. Narcotic analgesics, anticonvulsants, and antidepressants were identified as independent risk factors for injurious falls among community-living older adults who received care in emergency departments [39]. Among nursing home residents, lower extremity weakness, female sex, poor vision and hearing, disorientation, number of falls, impaired balance, dizziness, low body mass, and use of mechanical restraints have been identified as increasing the risk for an injurious fall [41–44]. Surprisingly, patients who were functionally independent and not depressed also had a greater risk for injury [44], probably because they were more active. Taken together, the risk factors for injurious falls are the same as for falls in general, with the addition of female sex and low body mass (both probably largely related to osteoporosis), and higher activity level. Beyond identifying individual risk factors, it is important to understand the interaction and probable synergism between multiple risk factors. Several studies showed that the risk for falling increases dramatically as the number of risk factors increases [14,15,37,45]. In their survey of community-living elderly persons, Tinetti and colleagues [45] reported that the percentage of persons falling increased from 27%, among those with none or one risk factor, to 78% among those with four or more risk factors. Their identified risk factors included sedative use, decreased cognition, leg and foot disabilities, gait and balance impairments, and the presence of primitive reflexes. Similar results were found among an institutionalized population [14]. In another study, Nevitt and colleagues [37] reported that the

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percentage of community-living persons with recurrent falls increased from 10% to 69% as the number of risk factors increased from one to four or more. Their identified risk factors included white race, a history of falls, arthritis, parkinsonism, difficulty rising, and poor tandem gait. In a study by Robbins and colleagues [15] that involved an institutionalized and outpatient population, many individual risk factors were related significantly to falls. Multivariate analysis simplified the model so that maximum predictive accuracy could be obtained using only three risk factors (ie, hip weakness assessed manually, unstable balance, and taking four or more prescribed medications) in a branching logic, algorithmic fashion. With this model the predicted 1-year risk for falling ranged from 12% for persons with none of the three risk factors to 100% for persons with all three risk factors. In summary, studies have shown that it is possible to identify persons who are at a substantially increased risk for sustaining a fall or fall-related injury by detecting the presence of risk factors. Many, if not all, of these risk factors are amenable to treatment or rehabilitative approaches to ameliorate them. Consequently, risk factor identification seems to be a promising first step in developing effective fall-prevention programs that are targeted to high-risk patients. To assist clinicians in the assessment of fall risk, evidence-based clinical practice guidelines on fall prevention and treatment were published by the American and British Geriatrics Societies [46]. Among other things, the guidelines recommend that a fall risk assessment be an integral part of primary health care for older persons, with the intensity of the assessment tailored to the target population (eg, low-risk versus high-risk individuals). Several published fall risk assessment tools are available for quantifying fall risk for older persons at home and in institutional settings. An analytic review of these assessment tools recommended several that seem to be valid and potentially useful [47]. Although the importance of fall risk factor identification is accepted generally, the question of how best to modify these risk factors to prevent falls continues to be a challenge for clinicians and researchers. Prevention strategies In general, fall prevention interventions can be categorized into several broad categories: multidimensional fall risk assessment coupled with risk reduction, exercise programs of various types, environmental assessment and modification, multifactorial interventions, and institutional interventions. Although the goal of preventing falls is common to each type of intervention, the approach taken by each is different. Multidimensional fall risk assessment and risk reduction The objectives of the multidimensional fall risk assessment is to identify risk factors for future falls and to implement appropriate interventions to

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reduce fall risk. The multidimensional fall risk assessment can be comprehensive or focused, depending on the target population. Comprehensive multidimensional fall risk assessment is most appropriate for high-risk individuals (eg, those who have just fallen or have multiple risk factors for falls), whereas a focused assessment generally is more appropriate for individuals of average risk (eg, independent community-living elderly populations). Clinical guidelines [46] recommend that a comprehensive multidimensional fall risk assessment should include the following: a history of fall circumstances and medical problems; review of medications; mobility assessment; an examination of vision, gait and balance, and lower extremity joint function; a basic neurologic examination, including muscle strength and mental status; and assessment of cardiovascular status. Other components of the fall risk assessment can include functional performance tests and an environmental assessment of the individual’s living location. Comprehensive multidimensional fall risk assessment usually is performed in a clinical setting (eg, clinic, day hospital, nursing home), often by a multidisciplinary team. Following the assessment a detailed plan for therapy usually is developed and implemented. This model of multidimensional fall risk assessment and risk reduction has been used in successful fall prevention trials for older patients who did or did not have cognitive impairment who presented to an emergency department after a fall [48,49], and for residents of a long-term care facility who experienced a fall [50]. Focused multidimensional fall risk assessment is used often to screen older populations to identify those who are appropriate for targeted interventions (eg, exercise programs, assistive devices, comprehensive fall risk assessment). Typically, this model of risk assessment includes simple performance-based tests of gait, balance, mobility, or strength, such as the Timed Up-and-Go test [51], the Performance Oriented Mobility Index [52], and the one-leg standing balance test [53]. Evaluations of vision, cognition, orthostatic blood pressure, and a review of medications also are included often. Focused multidimensional fall risk assessment has been performed frequently by nurses or therapists in clinics and in the home. Exercise interventions Numerous studies have shown that exercise can improve important fall risk factors, such as muscle weakness, poor balance, and gait impairment in healthy [54–56] and impaired older adults [57,58]. Consequently, exercise has become a widely studied fall prevention intervention. Different exercise models have been evaluated, including group [58–64] and individualized home programs [65–69], among healthy and impaired populations. Group exercise programs that are designed as fall prevention interventions typically are held two or three times per week for about an hour, and are supervised by a physical therapist or trained exercise instructor.

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Most group programs have included a combination of exercises to improve flexibility, strength, and balance, and some level of aerobic conditioning. Progressive strength training generally focuses on lower and upper extremity large muscle groups, and may use body weight, ankle weights, elastic bands, or weight machines for resistance. Balance training often includes a range of static and dynamic exercises (eg, standing on one foot, tandem stand, ball games, movement to music) and functional activities (eg, reaching, bending, transferring). To improve aerobic conditioning, exercise programs have used whole body exercises, walking and stair climbing and stationary bicycles. Although performed in a group setting, exercises usually are individualized to the participant’s abilities. Home exercise programs also are supervised by trained exercise professionals, but participants perform the exercises alone in their homes. In most published studies, participants attended a series of group meetings to learn and practice the exercises, and then were instructed to perform the exercises at home [66–68]. In other studies, a physical therapist or nurse visited participants at home several times over the course of the intervention to provide instruction and motivation to perform the exercises [65,69]. In both models, the participant performed the exercises unsupervised and kept a diary. Home exercise programs typically include the same types of exercises as do the group programs, only fewer and often at a lower intensity. Home exercise programs also incorporated a walking program frequently. Tai chi is another type of exercise that has been studied as a means of improving balance and reducing the risk for falling. Tai chi consists of a series of slow, rhythmic movements that require trunk rotation, dynamic weight shifting, and coordination between upper and lower extremity movements. Tai chi has been studied as group [62–64] and home programs [67]. Environmental assessment and modification Environmental assessment and modification is another promising fall prevention strategy, which is used as a means of identifying and removing potential hazards (eg, clutter, poor lighting, throw rugs) and for modifying the environment to improve mobility and safety (eg, installation of grab bars, raised toilet seats, lowered bed height). Several self-administered home safety checklists [70], which are designed for use by older people in their homes, assist in identifying important hazards and offer suggestions for improving safety. These checklists are most appropriate for use with average risk and cognitively intact older adults. For higher-risk populations, several fall prevention interventions [71–73] have used trained professionals, such as nurses or occupational therapists, to perform home environmental assessments. An in-home assessment provides an opportunity for the health care professional to observe how an older person functions within the home, which may help to identify safety problems that may not be identified with a self-administered checklist or interview.

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In institutional settings, environmental safety policies and practices are generally in place to protect patients and staff. Important safety issues for hospitals and nursing homes include adequate lighting and handrails in hallways, close monitoring for spilled liquids on the floors, unobstructed walkways, appropriate assistive devices in bathrooms (eg, grab bars, shower chairs, raised toilet seats), furniture that is easy to rise from, and proper bed height. Multifactorial interventions Multifactorial interventions are those that combine several fall prevention strategies into a coordinated program. Generally, multifactorial interventions include some degree of fall risk assessment, followed by one or more risk factor modification strategies, such as exercise, education, or environmental modification. One of the first multifactorial interventions that was described in the literature included a focused in-home risk assessment that was performed by a nurse and a physical therapist to identify selected fall risk factors (ie, postural hypotension, medication, impairments in mobility, vision, hearing, gait, balance, strength, and environmental hazards), followed by targeted interventions (ie, medication adjustment, environmental modifications, behavioral instructions, and exercise) [74]. Other multifactorial interventions that are designed for community-dwelling older adults have combined home environmental assessment, exercise, and cognitivebehavioral group education [71,75]. In residential care and nursing home facilities, multifactorial interventions often include prevention strategies for residents (eg, exercise, medication review, hip protectors), fall prevention education for staff, and facility-level environmental modifications [76–79]. On a subacute hospital ward, a multifactorial intervention included a falls risk alert card to identify high-risk patients, a fall prevention information brochure and education sessions for patients, balance exercises, and hip protectors [80]. Institutional interventions Fall risk assessment tools are used commonly in institutional settings to identify persons who are at greatest risk for sustaining a fall or fall-related injury, and to isolate specific risk factors that are amenable to intervention. There are many published assessment tools [47] that are used to assist health professions better target limited resources to those who would benefit most from preventive interventions. These instruments typically rank a person’s risk for falling as ‘‘high,’’ ‘‘medium,’’ or ‘‘low’’ based on the presence or absence of risk factors, such as cognitive impairment, mobility dysfunction, incontinence, acute/chronic illnesses, sensory deficits, medication use, and history of falling. The tools may or may not include physical assessments in addition to questions that rely on self-report. Most screening tools are

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brief and generally are administered by a nurse on admission to hospital or a nursing home, and usually are updated on a regular basis or when there is a change in health status. Once a patient has been identified as being at a high risk for falling, a nursing care plan usually is developed that includes interventions that are aimed at injury prevention. Such interventions can include indicating on the medical chart and the patient’s door that the patient is at a high risk for falls; moving high-risk patients to rooms that are close to the nursing station to increase observation; periodic reassessment of patients following new episodes of illness or change in medication; lowering side rails and bed height for patients who climb out of bed; increasing nurse-topatient ratio; use of bed and chair alarms; and fall prevention education for patients and staff. Until recently, the most common ‘‘devices’’ that were used in nursing homes and hospitals to prevent falls were physical restraints, such as soft restraining vests and bed rails. Over the past decade there has been a major move away from the use of physical restraints because research has shown that the adverse affects of physical restraints on functional status and quality of life outweigh any potential benefit in preventing falls. Specifically, there is evidence to suggest that physical restraints may contribute to falls, injuries, and death [81,82]. Other promising strategies that are aimed at reducing falls and fallrelated injuries in nursing homes include the use of vitamin D and calcium supplements to enhance bone and muscle strength [83,84], and the use of special hip protectors (worn in under garments shielding the greater trochanter of the hip) to prevent hip fractures that are due to falling [85,86]. Effectiveness of fall prevention strategies The recent heightened interest in finding effective fall prevention strategies has resulted in the publication of numerous studies. Studies have targeted healthy older adults; individuals who are at-risk for falling; community-living, hospitalized, and institutionalized populations; as well as caregivers and the home or institutional environment. Many intervention strategies have been evaluated, often unique to the study site, and there is great variation in duration and intensity of the intervention, outcome measurements, and length of follow-up. This diversity in the published literature has made it difficult to determine which type of intervention is most effective for preventing falls, and which target group of older adults will benefit most from which type of intervention. Fortunately, several study groups have performed meta-analyses of randomized controlled trials to assess the relative effectiveness of specific types of fall prevention interventions [87–89]. A recent meta-analysis [89] of randomized controlled trials of fall prevention interventions that were published through 2002 assessed the overall effectiveness of the overall interventions, as well as the relative effectiveness of intervention components: multidimensional risk assessment

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and management, exercise, environmental modifications, and education. The results of this meta-analysis indicate that the most effective fall prevention strategy used individualized multidimensional risk assessment combined with interventions that were directed toward reducing these risks. When analyzed as a group, interventions that used multidimensional risk assessment and risk reduction decreased the risk for falling by 18% and reduced the average number of falls by 43%. The next most effective single intervention that was identified in this meta-analysis was exercise that was intended to improve balance, strength, flexibility, or endurance. Overall, exercise interventions reduced the risk for falls by 12% and the mean number of falls by 19% [89]. Exercise was effective in reducing falls when used alone and when included as part of a multifactorial intervention. Exercise programs that were effective include Tai chi [62,67], balance and gait training, and strength building [60,65,66,76,79]. Although studies did not demonstrate that home modification alone reduces falls, several multifactorial interventions that included home modification were effective, particularly among individuals who had a history of falls [71–73,90]. Since this meta-analysis, many new trials of fall prevention interventions have been published, and these largely have been confirmatory of the conclusions of the meta-analyses. Randomized trials that have been most effective in reducing fall rates have involved multifactorial intervention programs, which is consistent with the concept that falls usually are the result of interactions between multiple intrinsic and extrinsic risk factors. The most effective interventions generally have included risk assessment; tailored exercise or physical therapy to improve gait, balance, and strength; medication management; and other elements, such as education about fall risk factors, referrals to health care providers for treatment of chronic conditions that may contribute to fall risk, and having vision assessed and corrected [48,73,75,90,91]. Another fall prevention intervention that seems to be effective in reducing fall rates is medication review and modification [92,93], particularly as part of a multicomponent intervention. A meta-analysis [83] of five randomized controlled trials reported that vitamin D supplementation seems to reduce the risk for falls by more than 20% among ambulatory or institutionalized older adults. The hypothesized mechanism is from a direct beneficial effect of vitamin D on neuromuscular function; however, the studies did not measure vitamin D levels at baseline, so it is not clear whether this apparent benefit stemmed from treating a deficiency or from a pharmacologic effect of the vitamin D in nondeficient individuals. Although hip protectors seem to be effective in preventing hip fracture in nursing home settings, their effect in community populations has not been demonstrated. This is likely because of poor patient compliance rates in the community. A meta-analysis [94] of six randomized trials concluded that hip protectors seem to reduce the risk for hip fracture in selected high-risk populations where compliance can be monitored closely.

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Considerations in designing fall prevention strategies From the above discussion it can be seen that fall prevention is a multifaceted endeavor. This stems from the multifactorial causes of falls, multiple contributing risk factors, fragility and lack of responsiveness by many older persons to interventions, and the double-edged effect of many intervention strategies that may increase one fall risk factor while reducing another. For example, although exercise is, and should be, encouraged as a positive goal that leads to higher function and quality of life, increased activity also provides additional opportunity for falling. The interaction between falls, activity levels, frailty, and injury needs to be studied much more carefully. Another issue has to do with the trade-off of targeting interventions only to those who are most likely to benefit. Although the impact per person enrolled is higher when narrowly targeting interventions, the population that is served by the intervention may be overly small and may have little overall effect on global fall rates. Finally, there are subgroups of individuals that have multiple or irreversible risk factors (eg, blindness, dementia, progressive neurologic diseases) for which it often is extremely difficult to devise effective interventions other than through dramatic limitation of physical activity. For these individuals the risks for falling must be weighed carefully against the not insubstantial risks of limiting activity. Summary A large proportion of falls and fall injuries in older people is due to multiple risk factors, many of which probably can be modified or eliminated with targeted fall prevention interventions. These interventions must be feasible, sustainable, and cost effective to be practical for widespread use. The most promising prevention strategies involve multidimensional fall risk assessment and exercise interventions. Incorporating these intervention strategies whenever feasible into a fall prevention program seems to be the most effective means for fall prevention in older adults.

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[75] Clemson L, Cumming RG, Kendig H, et al. The effectiveness of a community-based program for reducing the incidence of falls in the elderly: a randomized trial. J Am Geriatr Soc 2004;52:1487–94. [76] Jensen J, Nyberg L, Gustafson Y, et al. Fall and injury prevention in residential caredeffects in residents with higher and lower levels of cognition. J Am Geriatr Soc 2003;51:627–35. [77] Jensen J, Lundin-Olsson L, Nyberg L, et al. Fall and injury prevention in older people living in residential care facilities. Ann Intern Med 2002;36:733–41. [78] Dyer CA, Taylor GJ, Reed M, et al. Falls prevention in residential care homes: a randomized controlled trial. Age Ageing 2004;33:596–602. [79] Becker C, Kron M, Lindemann U, et al. Effectiveness of a multifaceted intervention on falls in nursing home resident. J Am Geriatr Soc 2003;51:306–13. [80] Haines TP, Bennell KL, Osborne RH, et al. Effectiveness of targeted falls prevention programme in subacute hospital setting: randomized controlled trial. BMJ 2004;328:676–9. [81] Tinetti ME, Liu WL, Ginter SF. Mechanical restraint use and fall-related injuries among residents of skilled nursing facilities. Ann Intern Med 1992;116:369–74. [82] Miles SH, Irvine P. Deaths caused by physical restraints. Gerontologist 1992;32:762–6. [83] Bischoff-Ferrari HA, Dawson-Hughes B, Willett WC, et al. Effect of vitamin D on falls: a meta-analysis. JAMA 2004;291:1999–2006. [84] Chapuy MC, Arlot ME, Duboeuf F, et al. Vitamin D3 and calcium to prevent hip fractures in the elderly women. N Engl J Med 1992;327:1637–42. [85] Lauritzen JB, Petersen MM, Lund B. Effect of external hip protectors on hip fractures. Lancet 1993;341:11–3. [86] Kannus PA. Effectiveness of hip protectors. Effectiveness of studied hip protector was uncertain. BMJ 2003;326:930. [87] Province MA, Hadley EC, Hornbrook MC, et al. The effects of exercise on falls in elderly patients: a preplanned meta-analysis of the FICSIT trials. JAMA 1995;273:1341–7. [88] Gillespie LD, Gillespie WJ, Cumming RG, et al. Interventions for preventing falls in elderly people. In: Cochrane Database Syst Rev 2003;4:CD000340. [89] Chang JT, Morton SC, Rubenstein LZ, et al. Interventions for the prevention of falls in older adults: systematic review and meta-analysis of randomized clinical trials. BMJ 2004;328: 680–3. [90] Day L, Fildes B, Gordon I, et al. Randomised factorial trial of falls prevention among older people living in their own homes. BMJ 2002;325(7356):128–33. [91] McMurdo MET, Millar AM, Dally F. A randomized controlled trial of fall prevention strategies in old peoples’ homes. Gerontology 2000;46:83–7. [92] Ray WA, Taylor JA, Meador KG, et al. A randomized trial of a consultation service to reduce falls in nursing homes. JAMA 1997;278:557–62. [93] Campbell AJ, Robertson MC, Gardner MM, et al. Psychotropic medication withdrawal and a home-based exercise program to prevent falls: a randomized, controlled trial. J Am Geriatr Soc 1999;47:850–3. [94] Parker MJ, Gillespie LD, Gillespie WJ. Hip protectors for preventing hip fractures in the elderly. In: The Cochrane Database Syst Rev 2003;3:CD001255.

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Urinary Incontinence: Selected Current Concepts Marget-Mary G. Wilson, MD, MRCPa,b,* a

Division of Geriatric Medicine, St. Louis University Health Sciences Center, 1402 South Grand Boulevard, Room M238, St. Louis, MO 63104, USA b Geriatric Research, Education, and Clinical Center, Veterans’ Administration Medical Center, Jefferson Barracks Division, 1 Jefferson Barracks Drive, St. Louis, MO 63125, USA

Introduction Urinary incontinence (UI) in older adults is a potentially life-threatening problem. Potential consequences include significant functional decline, impaired quality of life, frailty, institutionalization, and death [1,2]. Reported prevalence for urinary incontinence ranges from 15% among relatively healthy community-dwelling older adults to 65% among frail older adults [3,4]. Available figures most likely underestimate the true prevalence of UI for several reasons, including patient embarrassment, low rates of clinical detection, and lack of awareness of effective treatment options [5]. Health care costs for UI exceed $20 billion annually [6]. Additionally, the lifetime medical cost of treating an older adult who has urinary incontinence approaches $60,000 [7]. Added costs arising from complications of UI, such as loss of wages, poor quality of life, depression, and loss of self-esteem, increase the financial burden of UI even further [6].

Pathophysiology of urinary incontinence in older adults Age-related changes in bladder function set the stage for UI (Fig. 1). These include an increased frequency of uninhibited detrusor contractions, impaired bladder contractility, abnormal detrusor relaxation patterns, and reduced bladder capacity. There is also an age-related increase in the volume of nocturnal urine production. In men, prostatic size increases, whereas

* Division of Geriatric Medicine, St. Louis University Health Sciences Center, 1402 South Grand Boulevard, Room M238, St. Louis, MO 63104. E-mail address: [email protected] 0025-7125/06/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.mcna.2006.06.005 medical.theclinics.com

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Gender Anatomic Cultural Environmental Neurologic disease Childbirth Tissue disruption Pelvic surgery Constipation Occupation Obesity Surgery Advanced age Disease Dementia Drugs Debility Disease Environment Medications

Urinary Incontinence

Fig. 1. UI in the older adult: risk and predisposing factors.

urethral shortening and urethral sphincter weakening occur in women [8–11]. Aside from advancing age, other risk factors for UI include coexisting morbidity, cognitive dysfunction, functional impairment, gait abnormality, diuretic therapy, and obesity [3,12]. Female gender is an irreversible predisposing factor and mandates routine screening for UI in all women regardless of age. Anatomic genital abnormalities such as hypospadias, epispadias, and ambiguous genitalia may compromise continence. Coexisting illness, such as cerebrovascular disease, radical pelvic surgery, or autonomic neuropathy, may increase the risk for UI further [13,14]. Available data indicate that the occurrence of cerebrovascular disease doubles the risk for UI in the older woman. Obesity, frailty, and diabetes are strong predictors of the occurrence of UI Additionally, older adults are more likely to become incontinent following the onset of UI-promoting factors, such as constipation, obesity, and polyuria from uncontrolled hyperglycemia, hypercalcemia, or diuretic therapy [3,15,16]. Mechanistic classification of urinary incontinence UI can be categorized into five major groups: overactive bladder (OAB), stress incontinence, overflow incontinence, and functional incontinence; combinations of these categories constitute the fifth category, which is referred to as mixed incontinence. Symptoms of bladder hyperactivity and impaired contractility may coexist in patients who have diabetes mellitus. Likewise, benign prostatic enlargement can present with symptoms of bladder overactivity and urinary retention [17–19]. OAB occurs in one in four adults over the age of 65 years and accounts for 40% to 70% of all cases of UI in this cohort. Symptoms of OAB arise

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from involuntary contractions of the detrusor muscle at unusually low volumes of urine, resulting in a strong urge to pass urine. Clinically, OAB manifests with urgency, frequency, and nocturia, with or without urge incontinence [20]. People who have urge incontinence present with involuntary urine loss preceded by an urgent and compelling desire to void. Several physiologic mechanisms underlie detrusor muscle contraction. The major mechanism is cholinergic and is mediated through the effect of acetylcholine (Ach) on muscarinic bladder receptors. A second mechanism (purinergic) involves adenosine triphosphate- (ATP) mediated bladder contraction. A third non-neuronal mechanism probably exists, involving local uroepithelial Ach production and subsequent paracrine action on local muscarinic bladder. Available data indicate age-related compromise in cholinergic and purinergic bladder transmission. Purinergic transmission seems to play a greater role in bladder contraction with aging, suggesting disproportionate age-related compromise in cholinergic function. Available data also suggest an age-related compromise of non-neuronal uroepithelial Ach production [10,21]. Twenty-five percent of women who have UI present with symptoms of stress incontinence usually arising from anatomic or pathologic disruption of the angle between the bladder neck and the urethra. Causes of stress incontinence include vaginal childbirth and pelvic surgery, such as hysterectomy in women or prostate surgery in men. Generally, stress incontinence presents with involuntary urine loss associated with increases in intraabdominal pressure in the presence of a relatively incompetent urethral sphincter mechanism. In such patients, involuntary urine loss characteristically occurs when the patient laughs, coughs, or sneezes. In severe cases, UI may occur with a change in posture from supine or sitting to standing [22–24]. Overflow incontinence arises from bladder outlet obstruction that results in progressive bladder distension with a gradual increase in intravesical pressure until the mechanical outlet obstruction is overcome by sheer pressure. People who have overflow incontinence may complain of persistent trickling of urine in the presence of suprapubic distension or discomfort. In men, prostatic enlargement is the most common cause of overflow incontinence. Pelvic masses, such as uterine fibroids or cystoceles, may cause similar obstructive symptoms in women [25–27]. Functional incontinence refers to involuntary urine loss resulting from inability to gain prompt access to toileting facilities for reasons such as limited mobility, impaired cognition, lack of motivation, environmental barriers, or restricted access. This problem occurs commonly in frail elders who have dementia, cerebrovascular disease, Parkinson disease, or delirium. Altered mental status from narcotics, sedatives, or neuroleptic agents also may lead to functional UI [28,29]. Inappropriate use of physical or chemical restraints, poor vision, depression, reduced exercise tolerance, gait abnormality, or fear of falling are other causes of functional incontinence.

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Complications and consequences of urinary incontinence in elders Older adults who have urinary incontinence often experience embarrassment, loss of self-confidence, and poor self-esteem. Sixty percent develop depressive symptoms. Unpredictable episodes of UI may lead to withdrawal and social isolation. Limitation of physical activity in affected elders may compromise functional status and hasten progression to frailty. Intimate relationships may be avoided because of the fear of involuntary urine loss during sexual intercourse. Studies have shown an independent association between sexual dysfunction and urinary incontinence in older men [1,30–32]. Financially, UI can become burdensome. Protective garments and bedding often are not covered by insurance plans and are relatively expensive. Productivity of older adults in the workforce may be negatively affected by the threat of frequent and unpredictable episodes of incontinence. Likewise, the productivity of caregivers of patients who have UI may be compromised by their inability to cope with the demands of a relative who has urinary incontinence. Available data highlight UI as the most common cause of institutionalization of elders. Similarly, in long-term care facilities the resident who has urinary incontinence imposes an additional annual financial burden of approximately $5000 to total health care costs. [1,33]. In women aged over 65 years who have incontinence the incidence of falls and consequent fractures increases significantly. Approximately 20% to 40% of women who have UI will fall within 12 months and of these falls about 10% will result in fractures, usually of the hip. Available data show a strong association between UI, acute hospitalization, institutionalization, and death [34,35]. Thirty percent of women who have UI over the age of 65 years are likely to be hospitalized within 12 months. Older men are twice as likely to be hospitalized over a 12-month period. Of the myriad complications associated with UI, the most alarming is the independent association between UI and increased mortality [35]. Clinical assessment of the older adult who has urinary incontinence Health care providers should screen all older adults at risk for UI because few patients volunteer this information as a presenting complaint. Delayed presentation is not unusual and patients may not complain until symptoms become severe [36,37]. Providers should ask about the volume of urine lost, strength of urinary stream, body posture in which urine loss is most likely to occur, number of pads used, and associated fecal incontinence. Quality of life and caregiver burden should also be assessed. Additional information should be sought regarding risk factors and predisposing factors. Patients should be asked about a coexisting history of diabetes mellitus, hypercalcemia, impaired cognition, functional disability, or impaired sensory perception. Medication history is critical because diuretics or hyperosmolar

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infusions may contribute to polyuria and precipitate UI. Additionally, anticholinergic medications can cause obstruction and consequent overflow incontinence. Narcotics, sedatives, and hypnotics may impair cognition or cloud consciousness, thereby precipitating functional incontinence. An accurate voiding diary facilitates quantification, classification, and characterization of UI. Short voiding diaries (48 or 72 hours) have been shown to be just as reliable and valid as traditional 7-day diaries and are perceived as less burdensome by patients [38,39]. Physical examination must include a complete neurologic, abdominal, urogenital, pelvic, and rectal examination. Both the anal and bulbocavernosus reflexes should be assessed. Urethral sphincteric response to the cough reflex should be evaluated during pelvic examination to enable exclusion of stress incontinence. People who have stress incontinence may lose urine during coughing, whereas patients who have intact perineal reflexes exhibit tightening of the anal sphincter during coughing. Bedside measurement of postvoid residual volumes is helpful in the clinical diagnosis of overflow incontinence attributable to bladder outlet obstruction. Postvoid bladder residual volumes greater than 150 mL in the older adult suggest inadequate bladder emptying. Postvoid residual volumes greater than 200 mL indicate urinary retention. Where available, noninvasive bladder ultrasound measurements of postvoid residual volumes are preferred over direct measurement using a urethral catheter to minimize the risk for complicating urinary tract infection [40,41].

Practical management strategies Comprehensive physical examination should yield preliminary information relating to postvoid residual volumes and urethral sphincter competence. Providers should be aware of specific indications that prompt referral for specialist urologic evaluation. These include urinary retention attributable to obstructive uropathy, hematuria, prostate disease, recent pelvic surgery, recurrent urinary tract infections, and stress incontinence. Most older patients who have functional UI or urge incontinence associated with overactive bladder can be managed effectively by geriatric or primary care providers. Although urodynamic studies are frequently requested, available data indicate that results of these tests are unlikely to alter management in a significant proportion of older adults. Urodynamic studies are likely to be most helpful in older patients being considered for surgical intervention or in whom the diagnosis remains unclear after a thorough history and physical examination [42,43]. Guidelines issued by the Agency for Health care Policy and Research recommend limitation of initial diagnostic workup to urinalysis and measurement of postvoid residual volumes. The American Medical Director Association’s (AMDA) guidelines for the management of UI are

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even more conservative, recommending urinalysis only in patients who have suspected urinary tract infection and new or worsening UI. AMDA guidelines recommend postvoid residual measurements only in men and in female patients at risk for retention because of coexistent neurologic disorders or diabetes mellitus [44,45]. Bedside cystometric studies are no longer recommended for evaluation of UI because of poor correlation with results of urodynamic studies. In addition, bedside cystometry results usually do not alter management initiated based exclusively on clinical criteria [46,47]. The increased risk for urinary tract infection associated with urethral catheterization is an additional disadvantage of bedside cystometry [48]. Nonpharmacologic management should be the first line of therapy in all cases. In the subset of patients who fail to respond, the addition of pharmacologic agents is a viable option [49,50]. The increased risk for adverse drug effects and interactions in older adults, however, mandates due caution with drug selection and dosing. Invasive procedures or definitive surgical intervention occasionally are warranted in older adults who can tolerate such procedures. Nonpharmacologic treatment Nonpharmacologic intervention strategies vary with the type of UI. In patients who have OAB the mainstay of nonpharmacologic management is behavior modification tailored to suit the individual patient. Mentally competent, functionally intact, and highly motivated people are good candidates for patient-dependent intervention, such as biofeedback therapy. Caregiver-dependent toileting protocols are more appropriate in dependent or cognitively impaired patients. Prompted voiding is a caregiver-dependent strategy that offers the patient a regular opportunity to toilet. The designated caregiver offers toileting assistance at scheduled intervals, usually starting with a short period of about 2 hours. Prompted voiding has the added advantage of providing the patient an opportunity for social interaction and positive reinforcement. Habit training is a more complex variant of this method in which people who have UI are encouraged to link voiding to specific activities, such as meals, drinks, or just before outings. Eventually, regular toileting becomes a habit and involuntary urine loss is preempted. In older adults who have severe cognitive impairment and are unable to respond to communication a simple timed toileting schedule may be more helpful. In such cases the caregiver toilets the patient consistently at predetermined intervals. Prompted voiding and habit training also are helpful in the management of older adults who have functional incontinence. Environmental assessment, and modification if indicated, is critical to the effective management of functional UI. Adaptive equipment and assistive appliances may help facilitate efficient toileting and reduce incontinent episodes. Rehabilitative exercises focusing on pelvic muscles and biofeedback therapy can be helpful in patients who have stress incontinence or mixed

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incontinence. In patients who have mixed incontinence a combination of pelvic floor exercises and bladder sphincter biofeedback therapy has been shown to result in a reduction in episodes of involuntary loss [51]. Pharmacologic therapy Detrusor muscle contraction depends on the action of Ach on bladder muscarinic receptors. Antimuscarinic drugs therefore are effective in the treatment of overactive bladder. Side effects, such as delirium, cognitive impairment, orthostatic hypotension, falls, and cardiac arrhythmias, mandate caution in the use of these agents in older adults. Data suggest that the newer, selective antimuscarinic agents may provide a safer alternative, although in older patients the occurrence of delirium, dry mouth, urinary retention, constipation, and blurring of vision are still troubling concerns. Five muscarinic receptor subtypes have been cloned (Fig. 2). M1, M4, and M5 receptor subtypes predominate in the nervous system, whereas M2 and M3 receptors predominate in smooth muscle. M2 and M3 receptors are the major cholinergic receptors in the bladder. M3 receptors mediate direct detrusor muscle contraction, whereas M2 receptors seem to play a role in inhibition of bladder relaxation and modulation of bladder contraction in pathologic conditions, such as denervation injury or spinal cord disease. Differences in receptor subtype distribution are particularly important when considering adverse events associated with antimuscarinic agents in older adults. Oxybutynin and tolterodine are the two most commonly used antimuscarinic agents in the treatment of OAB. Oxybutynin is a relatively nonselective antimuscarinic agent and acts primarily on M1, M2, and M3 receptor

M1: CNS, salivary glands, stomach M4: CNS, basal ganglia, striatum M5: CNS: substantia nigra, eye

M2: Bladder, heart, smooth muscle M3: Bladder, salivary glands, brain, bowel, smooth muscle

Fig. 2. Distribution of human muscarinic receptor subtypes.

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subtypes. Although oxybutynin has been shown to reduce episodes of UI by almost 50% in 60% to 80% of patients, there is a relatively high incidence of anticholinergic side effects, such as dry mouth, constipation, and blurred vision. Additionally, neurologic side effects, such as dizziness, cognitive dysfunction, and delirium, have been reported in several studies, rendering oxybutynin a poor choice for the geriatric patient. Tolterodine is a more selective antimuscarinic agent that affects predominantly M2 and M3 receptor subtypes. Although the efficacy of tolterodine is comparable to oxybutynin, the incidence of peripheral anticholinergic side effects, such as dry mouth, is much lower. Additionally, cognitive dysfunction related to tolterodine use occurs only rarely. Available data favor use of the extended-release formulations of tolterodine over the immediate release because of greater efficacy, higher tolerability, and higher adherence rates [52]. M3 selective inhibitors, darifenacin and solifenacin, are another effective pharmacologic treatment option for OAB. Adverse effects, such as constipation and blurred vision, in conjunction with the notable paucity of safety and tolerability data in older adults, preclude objective comment regarding prescription of these agents in geriatric practice [53,54]. Trospium has been in use in Europe over the past three decades but has only been approved recently by the Federal Drug Administration for the treatment of OAB. Unlike the M2 and M3 selective agents, which are lipophilic tertiary amines, trospium is a hydrophilic quaternary amine rendering the blood–brain barrier relatively impermeable to trospium, thereby reducing the risk for unwanted central nervous system side effects. Trospium is not metabolized by the cytochrome p450 system and therefore may be less prone to drug interactions. Limited data are available regarding the safety of these agents in the frail elder. Further studies in this area are needed [55–57]. Invasive procedures and surgical management Periurethral sphincter collagen injections and vaginal pessaries are reasonably effective options for older adults unable to tolerate surgery. Sacral neuromodulation involves surgical implantation of a ‘‘bladder pacemaker’’ in the patient’s hip attached to a lead wire that is threaded to a site within the sacral canal at the base of the spine. External programming results in delivery of a painless electrical stimulus to the sacral nerves, which regulate bladder function. This process allows patients to control urine storage and expulsion. For some patients who have stress or overflow incontinence, surgery may be the only effective treatment. Older men who have overflow incontinence because of obstructive uropathy from prostatic hypertrophy may respond to prostatectomy. Several operations have been developed for the treatment of stress incontinence. Prolene suburethral sling insertion is a relatively new technique, with a documented cure rate of greater than 80%. Surgical complications of this procedure include retropubic hematoma, urinary tract infections and fibrosis, pubic osteomyelitis, urinary fistula, and

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transient postoperative urinary retention. Late complications include dysuria, urinary retention, detrusor instability, genital prolapse, sexual disorders, chronic pain, chronic urinary tract infections, and complications related to the use of biomaterials, including screws, synthetic tape, and artificial urinary sphincter. Nevertheless, quality-of-life studies after surgery for stress incontinence in younger patients show consistent improvement. Data in older adults are lacking. Tension-free vaginal tape surgery is a highly effective and minimally invasive alternative for treating patients who have stress urinary incontinence. Surgical complications include bladder perforation, urinary retention, pelvic hematoma, suprapubic wound infection, persistent suprapubic discomfort, and intravaginal tape erosion [58–60].

Summary UI is highly prevalent in older adults and associated with excess comorbidity and increased mortality. Intensive screening and comprehensive clinical examination of all elders enables prompt detection, accurate classification, and appropriate treatment. OAB is the most common cause of persistent incontinence in the older adult. As with other types of UI, behavior modification is first-line treatment of OAB. Although antimuscarinic agents have been shown to be highly effective in the treatment of OAB, limited data are available regarding the safety and tolerability of these agents in older adults. Patients who fail to respond to noninvasive treatment or those in whom surgery may be appropriate should be referred to the urologist for evaluation and further management.

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[54] Robinson D, Cardozo L. The emerging role of solifenacin in the treatment of overactive bladder. Expert Opin Investig Drugs 2004;13(10):1339–48. [55] Scheife R, Takeda M. Central nervous system safety of anticholinergic drugs for the treatment of overactive bladder in the elderly. Clin Ther 2005;27(2):144–53. [56] Gaines KK. Trospium chloride (Sanctura)dnew to the US for overactive bladder. Urol Nurs 2005;25(1):64–5, 52. [57] Rovner ES. Trospium chloride in the management of overactive bladder. Drugs 2004;64(21): 2433–46. [58] Abouassaly R, Steinberg JR, Lemieux M, et al. Complications of tension-free vaginal tape surgery: a multi-institutional review. BJU Int 2004;94(1):110–3. [59] Ayoub N, Chartier-Kastler E, Robain G, et al. [Functional consequences and complications of surgery for female stress urinary incontinence]. Prog Urol 2004;14(3):360–73. [60] Krissi H, Borkovski T, Feldberg D, et al. [Complications of surgery for stress incontinence in women]. Harefuah 2004;143(7):516–9, 548.

Med Clin N Am 90 (2006) 837–847

Frailty John E. Morley, MD, BCha,b,*, Matthew T. Haren, PhDa,b, Yves Rolland, MDc, Moon Jong Kim, MDd a

Division of Geriatric Medicine, Saint Louis University School of Medicine, 1402 South Grand Boulevard, M238, St. Louis, MO 63104, USA b Veterans Affairs Medical Center, GRECC, #1 Jefferson Barracks Dr., St. Louis, MO 63125, USA c Department of Internal Medicine and Geriatrics, Hoˆpital La Grave-Casselardit, 31300 Toulouse, France d Department of Family Medicine, Pochon CHA University, 351 Yatap-dong, Bundang-gu, Sungnam-si, Kyonggi-do, 463-712, Seoul, South Korea

Introduction The concept of older people becoming frail is not a new one. The ability to define frailty in a clinically meaningful manner has remained elusive, however. Frailty can be considered to occur when under stressful conditions an individual has diminished ability to carry out important practiced social activities of daily living. It represents a form of predisability and, as such, needs to be distinguished from functional impairment [1,2]. Recently, Linda Fried and her colleagues at Johns Hopkins University have developed objective criteria for the diagnosis of frailty [3,4]. These are: weight loss of more than 10 lb in one year, physical exhaustion by self report, weakness as measured by grip strength, decline in walking speed, and low physical activity. The importance of the recognition of frailty is that frail people are more likely to be precipitated into disability by exposure to a stressor (eg, influenza or death of a spouse). Early intervention to reverse some of the aspects of frailty may delay the onset of disability in an older person (Fig. 1). The development of frailty depends on the interaction of disease processes with the normal physiologic processes of aging. Genes, environment, and lifestyle all play a role in the pathway to frailty. In the final analysis, frail people usually have an excess loss of functional muscle associated * Corresponding author. Division of Geriatric Medicine, Saint Louis University School of Medicine, 1402 S. Grand Blvd., M238, St. Louis, MO 63104. E-mail address: [email protected] (J.E. Morley). 0025-7125/06/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.mcna.2006.05.019 medical.theclinics.com

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Age Related Physiological Deterioration

- Exercise

Socialization

- Adequate Nutrition

Mental Activity

+

Disease Processes e.g., anemia, heart failure

Frailty

Stressful Event

Recovery

e.g. influenza death of a spouse fall

Recovery Functional Decline

Disability

Hospitalization

Institutionalization

Death

Fig. 1. The frailty cascade.

with some decline in executive function. Pain, by limiting a person’s ability to exercise, is often an important precipitant of frailty. Diseases that limit a person’s cardiopulmonary function (eg, congestive heart failure, anemia, or chronic obstructive pulmonary disease), those that interfere with muscle function (eg, diabetes, peripheral vascular disease, and polymyalgia rheumatica), weight loss, and impaired executive function (eg, depression and cognitive deterioration) all interact to produce frailty.

Sarcopenia: a central factor in the pathophysiology of frailty Sarcopenia is the age-related loss of muscle mass [5]. It is derived from the Greek ‘‘sarx’’ for flesh and ‘‘penia’’ for loss. It has become conventional

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to consider an older person to be sarcopenic when the lean body mass is less than two standard deviations of the sex-specific mean in a young healthy sample. Operationally, this can be defined using the following formula derived from measurements using dual-energy x-ray absorptiometry: Appendicular skeletal mass/height2. These measurements fail to take into account the quality of muscle and with aging there can be a marked uncoupling of muscle cross-sectional area and muscle fiber strength. Also, there has been increased awareness recently that with aging there is fat accumulation in muscle (myosteatosis), which results in a decline in muscle function. Using this definition, the prevalence of sarcopenia is approximately 12% for adults 60 to 70 years of age rising to 30% by 80 years of age. In most studies, the development of sarcopenia is associated strongly with increased disability, gait and balance disorders, and mortality [6,7]. Muscle strength also declines with aging [8]. A second concept is that whereas obese people often have a larger lean body mass than normal weight people, a small subset actually are sarcopenic. This group has been called the sarcopenic obese or the ‘‘fat frail.’’ In the New Mexico Aging Process Study obese sarcopenia was found to be the best predictor of future disability and mortality [9]. The risk for developing disability in this prospective study was 2.63. Obesity, in the absence of adequate exercise, is a cause of frailty [10]. There are multiple causes of sarcopenia (Fig. 2). Genes and early life environment clearly play a role. Several genes have been demonstrated to relate clearly to muscle quality in sports stars. An example that can be extended to older people is the angiotensin converting enzyme (ACE) alleles. Emerging evidence suggests the ACE inhibitors may retard the loss of

Fig. 2. The causes of sarcopenia.

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muscle strength in some individuals [11]. People with a single or double I allele for ACE can generate more power when exercising regularly than people with the D allele. The Hartfordshire cohort study demonstrated that grip strength at 70 years of age is predicted by birth weight [12]. Epidemiologic studies have demonstrated that predictors of muscle mass and strength with aging include testosterone, insulinlike growth factor (IGF)-1, physical activity, energy intake, and age [12–14]. Muscle is continuously undergoing a process of rejuvenation (Fig. 3). Muscle proteins are degraded as they become unfolded leading to atrophy, and cells also can undergo apoptosis (cell death). Rejuvenation occurs because of incorporation of amino acids to drive protein synthesis leading to muscle hypertrophy and stimulation of stem cells to produce satellite cells that repair damaged muscle. It needs to be recognized that each time muscle contracts damage occurs and mechanoreceptors in muscle, such as titin, stimulate the rejuvenation process. The hypertrophy/atrophy process is regulated by the activation of the PI3K-AKT pathway, which leads to muscle hypertrophy. This pathway also inhibits muscle atrophy by phosphorylating forkhead transcription factors (FOXOs) and thus inhibiting the action of Atrogin I, which carries ubiquitin-tagged proteins to the proteasome (the cellular ‘‘death chamber’’) where they are degraded into small peptides and amino acids. The PI3K-AKT pathway is driven by anabolic factors, such as growth hormone and testosterone, that activate the IGF genes within muscle. There are three IGF genes. IGF-1 stimulates protein synthesis and muscle hypertrophy. This gene is regulated by growth hormone [15]. Mechanogrowth factor (MGF) is responsible for activating the production of satellite cells and stimulating the firing of motor unit cells. MGF is stimulated in the first instance by resistance exercise [16]. Growth hormone can then synergistically increase this process further but is not effective in the absence of resistance exercise. This ineffectiveness explains why the studies giving growth hormone to older people result in an increase in muscle mass but not in muscle strength [17,18]. Ghrelin, a growth hormone secretagogue, also increases

Fig. 3. The yin and yang of muscle death and rejuvenation.

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muscle mass and food intake [19]. The transgene for MGF, when inserted into muscle of older rats, has been shown to rejuvenate the muscle [20]. Testosterone is an anabolic hormone that has been demonstrated to increase muscle mass and strength in older hypogonadal men when given at high doses [21–29]. A small number of studies suggest similar effects in women [30,31]. Testosterone levels decline with aging at the rate of about 1% per year [32,33]. Low testosterone levels are associated with a decrease in muscle strength and function [34,35]. Androgen deprivation leads to a loss of muscle mass [36]. In animal models testosterone improves function in a stroke model [37]. Testosterone replacement results in improved function over a 3-year period in older men [38]. At the cellular level testosterone stimulates protein synthesis, inhibits the ubiquitin-proteasome pathway, and most importantly stimulates satellite cell production [39–41]. At present, testosterone would appear to be the best pharmacologic agent to treat sarcopenia, but as we have pointed out elsewhere, there are only a limited number of studies in support of this viewpoint [42]. Dehydroepiandrosterone, a weak androgen, failed in a well-controlled study to increase muscle mass or strength at a dose of 50 mg daily given for one year [43]. Myostatin is an inhibitor of muscle regeneration. It has a direct effect inhibiting satellite cell production. A double deletion of the myostatin gene leads to muscle hypertrophy in mice, cows, and in a single human [44]. Amgen has developed ‘‘peptobodies’’ to myostatin, which in animal studies appear to cause muscle hypertrophy. People who are vitamin D deficient have poor muscle function, which is improved with vitamin D administration [45]. In vitamin D–deficient people vitamin D supplementation decreases falls and reduces functional impairment [46,47]. Vitamin D levels have been shown to decline throughout the lifetime in a longitudinal study [48]. Adequate food intake is essential for the maintenance of muscle quality. Creatine is essential to maintenance of muscle quality [49]. With aging, many people experience an associated anorexia, which can lead to inadequate protein intake for muscle maintenance [50,51]. Motor unit firing, an important component of muscle maintenance, decreases in people more than 80 years of age [52]. Ciliary neurotrophic factor (CNTF) levels decline with aging and correlate with the decline in muscle strength that occurs with aging [53]. CNTF replacement leads to an increase in muscle mass in animals [54]. The increase in cytokines that occurs with agingdcytokine-related aging processdis associated with a decline in muscle strength and frailty [55]. Cesari and colleagues [56] showed that high levels of tumor necrosis factora and interleukin-6 are associated with a decline in hand grip strength and physical performance. Diabetes mellitus is associated with a decline in muscle strength, increased falls, and a decrease in function [57]. Diabetes is associated with an increase in angiotensin II, which stimulates caspase 3 to produce cleavage

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of actomyosin to actin and myosin. In addition, insulin resistance leads to fat infiltration within muscle cells (myosteatosis). This phenomenon seems to be associated with mitochondrial abnormalities [58]. Neuropathy leads to decreased motor unit firing. Atherosclerosis results in a decline in blood flow to muscle and, therefore, decreased muscle rejuvenation. Sarcopenia represents a major cause of frailty and functional impairment. Its causes are multifactorial. At present, the primary treatment is resistance exercise. In hypogonadal men testosterone may play a role. Nandrolone, an anabolic steroid, has been shown to produce positive effects in women [59]. The development of selective androgen receptor molecules represents an exciting research area for the future treatment of sarcopenia. Weight loss and frailty Most frail people have some degree of weight loss. This weight loss may be not only because of sarcopenia but also secondary to cachexia, dehydration, or anorexia. A physiologic anorexia of aging places older people at major risk for developing severe weight loss when they develop a disease [60,61]. The most common disease leading to weight loss in older people is depression [62,63]. Side effects of medication and therapeutic diets are common iatrogenic causes of weight loss [64]. Cachexia occurs when there is an excess of cytokines and usually is associated with major depletion of muscle and fat [65]. Cachexia commonly is associated with diseases such as cancer, congestive heart failure, AIDS, chronic obstructive pulmonary disease, chronic infections such as tuberculosis, and renal failure. Weight loss is associated with hip fracture, increased disability, and death [66,67]. Reversal of weight loss is associated with improved outcomes [68]. Disease and frailty Numerous diseases lead to frailty. Diabetes mellitus is a particular example of this [69]. Diabetes leads to a decline in functional status to a greater degree than other diseases [70,71]. Diabetes is associated with an increase in injurious falls [70]. The reasons people who have diabetes are at increased risk for frailty are multifactorial and include peripheral neuropathy, autonomic neuropathy leading to orthostasis and postprandial hypotension, peripheral vascular disease, cognitive dysfunction, and a decreased pain threshold [72–76]. People who have diabetes mellitus also have an increased rate of male hypogonadism [77]. Pain is a major precipitant of frailty. People who have pain have limitation of their activity. This limitation leads to muscle atrophy and eventually decreased function [78]. Anemia represents another cause of frailty. People who have anemia have increased syncope, disability, depression, cognitive dysfunction, and mortality

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[79,80]. Modern treatment of anemia (caused by chronic disease and chronic kidney failure) with erythropoietin or darbepoetin-alfa represents a major advance in limiting the onset of frailty in older people. Depression commonly is associated with frailty and functional deterioration [81,82]. Depression is often undertreated, especially in minority and low-level socioeconomic populations [81]. Although a minority of people who have cognitive dysfunction do not become frail, the majority eventually develop functional decline often associated with weight loss [83,84]. Frail people are particularly prone to develop delirium, which can lead to a cascade of increasing frailty. Hip fracture is an important precipitant of frailty. Several studies have shown that physicians often fail to treat osteoporosis [85]. Summary Frailty is a common condition in older people. It now can be objectively defined by the Fried criteria [3]. When recognized, early intervention should begin with the institution of endurance, resistance, and balance exercises [86]. In men with testosterone deficiency a trial of testosterone replacement should be considered [87]. Vitamin D deficiency needs to be recognized and treated. Appropriate treatment of underlying diseases, such as anemia, diabetes mellitus, and congestive heart failure, are a key management principle. In people who have frailty aggressive health promotion and disease prevention techniques can lead to an inhibition of the downward spiral to disability [88]. References [1] Morley JE, Perry HM 3rd, Miller DK. Editorial: something about frailty. J Gerontol Med Sci 2002;57A:M698–704. [2] Morley JE, Kim MJ, Haren MT, et al. Frailty and the aging male. Aging Male 2005;8: 135–40. [3] Fried LP, Tangen CM, Walston J, et al. Cardiovascular Health Study Collaborative Research Group. Frailty in older adults: evidence for a phenotype. J Gerontol Med Sci 2001; 56A:M146–56. [4] Fried LP, Ferrucci L, Darer J, et al. Untangling the concepts of disability, frailty, and comorbidity: implications for improved targeting and care. J Gerontol Med Sci 2004;59:255–63. [5] Morley JE. Anorexia, sarcopenia, and aging. Nutrition 2001;17:660–3. [6] Morley JE, Baumgartner RN, Roubenoff R, et al. Sarcopenia. J Lab Clin Med 2001;137: 231–43. [7] Janssen I, Heymsfield SB, Ross R. Low relative skeletal muscle mass (sarcopenia) in older persons is associated with functional impairment and physical disability. J Am Geriatr Soc 2002;50:889–96. [8] Forrest KY, Zmuda JM, Cauley JA. Patterns and determinants of muscle strength change with aging in older men. Aging Male 2005;8:151–6. [9] Baumgartner RN, Wayne SJ, Waters DL, et al. Sarcopenic obesity predicts instrumental activities of daily living disability in the elderly. Obes Res 2004;12:1995–2004. [10] Vermeulen A. The epidemic of obesity: obesity and health of the aging male. Aging Male 2005;8:39–41.

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[11] Carter CS, Onder G, Kritchevsky SB, et al. Angiotensin-converting enzyme inhibition intervention in elderly persons: effects on body composition and physical performance. J Gerontol Med Sci 2005;60:1437–46. [12] Baumgartner RN, Waters DL, Gallagher D, et al. Predictors of skeletal muscle mass in elderly men and women. Mech Ageing Dev 1999;107:123–36. [13] Szulc P, Duboeuf F, Marchand F, et al. Hormonal and lifestyle determinants of appendicular skeletal muscle mass in men: the MINOS study. Am J Clin Nutr 2004;80:496–503. [14] Iannuzzi-Sucich M, Prestwood KM, Kenny AM. Prevalence of sarcopenia and predictors of skeletal muscle mass in healthy, older men and women. J Gerontol Med Sci 2002;57A: M772–7. [15] Kann PH. Growth hormone in anti-aging medicine: a critical review. Aging Male 2003;6: 257–63. [16] Goldspink G. Age-related muscle loss and progressive dysfunction in mechanosensitive growth factor signaling. Ann N Y Acad Sci 2004;1019:294–8. [17] Johannsson G, Svensson J, Bengtsson BA. Growth hormone and ageing. Growth Horm IGF Res 2000;10(Suppl B):S25–30. [18] Roubenoff R, Rall LC, Veldhuis JD, et al. The relationship between growth hormone kinetics and sarcopenia in postmenopausal women: the role of fat mass and leptin. J Clin Endocrinol Metab 1998;83:1502–6. [19] Lago F, Gonzalez-Juanatey JR, Casanueva FF, et al. Ghrelin, the same peptide for different functions: player or bystander? Vitam Horm 2005;71:405–32. [20] Musaro A, McCullagh KJ, Naya FJ, et al. IGF-1 induces skeletal myocyte hypertrophy through calcineurin in association with GATA-2 and NF-ATc1. Nature 1999;400:581–5. [21] Sih R, Morley JE, Kaiser FE, et al. Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial. J Clin Endocrinol Metab 1997;82:1661–7. [22] Lunenfeld B, Saad F, Hoesl CE. ISA, ISSAM and EAU recommendations for the investigation, treatment and monitoring of late-onset hypogonadism in males: scientific background and rationale. Aging Male 2005;8:59–74. [23] Krause W, Mueller U, Mazur A. Testosterone supplementation in the aging male: which questions have been answered? Aging Male 2005;8:31–8. [24] Morley JE, Perry HM 3rd, Kaiser FE, et al. Effects of testosterone replacement therapy in old hypogonadal males: a preliminary study. J Am Geriatr Soc 1993;41:149–52. [25] Nieschlag E, Swerdloff R, Behre HM, et al. Investigation, treatment and monitoring of lateonset hypogonadism in males. Aging Male 2005;8:56–8. [26] Morley JE, Perry HM 3rd. Androgen treatment of male hypogonadism in older males. J Steroid Biochem Mol Biol 2003;85:367–73. [27] Jockenhovel F. Testosterone therapydwhat, when and to whom? Aging Male 2004;7:319–24. [28] Bhasin S, Woodhouse L, Casaburi R, et al. Older men are as responsive as young men to the anabolic effects of graded doses of testosterone on the skeletal muscle. J Clin Endocrinol Metab 2005;90:678–88. [29] Wittert GA, Chapman IM, Haren MT, et al. Oral testosterone supplementation increases muscle and decreases fat mass in healthy elderly males with low-normal gonadal status. J Gerontol Med Sci 2003;58:618–25. [30] Morley JE, Perry HM 3rd. Androgens and women at the menopause and beyond. J Gerontol Med Sci. 2003;58A:M409–16. [31] Morley JE, Kaiser FE. Female sexuality. Med Clin N America 2003;87:1077–90. [32] Morley JE, Kaiser FE, Perry HM 3rd, et al. Longitudinal changes in testosterone, luteinizing hormone, and follicle-stimulating hormone in healthy older men. Metab Clin Exper 1997;46: 410–3. [33] Li JY, Li XY, Li M, et al. Decline of serum levels of free testosterone in aging healthy Chinese men. Aging Male 2005;8:203–6. [34] Kratzik CW, Reiter WJ, Riedl AM, et al. Hormone profiles, body mass index and aging male symptoms: results of the Androx Vienna Municipality study. Aging Male 2004;7:188–96.

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[35] Perry HM 3rd, Miller DK, Patrick P, et al. Testosterone and leptin in older AfricanAmerican men: relationship to age, strength, function, and season. Metab Clin Exper. 2000;49:1085–91. [36] Boxer RS, Kenny AM, Dowsett R, et al. The effect of 6 months of androgen deprivation therapy on muscle and fat mass in older men with localized prostate cancer. Aging Male 2005;8: 207–12. [37] Pan Y, Zhang H, Acharya AB, et al. Effect of testosterone on functional recovery in a castrated male rat stroke model. Brain Res 2005;1043:195–204. [38] Page ST, Amory JK, Bowman FD, et al. Exogenous testosterone (T) alone or with finasteride increases physical performance, grip strength, and lean body mass in older men with low serum T. J Clin Endocrinol Metab 2005;90:1502–10. [39] Herbst KL, Bhasin S. Testosterone action on skeletal muscle. Curr Opin Clin Nutr Metab Care 2004;7:271–7. [40] Sinha-Hikim I, Taylor WE, Gonzalez-Cadavid NF, et al. Androgen receptor in human skeletal muscle and cultured muscle satellite cells: upregulation by androgen treatment. J Clin Endocrinol Metab 2004;7:271–7. [41] Morley JE, Kim MJ, Haren MT. Frailty and hormones. Rev Endocrine Metab Dis 2005;6: 101–8. [42] Morley JE. Hormones and the aging process. J Am Geriatr Soc 2003;51(7 Suppl):S333–7. [43] Percheron G, Hogrel JY, Denot-Ledunois S, et al. Effect of 1-year oral administration of dehydroepiandrosterone to 60- to 80-year-old individuals on muscle function and crosssectional area: a double-blind placebo-controlled trial. Arch Intern Med 2003;163:720–7. [44] Walsh FS, Celeste AJ. Myostatin: a modulator of skeletal-muscle stem cells. Biochem Soc Trans 2005;33:1513–7. [45] Sato Y, Iwamoto J, Kanoko T, et al. Low-dose vitamin D prevents muscular atrophy and reduces falls and hip fractures in women after stroke: a randomized controlled trial. Cerebrovasc Dis 2005;20:187–92. [46] Schacht E, Richy F, Reginster JY. The therapeutic effects of alfacalcidol on bone strength, muscle metabolism and prevention of falls and fractures. J Musculoskelet Neuronal Interact 2005;5:273–84. [47] Kannus P, Sievanen H, Palvanen M, et al. Prevention of falls and consequent injuries in elderly people. Lancet 2005;366:1885–93. [48] Perry HM 3rd, Horowitz M, Morley JE, et al. Longitudinal changes in serum 25-hydroxyvitamin D in older people. Metab Clin Exper 1999;48:1028–32. [49] Chrusch MJ, Chilibeck PD, Chad KE, et al. Creatine supplementation combined with resistance training in older men. Med Sci Sports Exerc 2001;33:2111–7. [50] Wilson MM, Morley JE. Invited review: aging and energy balance. J Appl Physiol 2003;95: 1728–36. [51] Morley JE. Anorexia of aging: physiologic and pathologic. Am J Clin Nutr 1997;66:760–73. [52] Roos MR, Rice CL, Connelly DM, et al. Quadriceps muscle strength, contractile properties, and motor unit firing rates in young and old men. Muscle Nerve 1999;22:1094–103. [53] Roth SM, Schrager MA, Ferrell RE, et al. CNTF genotype is associated with muscular strength and quality in humans across the adult age span. J Appl Physiol 2001;90:1205–10. [54] Marques MJ, Neto HS. Ciliary neurotrophic factor stimulates in vivo myotube formation in mice. Neurosci Lett 1997;234:43–6. [55] Morley JE, Baumgartner RN. Cytokine-related aging process. J Gerontol Med Sci. 2004; 59A:M924–9. [56] Cesari M, Penninx BW, Lauretani F, et al. Hemoglobin levels and skeletal muscle: results from the InCHIANTI study. J Gerontol Med Sci 2004;59A:249–54. [57] Morley JE. Diabetes mellitus: a major disease of older persons. J Gerontol Med Sci. 2000; 55A:M255–6. [58] Frisoli A Jr, Chaves PH, Pinheiro MM, et al. The effect of nandrolone decanoate on bone mineral density, muscle mass, and hemoglobin levels in elderly women with osteoporosis:

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[61] [62] [63] [64] [65] [66] [67] [68]

[69] [70]

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a double-blind, randomized, placebo-controlled clinical trial. J Gerontol Med Sci 2005;60: 648–53. Lowell BB, Chulman GI. Mitochondrial dysfunction and type 2 diabetes. Science 2005;307: 384–7. Wilson MM, Thomas DR, Rubenstein LZ, et al. Appetite assessment: simple appetite questionnaire predicts weight loss in community-dwelling adults and nursing home residents. Am J Clin Nutr 2005;82:1074–81. Chapman IM, MacIntosh CG, Morley JE, et al. The anorexia of ageing. Biogerontology 2002;3:67–71. Wilson MM, Vaswani S, Liu D, et al. Prevalence and causes of undernutrition in medical outpatients. Am J Med 1998;104:56–63. Morley JE, Kraenzle D. Causes of weight loss in a community nursing home. J Am Geriatr Soc 1994;42:583–5. Morley JE. Decreased food intake with aging. J Gerontol Med Sci. 2001;56A(Spec 2):81–8. Baez-Franceschi D, Morley JE. Pathophysiology of catabolism in undernourished elderly patients. [German] Z Gerontol Geriatr 1999;32(Suppl 1):I12–9. MacIntosh C, Morley JE, Chapman IM. The anorexia of aging. Nutrition 2000;16:983–95. Morley JE. Protein-energy malnutrition in older subjects. Proc Nutr Soc 1998;57:587–92. Sullivan DH, Morley JE, Johnson LE, et al. The GAIN (Geriatric Anorexia Nutrition) registry: the impact of appetite and weight on mortality in a long-term care population. J Nutr Hlth Aging 2002;6:275–81. Morley JE. An overview of diabetes mellitus in older persons. Clin Geriatr Med 1999;15: 211–24. Rodriquez-Saldana J, Morley JE, Reynoso MT, et al. Diabetes mellitus in a subgroup of older Mexicans: prevalence, association with cardiovascular risk factors, functional and cognitive impairment, and mortality. J Am Geriatr Soc 2002;50:111–6. Miller DK, Lui LY, Perry HM 3rd, et al. Reported and measured physical functioning in older inner-city diabetic African Americans. J Gerontol Med Sci. 1999;54:M230–6. Sinclair AJ. Diabetes in the elderly: a perspective from the United Kingdom. Clin Geriatr Med 1999;15:225–37. Rosenthal MJ, Fajardo M, Gilmore S, et al. Hospitalization and mortality of diabetes in older adults. A 3-year prospective study. Diabetes Care 1998;21:231–5. Morley JE, Loewnthal MN, Asvat MS, et al. Problems experienced in a diabetic clinic for Blacks. S Afr Med J 1977;52:215–8. Morley JE, Asvat MS, Klein C, et al. Autonomic neuropathy in Black diabetic patients. S Afr Med J 1977;52:115–6. Morley GK, Mooradian AD, Levine AS, et al. Mechanism of pain in diabetic peripheral neuropathy. Effect of glucose on pain perception in humans. Am J Med 1984;77:79–82. Morley JE, Melmed S. Gonadal dysfunction in systemic disorders. Metab Clin Exper. 1979; 28:1051–73. Reid MC, Williams CS, Gill TM. Back pain and decline in lower extremity physical function among community-dwelling older persons. J Gerontol Med Sci 2005;60:793–7. Cesari M, Penninx BW, Pahor M, et al. Inflammatory markers and physical performance in older persons: the InCHIANTI study. J Gerontol Med Sci. 2004;59:242–8. Chaves PH, Semba RD, Leng SX, et al. Impact of anemia and cardiovascular disease on frailty status of community-dwelling older women: the Women’s Health and Aging Studies I and II. J Gerontol Med Sci 2005;60:729–35. Miller DK, Malmstrom TK, Joshi S, et al. Clinically relevant levels of depressive symptoms in community-dwelling middle-aged African Americans. J Am Geriatr Soc 2004;52:741–8. Flaherty JH, McBride M, Marzouk S, et al. Decreasing hospitalization rates for older home care patients with symptoms of depression. J Am Geriatr Soc 1998;46:31–8. Malmstrom TK, Wolinsky FD, Andresen EM, et al. Cognitive ability and physical performance in middle-aged African Americans. J Am Geriatr Soc 2005;53:997–1001.

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[84] Ble A, Volpato S, Zuliani G, et al. Executive function correlates with walking speed in older persons: the InCHIANTI study. J Am Geriatr Soc 2005;53:410–5. [85] Kamel HK, Perry HM 3rd, Morley JE. Hormone replacement therapy and fractures in older adults. J Am Geriatr Soc 2001;49:179–87. [86] Fiatarone-Singh MA. Exercise in the oldest old: some new insights and unanswered questions. J Am Geriatr Soc 2002;50:2089–91. [87] Asthana S, Bhasin S, Butler RN, et al. Masculine vitality: pros and cons of testosterone in treating the andropause. J Gerontol Med Sci. 2004;59:461–5. [88] Miller DK, Morrison MJ, Blair DS, et al. Predilection for frailty remedial strategies among black and white seniors. South Med J 1998;91:375–80.

Med Clin N Am 90 (2006) 849–862

Heart Disease and Aging Wilbert S. Aronow, MD Department of Medicine, Divisions of Cardiology, Geriatrics, and Pulmonary/Critical Care Medicine, New York Medical College, Macy Pavilion, Room 138, Valhalla, NY 10595, USA

Age-related changes in the cardiovascular system, overt and occult cardiovascular disease, and reduced physical activity affect cardiovascular function in elderly persons [1]. With aging, there is a loss of myocytes in the left and right ventricles, with a progressive increase in myocyte cell volume per nucleus in both ventricles [2]. With aging, there also is a progressive reduction in the number of pacemaker cells in the sinus node, with 10% of the number of cells present at age 20 remaining at age 75 [3]. There is a progressive loss of myocytes and hypertrophy of the remaining myocytes with aging. The maximal heart rate, maximal cardiac output, and maximal VO2 decrease progressively with aging. The maximal stroke volume may be maintained or decreased with aging. Systemic vascular resistance is increased with aging [1]. With aging, left ventricular (LV) stiffness is increased, LV compliance is decreased, systolic blood pressure is increased, LV wall thickness is increased, early LV diastolic filling is decreased with a greater contribution to LV filling resulting from left atrial systole, and LV relaxation is impaired. The increase in LV diastolic dysfunction with aging predisposes elderly persons to develop congestive heart failure (CHF) with normal LV ejection fraction [1].

Coronary artery disease Coronary artery disease (CAD) is the most common cause of death in older men and women. American Heart Association Web site data state that more than 83% of persons who die of CAD are aged 65 years or older. The prevalence of CAD is similar in older women and men. CAD was present in 43% of 1160 men and 41% of 2464 women with a mean age 81 years [4].

E-mail address: [email protected] 0025-7125/06/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.mcna.2006.05.009 medical.theclinics.com

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CAD is diagnosed in older persons if they have coronary angiographic evidence of CAD, a documented myocardial infarction, a typical history of angina pectoris, or sudden cardiac death. The incidence of sudden cardiac death as the first clinical manifestation of CAD in men and in women increases with age. Dyspnea on exertion is a more common clinical manifestation of CAD in older men and women than is the typical chest pain of angina pectoris. Angina pectoris in older men and women is associated less often with exertion because older persons are more likely to be limited in their activities. Substernal pain due to angina pectoris is less frequent in older persons than in younger persons who have CAD. Angina pectoris in older persons may occur as a burning postprandial epigastric pain or as pain in the back or shoulders. Older persons describe their anginal pain as less severe and of shorter duration. In older persons, acute pulmonary edema that is unassociated with an acute myocardial infarction may be a clinical manifestation of unstable angina pectoris due to extensive CAD [5]. Many older men and women with Q-wave myocardial infarction documented by a routine electrocardiogram do not have a clinical history of myocardial infarction. In the Framingham Study, the percentages of myocardial infarction that were clinically unrecognized were 35% for women aged 65 to 74 years, 36% for women aged 75 to 84 years, and 46% for women aged 85 to 95 years [6]. Table 1 shows the prevalence of clinically unrecognized Q-wave myocardial infarction in older persons diagnosed by a routine electrocardiogram [6–12]. In a prospective study that investigated the prevalence of presenting clinical manifestations of acute myocardial infarction in 110 older nursing home residents, clinically unrecognized Q-wave myocardial infarction was diagnosed by a routine electrocardiogram in 21% of persons. The presenting clinical manifestation of acute myocardial infarction was dyspnea in 35% of persons, chest pain in 22% of persons, neurologic symptoms in 18% of persons, and gastrointestinal symptoms in 4% of persons [8].

Table 1 Prevalence of unrecognized Q-wave myocardial infarction in older persons Study

Age (y)

Unrecognized MI

Vokonas & Kannel (n ¼ 199 men) [6] Vokonas & Kannel (n ¼ 162 women) [6] Aronow et al (n ¼ 115) [7] Aronow (n ¼ 110) [8] Muller et al (n ¼ 46 men) [9] Muller et al (n ¼ 67 women) [9] Nadelmann et al (n ¼ 115) [10] Sigurdsson et al (n ¼ 237) [11] Sheifer et al (n ¼ 901) [12]

65–94 65–94 mean, 82 mean, 82 65–95 65–95 75–85 58–62 mean, 72

33% 36% 68% 21% 30% 51% 43% 35% 22%

Abbreviation: MI, myocardial infarction.

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Many studies have demonstrated that the incidence of new coronary events, including recurrent myocardial infarction, ventricular fibrillation, and sudden coronary death, in patients who have unrecognized myocardial infarction is similar to that in patients who have recognized myocardial infarction [6,10–13]. The Honolulu, Hawaii, Heart Program, however, showed that after adjustment for age at the time of myocardial infarction patients with clinically unrecognized myocardial infarction had a 60% to 70% higher risk for death, either from all causes or from cardiovascular disease [14]. Therefore, older patients who have had myocardial infarction diagnosed by a routine electrocardiogram with no clinical history of myocardial infarction should be treated with antiplatelet drugs, b-blockers, angiotensin-converting enzyme inhibitors, and lipid-lowering drugs, preferably statins, according to American College of Cardiology/American Heart Association guidelines [15]. Older persons are more likely to develop a non-ST-segment elevation acute myocardial infarction than an ST-segment elevation (Q-wave) acute myocardial infarction [16,17]. Table 2 shows the prevalence of unstable angina pectoris, non–ST-segment elevation acute myocardial infarction, and ST-segment elevation acute myocardial infarction in 91 women (mean age, 79 years) and in 86 men (mean age, 77 years) in a prospective study of 177 consecutive unselected patients aged 70 years and older who were hospitalized for an acute coronary syndrome [17]. Women had a 2.3 times higher incidence of non–ST-segment elevation acute myocardial infarction than ST-segment elevation acute myocardial infarction [17]. Men had a 4.3 times higher incidence of non–ST-segment elevation acute myocardial infarction than ST-segment elevation acute myocardial infarction [17]. Regardless of the type of acute myocardial infarction, elderly persons who have acute myocardial infarction demonstrate more LV dysfunction and have a more complicated hospital course than do younger persons. At 4-year follow-up, new coronary events (nonfatal or fatal myocardial infarction or sudden cardiac death) occurred in 46% of 1160 older men and in 44% of 2464 older women (difference not significant) [4]. Multivariate analysis demonstrated that independent risk factors for the development of new coronary events were increasing age, previous CAD, cigarette Table 2 Prevalence of unstable angina, non–ST-segment elevation acute myocardial infarction, and STsegment elevation acute myocardial infarction in elderly men and women who have acute coronary syndromes

Unstable angina pectoris Non–ST-segment elevation AMI ST-segment elevation AMI

Women (n ¼ 91)

Men (n ¼ 86)

50% 35% 15%

58% 34% 8%

Abbreviation: AMI, acute myocardial infarction. Data from Woodworth S, Nayak D, Aronow WS, et al. Comparison of acute coronary syndromes in men versus women R70 years of age. Am J Cardiol 2002;90:1145–7.

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smoking, hypertension, diabetes mellitus, high serum total cholesterol, and low serum high-density lipoprotein cholesterol in older men and women and high serum triglycerides in older women [18]. Obesity was a risk factor for new coronary events in older women by univariate analysis but not after multivariate analysis. Other studies have shown that age [6], previous CAD [6], cigarette smoking [19,20], hypertension [6,21–23], diabetes mellitus [6,23], high serum total cholesterol [6,19,23–25], low serum high-density lipoprotein cholesterol [6,23,25–27], and obesity [6,23] are independent risk factors for new coronary events in older men and women. In the Framingham Study, increased serum triglycerides also was an independent risk factor for new coronary events in older women [6,23]. Hypertensive heart disease A reduction in arterial compliance contributes more to the age-related increase in afterload than does the loss of peripheral vascular beds [28]. With aging, there is an increase in systolic blood pressure and a widening pulse pressure. A slight reduction in diastolic blood pressure occurs after the sixth decade [29]. The increase in systolic blood pressure is due to interactions of aging, cardiovascular disease, and lifestyle factors (eg, dietary sodium intake, level of physical activity, body weight). Hypertension is common in older men and women. Diastolic hypertension is diagnosed in older persons if the diastolic blood pressure is at least 90 mm Hg on three occasions. Systolic hypertension is diagnosed in older persons if the systolic blood pressure is at least 140 mm Hg on three occasions. Isolated systolic hypertension is diagnosed in older persons if the systolic blood pressure is at least 140 mm Hg and the diastolic blood pressure is less than 90 mm Hg on three occasions [30]. In a prospective study of 2464 older women and 1660 older men, mean age 81 years, older women had a similar prevalence of hypertension (60%) as did older men (57%) [4]. Isolated systolic hypertension was present in two thirds of the older men and women who had hypertension [4,30]. Age-associated LV hypertrophy is caused by an increase in the volume, but not in the number, of cardiac myocytes. Aging also is associated with an increase in the prevalence of hypertension and cardiovascular disease. Therefore, the prevalence of LV hypertrophy increases with age. Electrocardiographic LV hypertrophy was present in 15% of older whites and in 20% of older African Americans who had hypertension [30]. Echocardiographic LV hypertrophy was present in 56% of older whites and in 71% of older African Americans who had hypertension [30]. Echocardiographic LV hypertrophy also was present in 44% of 1881 women and in 43% of 924 men with a mean age of 81 years (Table 3) [31]. At 42-month follow-up, electrocardiographic and echocardiographic LV hypertrophy increased the incidence of new coronary events. Multivariate

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Table 3 Prevalence of echocardiographic findings in 1881 women and 924 men, mean age 81 years Prevalence (%) Variable

Men

Women

Aortic stenosis R1þ Aortic regurgitation Rheumatic mitral stenosis R1þ Mitral regurgitation Mitral annular calcium Hypertrophic cardiomyopathy Idiopathic dilated cardiomyopathy Left atrial enlargement Left ventricular hypertrophy Abnormal left ventricular ejection fraction

15 31 0.3 32 36 3 1 43 43 29

17 29 2 33 52 4 1 38 44 22

Data from Aronow WS, Ahn C, Kronzon I. Comparison of echocardiographic abnormalities in African-American, Hispanic, and white men and women aged O60 years. Am J Cardiol 2001;87:1131–3.

analysis showed that in older whites and African Americans who had hypertension the odds ratio for developing new coronary events was 1.11 for electrocardiographic LVH and 3.21 for echocardiographic LVH. Echocardiographic LV hypertrophy was the most powerful independent risk factor for the development of new coronary events in older persons who had hypertension [30]. In the Framingham Study, echocardiographic LV hypertrophy was 4.3 times more sensitive than was electrocardiographic LV hypertrophy in predicting new coronary events in older women, and was 15.3 times more sensitive than was electrocardiographic LV hypertrophy in predicting new coronary events in older men [32]. In older men and women who had CAD or hypertension, echocardiographic LV hypertrophy was 4.3 times more sensitive than was electrocardiographic LV hypertrophy in predicting new coronary events [33]. Echocardiographic LV hypertrophy also was a powerful independent predictor of new atherothrombotic brain infarction (odds ratio ¼ 4.17) and of new CHF (odds ratio ¼ 2.57) in older persons who had hypertension [30].

Valvular aortic stenosis Valvular aortic stenosis in older persons usually is due to stiffening, scarring, and calcification of the aortic valve leaflets. The prevalence of valvular aortic stenosis increases with age. In a prospective study of 1881 older women and 924 older men, mean age 81 years, Doppler echocardiography showed that valvular aortic stenosis was present in 17% of women and in 15% of men (difference not significant) (Table 3) [31]. The valvular aortic stenosis was mild in 9% of the older persons, moderate in 5% of the older persons, and severe in 2% of the older persons. In the Helsinki Ageing

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Study, Doppler echocardiography demonstrated that critical valvular aortic stenosis was present in 3% of 501 persons aged 75 to 86 years [34]. Older women and men who had mild, moderate, or severe aortic stenosis had a higher incidence of new coronary events than did older persons who did not have aortic stenosis [35]. Table 4 shows the prevalence of physical signs in older persons who had mild (n ¼ 74), moderate (n ¼ 49), and severe (n ¼ 19) valvular aortic stenosis [36]. The intensity of the aortic systolic ejection murmur, the maximal location of the aortic systolic ejection murmur, transmission of the aortic systolic ejection murmur to the right carotid artery, and presence of an aortic ejection click did not differentiate between mild, moderate, and severe valvular aortic stenosis. Persons who have CHF that is due to severe aortic stenosis have a low cardiac output that may cause the aortic systolic ejection murmur to become softer or absent. In some older persons who have aortic stenosis, the systolic ejection murmur may be heard only at the apex or may be louder or more musical at the apex than at the base. The intensity of the aortic systolic ejection murmur decreases during the Valsalva maneuver and increases with squatting and inhalation of amyl nitrite. The three classic clinical manifestations of severe valvular aortic stenosis are angina pectoris, CHF, and syncope. Angina pectoris, CHF, or syncope occurred in 27% of 165 older persons who had mild aortic stenosis, in 69% of 96 older persons who had moderate aortic stenosis, and in 90% of 40 older persons who had severe aortic stenosis [35]. The prognosis of unoperated severe valvular aortic stenosis in older women and men who have CHF is poor [37]. The management of aortic stenosis in the elderly is discussed in detail elsewhere [38]. Aortic regurgitation The prevalence of aortic regurgitation increases with age. In a prospective study of 1881 older women and 924 older men, mean age 81 years, Doppler Table 4 Prevalence of physical signs in persons, mean age 82 years, who have valvular aortic stenosis Physical sign

Mild aortic stenosis (%)

Moderate aortic stenosis (%)

Severe aortic stenosis (%)

Aortic systolic ejection murmur Prolonged duration of systolic murmur Late peaking of systolic murmur A2 absent A2 absent or reduced Prolonged carotid upstroke time

95 3 3 0 5 3

100 63 63 10 49 33

100 84 84 16 74 53

Data from Aronow WS, Kronzon I. Prevalence and severity of valvular aortic stenosis determined by Doppler echocardiography and its association with echocardiographic and electrocardiographic left ventricular hypertrophy and physical signs of aortic stenosis in elderly patients. Am J Cardiol 1993;72:846–8.

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echocardiography demonstrated that at least 1þ aortic regurgitation was present in 31% of men and in 29% of women (difference not significant) (see Table 3) [31]. Severe or moderate aortic regurgitation was present in 16% of the older persons. The heart murmur that is associated with aortic regurgitation typically is a high-pitched blowing diastolic murmur that begins immediately after the onset of A2. If aortic regurgitation is caused by aortic valve disease, the diastolic murmur is heard best along the left sternal border in the third and fourth intercostal spaces. If aortic regurgitation is caused by dilatation of the ascending aorta, the diastolic murmur is heard best along the right sternal border. The diastolic murmur of aortic regurgitation is heard best with the diaphragm of the stethoscope with the person sitting up, leaning forward, and holding the breath in deep expiration. The severity of the aortic regurgitation correlates with the duration of the diastolic murmur and not with the intensity of the diastolic murmur. In older persons, a diastolic murmur of aortic regurgitation was heard in 95% of persons who had chronic severe or moderate aortic regurgitation, in 61% of persons who had chronic mild regurgitation, and in 3% of persons who did not have aortic regurgitation [39]. Older persons who have chronic aortic regurgitation may be asymptomatic for many years; however, the prognosis of persons who have CHF and unoperated severe aortic regurgitation is poor [40]. The management of aortic regurgitation in the elderly is discussed in detail elsewhere [38]. Rheumatic mitral stenosis In a prospective study of 1881 older women and 924 older men, mean age 81 years, the prevalence of rheumatic mitral stenosis was higher in older women (2%) than in older men (0.3%) (see Table 3) [31]. In a prospective study of 1699 older persons, the prevalence of rheumatic mitral stenosis was 6% in persons who had atrial fibrillation and 0.4% in persons who had sinus rhythm [41]. The most common cause of mitral stenosis in older women and men is mitral annular calcium (MAC). The prevalence of mitral stenosis in older persons who had MAC was 6% [42]. The low-pitched diastolic rumble that is caused by mitral stenosis is heard best with the bell of the stethoscope touched lightly to the chest wall at the point of maximum apical impulse. The diastolic murmur of mitral stenosis begins in mid-diastole after the opening of the mitral valve, and it may have a presystolic accentuation, which usually is not heard if atrial fibrillation is present. The severity of the mitral stenosis correlates with the duration of the diastolic murmur and not with the intensity of the diastolic murmur. Mitral regurgitation In a prospective study of 1881 older women and 924 older men, mean age 81 years, Doppler echocardiography showed that at least 1þ mitral

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regurgitation was present in 33% of women and in 32% of men (difference not significant; see Table 3) [31]. The most common cause of mitral regurgitation in older women and men is MAC [43]. Doppler echocardiography showed moderate to severe mitral regurgitation in 18% of older persons who had MAC and mild mitral regurgitation in 36% of older persons who had MAC [42]. Other disorders that cause mitral regurgitation in older women and men include CAD, mitral valve prolapse, and rheumatic heart disease. The heart murmur that is associated with mitral regurgitation is heard as an apical holosystolic murmur, late systolic murmur, or early systolic murmur that begins with the first heart sound but ends in mid-systole. A detailed discussion of the management of older persons who have mitral stenosis, mitral regurgitation, and MAC is presented elsewhere [44]. Mitral annular calcium MAC is a chronic degenerative process that increases with age [45]. In a prospective study of 1881 older women and 924 older men, mean age 81 years, the prevalence of MAC was higher in women (52%) than in men (36%) (see Table 3) [31]. Persons who have MAC have a higher prevalence of atrial fibrillation [45,46], new coronary events [47,48], CHF [47], bacterial endocarditis [48], permanent pacemaker implantation [47], thromboembolic stroke [46–51], and transient cerebral ischemic attack [51] than do persons who do not have MAC. Cardiomyopathies Hypertrophic cardiomyopathy is a primary myocardial disorder with a hypertrophied and nondilated left ventricle that is not caused by other cardiovascular disease. In a prospective study of 1881 older women and 924 older men, mean age 81 years, Doppler echocardiography demonstrated that hypertrophic cardiomyopathy was present in 4% of women and in 3% of men (difference not significant; see Table 3) [31]. MAC also was present in 76% of older persons who had hypertrophic cardiomyopathy [52]. Idiopathic dilated cardiomyopathy is a primary disorder of ventricular muscle that can be diagnosed by echocardiography. In a prospective study of 1881 older women and 924 older men, mean age 81 years, echocardiography showed that idiopathic dilated cardiomyopathy was present in 1% of women and men (see Table 3) [31]. A detailed discussion of cardiomyopathies in older persons is presented elsewhere [53].

Congestive heart failure The prevalence and incidence of CHF increase with age [54]. CHF is the most common cause of hospitalization in persons aged 65 years and older.

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CHF developed in 29% of 1160 older men and in 26% of 2464 older women, mean age 81 years [4]. The physician must measure LV ejection fraction in all persons who have CHF and preferably by echocardiography to determine the appropriate therapy for CHF [55–58]. The prevalence of diastolic dysfunction with normal LV ejection fraction in 674 older men and women, mean age 81 years, with CHF was 51% and increased with age [59]. The prevalence of normal LV ejection fraction associated with CHF is higher in older women than in older men [59–63]. Table 5 shows the prevalence of a normal LV ejection fraction in 572 older men and women, mean age 81 years, with CHF associated with prior myocardial infarction or hypertensive heart disease [61]. Dr. Michael W. Rich extensively discusses CHF in older persons elsewhere in this issue. Atrial fibrillation The incidence of chronic atrial fibrillation increases with age [64,65]. In a prospective study of 2101 persons, mean age 81 years, atrial fibrillation was present in 16% of 650 older men and in 13% of 1451 older women (difference not significant) [65]. Atrial fibrillation was present in 5% of persons aged 60 to 70 years, in 14% of persons aged 71 to 80 years, in 13% of persons aged 81 to 90 years, and in 22% of persons aged 91 to 103 years [65]. In a prospective study, chronic atrial fibrillation was present in 16% of 1160 older men and in 13% of 2464 older women, mean age 81 years (P ¼ .019) [4]. In another prospective study of 1699 older persons, those who had chronic atrial fibrillation had a 1.7-fold greater prevalence of MAC, a 17.1-fold greater prevalence of rheumatic mitral stenosis, a 2.2-fold greater prevalence of at least 1þ mitral regurgitation, a 2.3-fold greater prevalence of valvular aortic stenosis, a 2.1-fold greater prevalence of at least 1þ aortic regurgitation, a 2.9-fold greater prevalence of left atrial enlargement, a 2.0fold greater prevalence of LV hypertrophy, and a 2.5-fold greater prevalence of abnormal LV ejection fraction than did older persons who had sinus rhythm [41]. Table 5 Prevalence of normal left ventricular ejection fraction in 572 older women and men who have congestive heart failure associated with previous myocardial infarction or hypertension Normal LVEF(%) Age

Men

Women

60–69 y (n ¼ 38 women and 18 men) 70–79 y (n ¼ 79 women and 54 men) 80–89 y (n ¼ 219 women and 86 men) R 90 y (n ¼ 59 women and 19 men)

22 33 41 47

37 44 59 73

Abbreviation: LVEF, left ventricular ejection fraction. Data from Aronow WS, Ahn C, Kronzon I. Normal left ventricular ejection fraction in older persons with congestive heart failure. Chest 1998;113:867–9.

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Atrial fibrillation is an independent predictor of new coronary events [66,67] and of new thromboembolic stroke in older persons [64,65]. The 3-year incidence of new thromboembolic stroke was higher in older persons who had atrial fibrillation (38%) than in older persons who had sinus rhythm (11%) [65]. The 5-year incidence of thromboembolic stroke was higher in older persons who had atrial fibrillation (72%) than in older persons who had sinus rhythm (24%) [65]. A detailed discussion of the optimal therapy of older persons who have atrial fibrillation is presented elsewhere [68].

Pacemakers In a prospective study of 1153 older persons, mean age 82 years, 4% had a permanent pacemaker implanted for appropriate reasons [69]. In a prospective study, 5% of 1160 older men and 5% of 2464 older women, mean age 81 years, had a permanent pacemaker implanted for appropriate reasons [4]. In another prospective study of 148 older persons, mean age 82 years, who had unexplained syncope, 21 persons (14%) had pauses of longer than 3 seconds detected by 24-hour ambulatory electrocardiograms that required pacemaker implantation. Of these 21 persons, 8 had sinus arrest, 7 had advanced second-degree atrioventricular block, and 6 had atrial fibrillation with a slow ventricular rate that was not induced by drugs. At 38-month follow-up after permanent pacemaker implantation, 86% of the 21 persons had no episodes of recurrent syncope [70].

Summary CAD is the most common cause of death in older persons and was present in 43% of 1160 men and in 41% of 2464 women, mean age 81 years. Hypertension was present in 60% of these older women and in 57% of these older men. The prevalence of valvular aortic stenosis, aortic regurgitation, mitral regurgitation, and MAC increases with age in older men and in older women. The prevalence and incidence of CHF increase with age. CHF is the most common cause of hospitalization in persons aged 65 years and older. The prevalence of normal LV ejection fraction associated with CHF increases with age and is higher in older women than in older men. The prevalence of chronic atrial fibrillation increases with age and was present in 16% of 1160 older men and in 13% of 2464 older women. Atrial fibrillation is an independent predictor of new coronary events and thromboembolic stroke in older persons. Older persons who have unexplained syncope should have 24-hour ambulatory electrocardiograms to determine whether pauses of longer than 3 seconds are present that require permanent pacemaker implantation.

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[22] SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA 1991;265:3255–64. [23] Castelli WP, Wilson PWF, Levy D, et al. Cardiovascular disease in the elderly. Am J Cardiol 1989;63:12H–9H. [24] Wong ND, Wilson PWF, Kannel WB. Serum cholesterol as a prognostic factor after myocardial infarction: The Framingham Study. Ann Intern Med 1991;115:687–93. [25] Aronow WS, Ahn C. Correlation of serum lipids with the presence or absence of coronary artery disease in 1,793 men and women aged R62 years. Am J Cardiol 1994;73:702–3. [26] Corti M-C, Guralnik JM, Salive ME, et al. HDL cholesterol predicts coronary heart disease mortality in older persons. JAMA 1995;274:539–44. [27] Lavie CJ, Milani RV. National Cholesterol Education Program’s recommendations, and implications of ‘‘missing’’ high-density lipoprotein cholesterol in cardiac rehabilitation programs. Am J Cardiol 1991;68:1087–8. [28] Nichols WW, O’Rourke MF, Avolio AP, et al. Effects of age on ventricular-vascular coupling. Am J Cardiol 1985;55:1179–84. [29] Landahl S, Bengtsson C, Sigurdsson JA, et al. Age-related change in blood pressure. Hypertension 1986;8:1044–9. [30] Aronow WS, Ahn C, Kronzon I, et al. Congestive heart failure, coronary events, and atherothrombotic brain infarction in elderly blacks and whites with systemic hypertension and with and without echocardiographic and electrocardiographic evidence of left ventricular hypertrophy. Am J Cardiol 1991;67:295–9. [31] Aronow WS, Ahn C, Kronzon I. Comparison of echocardiographic abnormalities in African-American, Hispanic, and white men and women aged O60 years. Am J Cardiol 2001;87:1131–3. [32] Levy D, Garrison RJ, Savage DD, et al. Left ventricular mass and incidence of coronary heart disease in an elderly cohort. The Framingham Heart Study. Ann Intern Med 1989; 110:101–7. [33] Aronow WS, Koenigsberg M, Schwartz KS. Usefulness of echocardiographic and electrocardiographic left ventricular hypertrophy in predicting new cardiac events and atherothrombotic brain infarction in elderly patients with systemic hypertension or coronary artery disease. Am J Noninvasive Cardiol 1989;3:367–70. [34] Lindroos M, Kupari M, Heikkila J, et al. Prevalence of aortic valve abnormalities in the elderly: an echocardiographic study of a random population sample. J Am Coll Cardiol 1993; 21:1220–5. [35] Aronow WS, Ahn C, Shirani J, et al. Comparison of frequency of new coronary events in older persons with mild, moderate, and severe valvular aortic stenosis with those without aortic stenosis. Am J Cardiol 1998;81:647–9. [36] Aronow WS, Kronzon I. Prevalence and severity of valvular aortic stenosis determined by Doppler echocardiography and its association with echocardiographic and electrocardiographic left ventricular hypertrophy and physical signs of aortic stenosis in elderly patients. Am J Cardiol 1993;72:846–8. [37] Aronow WS, Ahn C, Kronzon I, et al. Prognosis of congestive heart failure in patients aged R62 years with unoperated severe valvular aortic stenosis. Am J Cardiol 1993;72:846–8. [38] Aronow WS, Weiss MB. Aortic valve disease in the elderly. In: Aronow WS, Fleg JL, editors. Cardiovascular disease in the elderly. 3rd edition. New York: Marcel Dekker; 2004. p. 417–42. [39] Aronow WS, Kronzon I. Correlation of prevalence and severity of aortic regurgitation detected by pulsed Doppler echocardiography with the murmur of aortic regurgitation in elderly patients in a long-term health care facility. Am J Cardiol 1989;63:128–9. [40] Aronow WS, Ahn C, Kronzon I, et al. Prognosis of patients with heart failure and unoperated severe aortic valvular regurgitation and relation to ejection fraction. Am J Cardiol 1994;74:286–8.

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[41] Aronow WS, Ahn C, Kronzon I. Echocardiographic findings associated with atrial fibrillation in 1,699 patients aged O60 years. Am J Cardiol 1995;76:1191–2. [42] Aronow WS, Kronzon I. Correlation of prevalence and severity of mitral regurgitation and mitral stenosis determined by Doppler echocardiography with physical signs of mitral regurgitation and mitral stenosis in 100 patients aged 62 to 100 years with mitral annular calcium. Am J Cardiol 1987;60:1189–90. [43] Aronow WS, Schwartz KS, Koenigsberg M. Correlation of murmurs of mitral stenosis and mitral regurgitation with presence or absence of mitral annular calcium in persons older than 62 years in a long-term health care facility. Am J Cardiol 1987;59:181–2. [44] Cheitlin MD, Aronow WS. Mitral regurgitation, mitral stenosis, and mitral annular calcification in the elderly. In: Aronow WS, Fleg JL, editors. Cardiovascular disease in the elderly. 3rd edition. New York: Marcel Dekker; 2004. p. 443–76. [45] Aronow WS, Schwartz KS, Koenigsberg M. Correlation of atrial fibrillation with presence or absence of mitral annular calcium in 604 persons older than 60 years. Am J Cardiol 1987; 59:1213–4. [46] Aronow WS, Ahn C, Kronzon I, et al. Association of mitral annular calcium with new thromboembolic stroke at 44-month follow-up of 2,148 persons, mean age 81 years. Am J Cardiol 1998;81:105–6. [47] Nair CK, Thomson W, Ryschon K, et al. Long-term follow-up of patients with echocardiographically detected mitral annular calcium and comparison with age- and sex- matched control subjects. Am J Cardiol 1989;63:465–70. [48] Aronow WS, Koenigsberg M, Kronzon I, et al. Association of mitral annular calcium with new thromboembolic stroke and cardiac events at 39-month follow-up in elderly patients. Am J Cardiol 1990;65:1511–2. [49] Benjamin EJ, Plehn JF, D’Agostino RB, et al. Mitral annular calcification and the risk of stroke in an elderly cohort. N Engl J Med 1992;327:374–9. [50] Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators. The effect of lowdose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation. N Engl J Med 1990;323:1505–11. [51] Aronow WS, Schoenfeld MR, Gustein H. Frequency of thromboembolic stroke in persons R60 years of age with extracranial carotid arterial disease and/or mitral annular calcium. Am J Cardiol 1992;70:123–4. [52] Aronow WS, Kronzon I. Prevalence of hypertrophic cardiomyopathy and its association with mitral annular calcium in elderly patients. Chest 1988;94:1295–1296. [53] McClung JA, Aronow WS, Belkin RN, et al. Cardiomyopathies in the elderly. In: Aronow WS, Fleg JL, editors. Cardiovascular disease in the elderly. 3rd edition. New York: Marcel Dekker; 2004. p. 489–509. [54] Kannel WB, Belanger AJ. Epidemiology of heart failure. Am Heart J 1991;121:951–7. [55] Konstam M, Dracup K, Baker D, et al. Heart failure: management of patients with left ventricular systolic dysfunction. Quick reference guide for clinicians, No. 11. AHCPR Publication No. 94–0613. Rockville (MD): Agency for Health Care Policy and Research; 1994. [56] Aronow WS. Echocardiography should be performed in all elderly patients with congestive heart failure. J Am Geriatr Soc 1994;42:1300–2. [57] Williams JF Jr, Bristow MR, Fowler MB, et al. Guidelines for the evaluation and management of heart failure. Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Evaluation and Management of Heart Failure). J Am Coll Cardiol 1995;26:1376–98. [58] Aronow WS. Commentary on American Geriatrics Society Clinical Practice Guidelines from AHCPR Guidelines on Heart Failure: evaluation and treatment of patients with left ventricular systolic dysfunction. J Am Geriatr Soc 1998;46:525–9. [59] Aronow WS, Ahn C, Kronzon I. Comparison of incidences of congestive heart failure in older African-Americans, Hispanics, and whites. Am J Cardiol 1999;84:611–2.

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[60] Pernenkil R, Vinson JM, Shah AS, et al. Course and prognosis in patients R70 years of age with congestive heart failure and normal versus abnormal left ventricular ejection fraction. Am J Cardiol 1997;79:216–9. [61] Aronow WS, Ahn C, Kronzon I. Normal left ventricular ejection fraction in older persons with congestive heart failure. Chest 1998;113:867–9. [62] Vasan RS, Larson MG, Benjamin EJ, et al. Congestive heart failure in subjects with normal versus reduced left ventricular ejection fraction. J Am Coll Cardiol 1999;33:1948–55. [63] Gottdiener JS, McClelland RL, Marshall R, et al. Outcome of congestive heart failure in elderly persons: influence of left ventricular systolic function. The Cardiovascular Health Study. Ann Intern Med 2002;137:631–9. [64] Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: The Framingham Study. Stroke 1991;22:983–8. [65] Aronow WS, Ahn C, Gutstein H. Prevalence of atrial fibrillation and association of atrial fibrillation with prior and new thromboembolic stroke in older patients. J Am Geriatr Soc 1996;44:521–3. [66] Kannel WB, Abbott RD, Savage DD, et al. Epidemiologic features of chronic atrial fibrillation. The Framingham Study. N Engl J Med 1982;306:1018–22. [67] Aronow WS, Ahn C, Mercando AD, et al. Correlation of atrial fibrillation, paroxysmal supraventricular tachycardia, and sinus rhythm with incidences of new coronary events in 1,359 patients, mean age 81 years, with heart disease. Am J Cardiol 1995;75:182–4. [68] Aronow WS. Management of the older person with atrial fibrillation. J Gerontol A Biol Sci Med Sci 2002;57A:M352–63. [69] Aronow WS. Correlation of arrhythmias and conduction defects on the resting electrocardiogram with new cardiac events in 1,153 elderly patients. Am J Noninvasive Cardiol 1991;75:182–4. [70] Aronow WS, Mercando AD, Epstein S. Prevalence of arrhythmias detected by 24-hour ambulatory electrocardiography and value of antiarrhythmic therapy in elderly patients with unexplained syncope. Am J Cardiol 1992;70:408–10.

Med Clin N Am 90 (2006) 863–885

Heart Failure in Older Adults Michael W. Rich, MD Department of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8086, St. Louis, MO 63110, USA

Heart failure (HF) affects approximately 5 million Americans, and more than 550,000 new cases are reported each year [1,2]. Additionally, despite recent advances in the diagnosis and treatment of HF, as well as reductions in age-adjusted mortality from coronary heart disease and hypertensive cardiovascular disease [1,2], the incidence and prevalence of HF are increasing, primarily because of the aging of the population [3]. HF is predominantly a disorder of the elderly, with prevalence rates increasing exponentially from less than 1% in the population younger than age 50 years to about 10% in individuals older than age 80 years [4]. Consequently, more than 75% of hospitalizations for HF occur in persons 65 years of age or older [5], the median age for all HF admissions is 75 years [6], and HF is the leading indication for hospitalization in older adults [5,6]. HF also is a major source of chronic disability and impaired quality of life in the elderly [7], and it is a common factor that contributes to institutionalization in a chronic care facility. Furthermore, HF is the most costly medical illness in the United States, with annual expenditures in excess of $40 billion, which represents 5.4% of the total health care budget [8]. HF also contributes to more than 250,000 deaths each year [1,2], and 88% of these deaths are in persons older than 65 years [6]. Thus, HF imposes a striking clinical and economic burden on our society. Given the projected doubling in the number of Americans older than 65 years of age in the next 3 decades, it may be anticipated that the magnitude of this burden will continue to increase and potentially result in a public health crisis.

Pathophysiology Aging is associated with significant alterations in cardiovascular structure and function that diminish homeostatic reserve and predispose older E-mail address: [email protected] 0025-7125/06/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.mcna.2006.05.012 medical.theclinics.com

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individuals to the development of HF (Box 1) [3,9,10]. In general, cardiac output is determined by four factorsdheart rate, preload, afterload, and contractile statedand age-related cardiovascular changes impact significantly on each of these parameters. Thus, diminished b-adrenergic responsiveness and degenerative changes in the sinoatrial node impair the heart rate response to stress; impaired myocardial relaxation and decreased compliance compromise ventricular filling and alter preload; increased vascular stiffness and a reduction in b2-mediated systemic vasodilation serve to increase afterload; and reduced capacity of mitochondria to generate ATP, in conjunction with diminished responsiveness to b1-stimulation, lead to a decrease in contractile reserve. In the absence of cardiovascular disease, these changes have minimal effect on resting cardiac performance (ie, resting left ventricular systolic function and cardiac output are reasonably well preserved, even at advanced age). A marked age-dependent reduction in cardiovascular reserve, however, attenuates the heart’s ability to respond to common stressors, such as ischemia, tachycardia (eg, due to atrial fibrillation), systemic illness (eg, infections), and physical exertion. As a result, clinical events that generally are tolerated well in younger individuals frequently precipitate HF in older persons. An important feature that distinguishes HF in the elderly from HF in middle age is a striking increase in the proportion of cases that occurs in the setting of normal or near normal left ventricular systolic function [11,12]. Aging is associated with impaired left ventricular filling that is due to changes in myocardial relaxation and compliance. These alterations lead to a shift in the left ventricular pressure–volume relationship, such that small increments in left ventricular volume result in greater increases in left ventricular diastolic pressure [13]. This increase in diastolic pressure further

Box 1. Principal effects of aging on cardiovascular structure and function Increased vascular ‘‘stiffness,’’ impedance to ejection, and pulse wave velocity Impaired left ventricular early diastolic relaxation and mid-to-late diastolic compliance Diminished responsiveness to neurohumoral stimuli, especially b1 and b2 adrenergic stimulation Altered myocardial energy metabolism and reduced mitochondrial ATP-production capacity Reduced number of sinus node pacemaker cells and impaired sinoatrial function Endothelial dysfunction and vasomotor dysregulation Net effect: Marked reduction in cardiovascular reserve

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compromises left ventricular filling, and leads to increases in left atrial, pulmonary venous, and pulmonary capillary pressures, and, thus, predisposes to pulmonary congestion and HF. ‘‘Diastolic’’ HF, as it is often called, accounts for less than 10% of HF cases in persons who are younger than age 60, but more than 50% of cases after age 75 [11,12,14]. Diastolic HF also is more common in women than in men, and accounts for nearly two thirds of all HF cases among women who are older than age 80 [12]. Clinical features Symptoms and signs Exertional dyspnea, orthopnea, lower extremity swelling, and impaired exercise tolerance are the cardinal symptoms of HF at younger and older age; however, with increasing age, which often is accompanied by a progressively more sedentary lifestyle, exertional symptoms become less prominent [15]. Conversely, atypical symptoms, such as confusion, somnolence, irritability, fatigue, anorexia, or diminished activity level, become increasingly more common manifestations of HF, especially after age 80. Physical signs of HF include elevated jugular venous pressure, hepatojugular reflux, an S3 gallop, pulmonary rales, and dependent edema. Each of these features occurs less commonly in older patients who have HF, in part because of the increasing prevalence of diastolic HF, in which signs of rightsided HF are a late manifestation and a third heart sound typically is absent. Conversely, behavioral changes and altered cognition, which may range from subtle abnormalities to overt delirium, frequently accompany HF at elderly age, particularly among institutionalized or hospitalized patients [16]. Diagnosis Accurate diagnosis of the HF syndrome at older age is confounded, in part, by the increasing prevalence of atypical symptoms and signs [15]. Additionally, exertional symptoms may be attributable to noncardiac causes, such as pulmonary disease, anemia, depression, physical deconditioning, or aging itself. Likewise, peripheral edema may be due to venous insufficiency, hepatic or renal disease, or medication side effects (eg, calcium channel blockers), and pulmonary crepitus may be due to atelectasis or chronic lung disease. Despite these limitations, careful clinical assessment for the presence of multiple symptoms and signs should lead to the correct diagnosis in most cases. Chest radiography is indicated when HF is suspected, and it remains the most useful diagnostic test for determining the presence of pulmonary congestion; however, chronic lung disease or altered chest geometry (eg, due to kyphosis) may confound interpretation of the chest radiograph in elderly individuals.

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Recently, plasma B-type natriuretic peptide (BNP) levels were shown to be a valuable aid in distinguishing dyspnea that is due to HF from that which is related to other causes, such as pulmonary disorders [17]. BNP levels tend to be elevated in systolic and diastolic HF [18,19], and they correlate with response to therapy and prognosis [20–22]. BNP levels also increase, however, with age in healthy individuals who do not have HF, particularly women (Fig. 1), and, as a result, the specificity and predictive accuracy of BNP levels declines with age [23]. Nonetheless, in cases of diagnostic uncertainty, a low or normal BNP level effectively excludes HF, whereas a markedly elevated level provides strong evidence in support of the diagnosis. Proper management of HF is critically dependent on establishing the pathophysiology of left ventricular dysfunction (ie, systolic versus diastolic), determining the primary and any secondary causes (Box 2), and identifying potentially treatable precipitating or contributory factors (Box 3). Differentiating systolic from diastolic dysfunction requires an assessment of left ventricular contractility by echocardiography, radionuclide ventriculography, magnetic resonance imaging (MRI), or contrast angiography. Among these, echocardiography is the most widely used and clinically useful noninvasive test for evaluating systolic and diastolic function, and echocardiography is recommended for all patients who have newly diagnosed HF or unexplained disease progression [24]. Other diagnostic studies that may be indicated in selected patients include an assessment of thyroid function (especially in the presence of atrial fibrillation), an exercise or pharmacologic stress test to evaluate for the presence and severity of ischemia, and cardiac catheterization if revascularization or other corrective procedure (eg, valve repair or replacement) is being contemplated.

70

BNP level, pg/mL

60 50 40 MEN WOMEN

30 20 10 0 45–54

55–64

65–74

75+

Age, years Fig. 1. Mean BNP levels in healthy volunteers according to age and gender. (Adapted from Redfield MM, Rodeheffer RJ, Jacobsen SJ, et al. Plasma brain natriuretic peptide concentration: impact of age and gender. J Am Coll Cardiol 2002;40:977; with permission.)

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Box 2. Common causes of heart failure in older adults Coronary artery disease Acute myocardial infarction Chronic ischemic cardiomyopathy Hypertensive heart disease Hypertensive hypertrophic cardiomyopathy Valvular heart disease Aortic stenosis or insufficiency Mitral stenosis or insufficiency Prosthetic valve malfunction Infective endocarditis Cardiomyopathy Dilated (nonischemic) Alcohol Chemotherapeutic agents Inflammatory myocarditis Idiopathic Hypertrophic Obstructive Nonobstructive Restrictive (esp. amyloid) Pericardial disease Constrictive pericarditis High output syndromes Chronic anemia Thiamine deficiency Hyperthyroidism Arteriovenous shunting Age-related diastolic dysfunction

Etiology and precipitating factors Systemic hypertension and coronary heart disease account for 70% to 80% of cases of HF at older age [25,26]. Hypertension is the most common cause in older women, particularly those with preserved systolic function [12,26]. In older men, HF is attributable more often to coronary heart disease [26]. Other common causes include valvular heart disease (especially aortic stenosis and mitral regurgitation) and nonischemic cardiomyopathy

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Box 3. Common precipitants of heart failure in older adults Myocardial ischemia or infarction Uncontrolled hypertension Dietary sodium excess Medication noncompliance Excess fluid intake Self-induced Iatrogenic Arrhythmias Supraventricular, especially atrial fibrillation Ventricular Bradycardia, especially sick sinus syndrome Associated medical conditions Fever Infections, especially pneumonia or sepsis Hyperthyroidism or hypothyroidism Anemia Renal insufficiency Thiamine deficiency Pulmonary embolism Hypoxemia due to chronic lung disease Drugs and medications Alcohol b-Adrenergic blockers (including ophthalmologicals) Calcium channel blockers Antiarrhythmic agents Nonsteroidal anti-inflammatory drugs Glucocorticoids Mineralocorticoids Estrogen preparations Antihypertensive agents (eg, clonidine, minoxidil)

(see Box 2). HF in the elderly frequently is multifactorial, and, thus, it is essential to identify all potentially treatable causes. In addition to determining etiology, it is important to identify factors that precipitate or contribute to HF exacerbations (see Box 3). Noncompliance with medications and diet is the most common cause of recurrent HF admissions [27,28], and patients should be questioned closely about their dietary and medication habits. Other common factors that contribute to worsening symptoms include ischemia, volume overload that is due to excess fluid

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intake (self-inflicted or iatrogenic) [29], tachyarrhythmias (especially atrial fibrillation or flutter), intercurrent infections, anemia, thyroid disease, and various medications or toxins (eg, alcohol). Comorbidity A hallmark of aging is the increasing prevalence of multiple comorbid conditions, many of which impact directly or indirectly on the diagnosis, clinical course, treatment, and prognosis of HF in the elderly (Table 1) [30]. As shown in Fig. 2, Medicare beneficiaries who are hospitalized with HF typically have two to six coexisting noncardiac conditions, and many patients have seven or more such conditions [31]. Additionally, the number of noncardiac comorbidities is a strong predictor of rehospitalization within 1 year [31]. Although discussion of individual comorbidities is beyond the scope of this article, it is important to recognize that HF in the elderly virtually never occurs in isolation; therefore, diagnosis and management must be viewed in the context of the patient’s other comorbidities and competing risks [30].

Management The principal goals of HF therapy are to relieve symptoms, maintain or enhance functional capacity and quality of life, preserve independence, and extend survival. Although it often is stated that quality of life is more important than quantity of life in the elderly, this, in fact, is a matter of personal preference. Furthermore, because the elderly HF population is characterized by marked heterogeneity in terms of lifestyle, comorbidity, and personal goals and perspectives, management of HF in the elderly first and foremost must be individualized to each patient’s circumstances and needs. The basic approach to HF management involves identification and treatment of the underlying etiology and contributing factors, implementation of an effective therapeutic regimen, and coordination of care through the use of a multidisciplinary team. Etiology and precipitating factors Although HF in the elderly rarely is ‘‘curable,’’ proper treatment of the underlying etiology often improves symptoms and delays disease progression. Thus, hypertension should be treated aggressively [32], and coronary heart disease should be managed appropriately with medications or percutaneous or surgical revascularization. Patients who have severe aortic or mitral valve disease should be considered for surgery in the absence of specific contraindications [33–36]. Atrial fibrillation, a common precipitant of HF in older adults, should be treated with rate-controlling agents, warfarin, and, in some cases, restoration of normal sinus rhythm [37,38]. Anemia, thyroid

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Table 1 Common comorbidities in older patients Condition

Implications

Renal dysfunction Anemia Chronic lung disease Cognitive dysfunction Arthritis

Exacerbated by diuretics, ACE inhibitors Worsens symptoms and prognosis Contributes to uncertainty about diagnosis/volume status Interferes with dietary, medication, activity compliance NSAIDs promote salt and water retention, antagonize HF and blood pressure medications Worsens prognosis, interferes with compliance Exacerbated by vasodilators, diuretics, b-blockers Aggravated by diuretics, ACE inhibitors (cough) Interferes with compliance Exacerbated by dietary restrictions Compliance issues, drug interactions Exacerbated by hospitalization; increased fall risk

Depression, social isolation Postural hypotension, falls Urinary incontinence Sensory deprivation Nutritional disorders Polypharmacy Frailty

Abbreviations: ACE, angiotensin-converting enzyme; NSAIDs, nonsteroidal anti-inflammatory drugs.

disease, and other systemic illnesses should be identified and treated accordingly. Therapy for diabetes and dyslipidemia should be optimized, smoking should be discouraged strongly, and a suitable level of regular physical activity should be prescribed. Alcohol intake should be limited to no more than two drinks per day in men and one drink per day in women, and alcohol use should be proscribed strictly in patients who have suspected alcoholic cardiomyopathy. The importance of compliance with medications and dietary restrictions, including avoidance of excessive fluid intake, cannot be overemphasized. Nonsteroidal anti-inflammatory drugs are used widely by older individuals to treat arthritis and relieve chronic pain, but these agents promote sodium

18% 16% 14% 12% 10% 8% 6% 4% 2% 0%

N = 122,630 Mean age 79.6 years Female = 60%

0

1

2

3

4

5

6

7

8

9 10+

Number of Non-Cardiac Comorbidities Fig. 2. Prevalence of noncardiac comorbidities in Medicare beneficiaries who have heart failure. (Adapted from Braunstein JB, Anderson GF, Gerstenblith G, et al. Noncardiac comorbidity increases preventable hospitalizations and mortality among Medicare beneficiaries with chronic heart failure. J Am Coll Cardiol 2003;42:1228; with permission.)

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and water retention, interfere with the actions of angiotensin-converting enzyme (ACE) inhibitors and other anti-hypertensive agents, and may worsen renal function; their use should be avoided whenever possible [39]. Similarly, the use of other medications that may aggravate HF should be monitored closely. Pharmacotherapy The design of an effective therapeutic regimen is based, in part, on whether the patient has predominantly systolic or predominantly diastolic left ventricular dysfunction. Although these two abnormalities frequently coexist (virtually all individuals over age 70 have some degree of diastolic dysfunction), for purposes of this discussion patients with an ejection fraction of less than 45% (ie, moderate or severe left ventricular systolic dysfunction) will be considered as having systolic HF, whereas patients with an ejection fraction of at least 45% will be considered as having diastolic HF. Systolic heart failure In the past 25 years there has been considerable progress in the treatment of systolic HF. Although most studies have excluded individuals who were older than 75 to 80 years of age, or have enrolled too few elderly subjects to permit definitive conclusions, available data indicate that older patients respond to standard therapies as well or better than do younger patients. Therefore, current recommendations for drug treatment of systolic HF are similar in younger and older patients [24]. Angiotensin-converting enzyme inhibitors. ACE inhibitors are the cornerstone of therapy for left ventricular systolic dysfunction, whether or not clinically overt HF is present [24], and there is strong evidence that ACE inhibitors are as effective in older patients as in younger patients, both in terms of reducing mortality and improving quality of life [40,41]. Conversely, older patients are more likely to have potential contraindications to ACE inhibitors (eg, renal dysfunction, renal artery stenosis, orthostatic hypotension), and they also may be at increased risk for ACE inhibitor– related side effects, such as worsening renal function, electrolyte disturbances, and hypotension. Nonetheless, a trial of ACE inhibitors is indicated in virtually all older patients who have documented left ventricular systolic dysfunction. Blood pressure, renal function, and serum potassium levels should be monitored during the period of drug initiation and dose titration, and periodically during maintenance therapy. Angiotensin receptor blockers. Angiotensin receptor blockers (ARBs) have a more favorable side effect profile than do ACE inhibitors, but there is insufficient evidence to conclude that the effects of ARBs on major clinical

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outcomes (eg, death, hospitalizations) are equivalent to those of ACE inhibitors [42–44]. Recent studies, however, indicate that ARBs reduce mortality and hospitalizations in patients who have systolic HF who are intolerant to ACE inhibitors because of cough or other side effects [45,46]. Additionally, combining an ARB with an ACE inhibitor improves outcomes compared with an ACE inhibitor alone [47,48], although in one study triple therapy with an ACE inhibitor, a b-blocker, and an ARB was associated with increased mortality compared with treatment with only two of these classes of agents [47]. Based on available evidence, and pending the results of ongoing clinical trials, ACE inhibitors still should be considered first-line therapy for HF, but ARBs offer an excellent alternative for patients who are intolerant to ACE inhibitors, and as conjunctive therapy in patients who have persistent symptoms despite conventional treatment. Hydralazine and isosorbide dinitrate. The combination of hydralazine, 75 mg four times a day, and isosorbide dinitrate, 40 mg four times a day, was associated with decreased mortality in a small trial of patients who had HF who were younger than 75 years of age [49]. Although ACE inhibitors are superior to hydralazine-nitrates in improving survival [50], the combination provides an additional alternative for patients who are intolerant to ACE inhibitors. Recently, this combination was shown to be of particular benefit in men of African descent [51]. Side effects are common with hydralazine and high-dose nitrates, and the dosing schedule (four times daily) is a particular disadvantage for older patients. b-Blockers. b-Blockers, once viewed widely as contraindicated in patients who have HF, have been shown to improve left ventricular function and decrease mortality in a broad population of patients who have HF, including those who have New York Heart Association (NYHA) class IV symptoms and patients who are up to 80 years of age [52–55]. As a result, b-blockers are now considered standard therapy for clinically stable patients without major contraindications [24]. The use of b-blockers in older patients may be limited by a higher prevalence of bradyarrhythmias and severe chronic lung disease, and older patients also may be more susceptible to the development of fatigue and impaired exercise tolerance during long-term b-blocker administration. Carvedilol, metoprolol, and bisoprolol have been shown to improve outcomes in patients who have systolic HF, and a recent study found that carvedilol, 25 mg twice daily, was more effective than was metoprolol, 50 mg twice daily, in reducing mortality [56]. Contraindications to b-blockade include marked sinus bradycardia (resting heart rate !45–50 beats per minute), PR interval of at least 0.24 seconds, heart block greater than first degree, systolic blood pressure less than 90 to 100 mm Hg, active bronchospastic lung disease, and severe decompensated HF.

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Digoxin. Digoxin improves symptoms and reduces hospitalizations in patients who have symptomatic systolic HF that is treated with ACE inhibitors and diuretics, but has no effect on total or cardiovascular mortality [57]. The effects of digoxin are similar in younger and older patients, including octogenarians [58]. Although digoxin is no longer a first-line agent, it remains a useful drug for the treatment of systolic HF in patients of all ages who have limiting symptoms despite standard therapy. The volume of distribution and renal clearance of digoxin decline with age. In addition, recent data indicate that the optimal therapeutic concentration for digoxin is 0.5 to 0.8 ng/ml [59] (ie, substantially lower than the traditional therapeutic range of 0.8 to 2.0 ng/mL). Moreover, higher concentrations of digoxin are associated with increased toxicity but no greater efficacy [59,60]. For most older patients with preserved renal function (estimated creatinine clearance R60 cm3/min), digoxin, 0.125 mg/d, provides a therapeutic effect. Lower dosages should be used in patients who have renal insufficiency. Although routine monitoring of serum digoxin levels is no longer recommended, it seems reasonable to measure the serum digoxin concentration 2 to 4 weeks after initiating therapy to ensure that the level does not exceed 0.8 ng/mL. Additionally, a digoxin level should be obtained whenever digoxin toxicity is suspected. Digoxin side effects include arrhythmias, heart block, gastrointestinal disturbances, and altered neurologic function (eg, visual disturbances). Although older patients often are believed to be at increased risk for digitalis toxicity, this was not confirmed in a recent analysis from the Digitalis Investigation Group trial [58]. Diuretics. Diuretics are an essential component of therapy for most patients who have HF, and are the most effective agents for relieving congestion and maintaining euvolemia. Some patients who have mild HF can be controlled with a thiazide diuretic, but most require a loop diuretic, such as furosemide or bumetanide. In patients who have more severe HF or significant renal dysfunction (serum creatinine R2.0 mg/dL), the addition of metolazone, 2.5 to 10 mg daily, may be necessary to achieve effective diuresis. In general, diuretic dosages should be titrated to eliminate signs of pulmonary and systemic venous congestion. Common side effects include worsening renal function (often due to overdiuresis) and electrolyte disorders. Aldosterone antagonists. Spironolactone is a weak, potassium-sparing diuretic that acts by antagonizing aldosterone. Recently, the addition of spironolactone, 12.5 to 50 mg daily, to standard HF therapy was shown to reduce mortality in patients who had NYHA class III–IV systolic HF, with similar benefits in older and younger patients [61,62]. Eplerenone, a selective aldosterone antagonist, also was shown to reduce mortality and sudden cardiac death in patients who had left ventricular dysfunction following

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acute myocardial infarction [63]. Spironolactone and eplerenone are contraindicated in patients who have severe renal insufficiency or hyperkalemia. Additionally, up to 10% of patients who are treated with spironolactone develop painful gynecomastia; this side effect occurs less frequently with eplerenone. Older patients who receive spironolactone in combination with an ACE inhibitor are at increased risk for hyperkalemia, particularly in the presence of preexisting renal insufficiency or diabetes, and at dosages in excess of 25 mg/d [64]. Approach to treatment. Fig. 3 provides a suggested approach to the pharmacologic treatment of systolic HF. All patients who have left ventricular systolic dysfunction, whether asymptomatic or symptomatic, should receive an ACE inhibitor (or an ARB or alternative vasodilator if ACE inhibitors are contraindicated or not tolerated). Patients with stable symptoms and no contraindications also should receive a b-blocker, and diuretics should be administered in sufficient doses to maintain euvolemia. Digoxin or an ARB should be considered in patients who remain symptomatic despite the above regimen, and spironolactone should be used in patients who have persistent NYHA class III–IV symptoms. Diastolic heart failure Despite the fact that more than 50% of elderly patients who have HF have preserved left ventricular systolic function [11,12], until recently none of the major HF trials has targeted this disorder specifically. As a result, treatment of diastolic HF remains largely empiric. As with systolic HF, the underlying cardiac disorder and associated contributing conditions should be treated appropriately. In particular, hypertension and coronary heart disease should be managed aggressively. Diuretics should be used judiciously to relieve congestion while avoiding overdiuresis and prerenal azotemia. Topical or oral nitrates may be beneficial in reducing pulmonary

Fig. 3. Approach to treatment of systolic heart failure. Shaded areas represent treatments demonstrated to be beneficial in prospective randomized clinical trials.

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congestion and orthopnea. Based on the results of the Heart Outcomes Prevention Evaluation [65], an ACE inhibitor, such as ramipril, 2.5 to 10 mg daily, is appropriate for most older adults who have vascular disease, but the value of ACE inhibitors in the treatment of diastolic HF per se has not been established. Similarly, the role of ARBs in the management of diastolic HF is evolving. In the recently reported CHARM-preserved trial (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity), the ARB candesartan reduced HF admissions by 16% but had no effect on mortality in patients who had HF and a left ventricular ejection fraction of greater than 40% [66]. The mean age of patients in the CHARM-preserved trial was 67 years, and 807 patients (27% of the total population) were at least 75 years of age. b-blockers are indicated in patients who have coronary heart disease (especially previous myocardial infarction), and the recently reported Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors with Heart Failure trial suggested that the b-blocker nebivolol may be beneficial in older patients who have systolic or diastolic HF [67] . Calcium channel blockers are effective antihypertensive agents in the elderly, and these drugs may provide symptomatic palliation in selected patients who have diastolic HF [68]. Digoxin, in addition to its inotropic effect, also facilitates diastolic relaxation, and may improve symptoms and reduce HF hospitalizations in patients with preserved systolic function [57,58]. In summary, the physician who is treating diastolic HF is presented with an array of therapeutic options, none of proven benefit, and therapy should be individualized and guided by prevalent comorbidities and the observed response to specific therapeutic interventions. Device therapy Although most patients who have HF can be managed effectively with behavioral interventions and medications, implantable devices are playing an increasingly important role in the management of selected subgroups of the HF population. Cardiac pacemakers Aging is associated with a progressive decline in the number of functioning sinus nodal pacemaker cells, which often leads to the ‘‘sick sinus syndrome,’’ characterized by inappropriate sinus bradycardia, sinus pauses, and chronotropic incompetence (failure to increase heart rate adequately in response to increased demands) [69]. Because cardiac output is directly proportional to heart rate (cardiac output ¼ heart rate
stroke volume), age-related bradyarrhythmias may contribute to HF symptoms and impaired exercise tolerance. Because there is no effective medical therapy for sick sinus syndrome, implantation of a pacemaker is appropriate in symptomatic patients. The use of b-blockers also may precipitate symptomatic

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bradyarrhythmias in elderly patients who have HF. Because b-blockers improve ventricular function and reduce mortality and hospitalizations in patients who have systolic HF [52–55], placement of a pacemaker often is preferable to discontinuation of b-blocker therapy. Cardiac resynchronization therapy Recently, a new role has evolved for pacemakers in treating selected patients who have advanced HF. Approximately 30% of patients who have HF have left bundle branch block or an intraventricular conduction abnormality that results in significant prolongation of the QRS interval (R120 milliseconds). In these patients, left ventricular contraction often is dysynchronous and out of phase with right ventricular contraction. Biventricular pacing, with one lead pacing the right ventricle and a second lead pacing the left ventricle through retrograde insertion into the coronary sinus, can ‘‘resynchronize’’ ventricular contraction, and, thus, improve ejection fraction and cardiac output [70,71]. The addition of atrial pacing may provide further benefit by optimizing the timing of atrial and ventricular contraction. The benefits of cardiac resynchronization therapy in improving ejection fraction, reducing left ventricular cavity size, enhancing exercise tolerance and quality of life, and decreasing mortality have been well documented in several randomized trials that involved patients who had advanced HF symptoms (NYHA class III–IV), reduced ejection fractions, and prolonged QRS durations [72–76]. Although the use of biventricular pacemakers in older patients must be individualized, cardiac resynchronization therapy is a reasonable option for carefully selected older patients who have advanced HF symptoms despite conventional therapies. Implantable cardioverter defibrillators Approximately 40% of all deaths in patients who have HF are attributable to ventricular tachycardia (VT) and ventricular fibrillation (VF). Implantable cardioverter defibrillators (ICDs) have the capacity to recognize VT and VF, and to restore normal rhythm by pacing techniques (in the case of VT) or by delivering an intracardiac electrical shock (refractory VT or VF). Moreover, these devices improve survival significantly in certain high-risk subgroups of the HF population, including those who have symptomatic sustained VT, ischemic or nonischemic cardiomyopathy with ejection fraction less than 35% or restricted cardiac arrest [77–80]. The survival benefit of ICDs is greatest in patients who are older than 70 years of age with ejection fractions of less than 35% and NYHA class III or IV HF symptoms [81]. In the United States, more than half of ICDs are implanted in patients 65 years of age or older; however, despite the established benefits of ICDs in appropriately selected patients, the clinical role of ICDs in elderly patients who have HF remains a subject of debate [82–84]. These devices are expensive, with a total cost of approximately $40,000 to $50,000 per device,

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although a $10,000 ‘‘generic’’ version recently has gained approval. Additionally, the societal cost burden is likely to increase substantially as the indications for these devices continue to expand. There also are ethical questions, such as how and when to turn off the device in the terminal stages of HF, or in cases where another life-threatening illness develops (eg, stroke or cancer). In part for these reasons, many older patients may elect to forego ICD implantation, even though survival may be enhanced. Although additional study is needed, it is clear that the use of ICDs must be individualized, and that older age should not constitute the sole grounds for withholding ICD therapy. Multidisciplinary care The presence of multiple comorbid conditions, polypharmacy, dietary concerns, and a host of psychosocial and financial issues frequently complicate the management of HF in older patients. Moreover, these factors often contribute to poor outcomes in older adults, including recurrent hospitalizations [28,85]. To address these issues, and to provide comprehensive, yet individualized, care for older patients who have HF, a coordinated multidisciplinary approach is recommended. Several recent studies have documented the efficacy of multidisciplinary HF disease management programs in reducing hospitalizations and improving quality of life in older patients, and these interventions also were reported to decrease overall medical costs [86–88]. Elements of an effective HF disease management program include patient and caregiver education, enhancement of self-management skills, optimization of pharmacotherapy (including consideration of polypharmacy issues), and close follow-up. The structure of an HF disease management team is similar to that of a multidisciplinary geriatric assessment team, and typically includes a nurse coordinator or case manager, dietitian, social worker, clinical pharmacist, home health representative, primary care physician, and cardiology consultant. Specific goals of disease management are to improve patient compliance with medications, diet, and exercise recommendations by enhancing education and self-management skills; to provide close follow-up and improved health care access through telephone contacts, home health visits, and nurse or physician office visits; and to optimize the medication regimen by promoting physician adherence to recommended HF treatment guidelines [24], simplifying and consolidating the regimen when feasible, eliminating unnecessary medications, and minimizing the risks for drug–drug and drug–disease interactions. Exercise HF and normal aging are associated with reduced exercise capacity, in part due to sarcopenia (loss of muscle mass) and alterations in skeletal

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muscle blood flow and metabolism. Regular physical activity improves exercise performance in healthy older adults, as well as in those who have HF, and regular exercise is now recommended for most older patients who have HF [24,89–93]. Although supervised exercise programs have been associated with the greatest improvements in exercise performance, such programs are not feasible for most older patients because of the lack of availability, travel concerns, and cost constraints. Therefore, most older patients who have HF should be encouraged to engage in a self-monitored home exercise program that includes stretching exercises, strengthening exercises, and aerobic activities. Stretching increases or maintains muscle flexibility and decreases the risk for injury. Strength training increases muscle mass and reduces the risk for falls and frailty [94]. Aerobic exercise leads to improved physical performance and quality of life, and may increase the likelihood that older adults will remain independent in activities of daily living [90–93]. Contraindications to exercise in elderly patients who have HF include decompensated HF, unstable coronary disease or arrhythmias, neurologic or muscular disorders that preclude participation in an exercise program, or any other condition that would render exercise unsafe. Additionally, patients should be instructed to stop exercising and contact their physician if they develop chest pain, undue shortness of breath, dizziness or syncope, or any other symptom that may indicate clinical instability. End of life The overall 5-year survival rate for older patients who have established HF is less than 50% (ie, the prognosis is worse than for most forms of cancer) [95–97]. Clinical features that portend a less favorable outcome include older age, more severe symptoms and functional impairment, lower left ventricular ejection fraction, underlying coronary heart disease, and impaired renal function [98]. Older patients who have advanced HF, as evidenced by NYHA class III–IV symptoms, have a 1-year mortality of 25% to 50%; for these patients, HF can be considered a terminal illness. Additionally, all patients who have HF are at risk for sudden arrhythmic death, which may occur during periods of apparent clinical stability. For these reasons, it is appropriate to address end-of-life issues early in the course of HF care, and to reconsider these issues periodically as the disease progresses or when changes in clinical status occur. Patients should be encouraged to develop an advance directive and to appoint a durable power of attorney. The advance directive should be as explicit as possible in defining circumstances under which the patient does not want to be hospitalized, intubated, subjected to other life-sustaining interventions (eg, a feeding tube), or resuscitated. Because patients often change their minds about these issues as clinical circumstances evolve [99], it is important to maintain open communication throughout the disease process.

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End-stage HF is accompanied frequently by considerable discomfort and anxiety, and data from the Study to Understand Prognoses and Preferances for Outcomes and Risks of Treatments indicate that most patients and families express concerns about the quality of end-of-life care [100,101]. A cardinal principal of end-of-life care is to provide adequate relief of pain and suffering through the judicious use of conventional therapies in conjunction with narcotics (eg, morphine), sedatives (eg, benzodiazepines), and other comfort measures. Equally important is the provision of emotional support for the patient and family, assisted by nurses, members of the clergy, social service representatives, and other qualified health care professionals.

Future directions In light of the high prevalence and poor prognosis that are associated with HF in the elderly, it is evident that more effective means for the prevention and treatment of this disorder are needed. The most effective preventive strategies involve aggressive treatment of established risk factors for the development of HF (ie, hypertension and coronary heart disease) [102–108]. Similarly, it is likely that smoking cessation, weight control in obese patients, and aggressive control of diabetes will lead to a reduction in HF. In addition to existing therapies, several new pharmacologic and technologic treatments for HF are under active investigation (Box 4). Although it

Box 4. New approaches to the treatment of chronic heart failure Pharmacologic agents Neutral endopeptidase inhibitors Endothelin receptor antagonists Cytokine inhibitors Calcium sensitizers Therapeutic angiogenesis and antiangiogenesis Inhibition of apoptosis Gene therapy and pharmacogenomics Hereditary disorders (eg, cardiomyopathies, dyslipidemias) Modulation of signaling pathways Targeted therapy based on specific genetic profile Biventricular pacing Implantable assist devices Cell transplantation and growth factor therapy Xenotransplantation Prevention of cardiovascular aging

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is difficult to project which of these new therapies will come into widespread clinical use, it is likely that the management of HF will undergo substantial evolution over the course of the next several decades.

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[60] Slatton ML, Irani WN, Hall SA, et al. Does digoxin provide additional hemodynamic and autonomic rhythm? J Am Coll Cardiol 1997;29:1206–13. [61] Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999;341:709–17. [62] Pitt B, Perez A. for the Randomized Aldactone Study Investigators. Spironolactone in patients with heart failure. N Engl J Med 2000;342:133–4. [63] Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003;348: 1309–21. [64] Wrenger E, Muller R, Moesenthin M, et al. Interaction of spironolactone with ACE inhibitors or angiotensin receptor blockers: analysis of 44 cases. BMJ 2003;327:147–9. [65] Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:145–53. [66] Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved trial. Lancet 2003;362:777–81. [67] Flather MD, Shibata MC, Coats AJ, et al. Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J 2005;26(3):215–25. [68] Setaro JF, Zaret BL, Schulman DS, et al. Usefulness of verapamil for congestive heart failure associated with abnormal left ventricular diastolic filling and normal left ventricular systolic performance. Am J Cardiol 1990;66:981–6. [69] Adan V, Crown LA. Diagnosis and treatment of sick sinus syndrome. Am Fam Phys 2003; 67:1725–32. [70] Kerwin WF, Botvinick EH, O’Connell JW, et al. Ventricular contraction abnormalities in dilated cardiomyopathy: effect of biventricular pacing to correct interventricular dyssynchrony. J Am Coll Cardiol 2000;35:1221–7. [71] Bakker P, Meijburg H, de Bries J, et al. Biventricular pacing in end-stage heart failure improves functional capacity and left ventricular function. J Interv Card Electrophysiol 2000; 4:395–404. [72] Abraham WT, Fisher WG, Smith AL, et al, for the MIRACLE Study Group. Cardiac resynchronization in chronic heart failure. N Engl J Med 2002;346:1845–53. [73] Linde C, Leclercq C, Rex S, et al. Long-term benefits of biventricular pacing in congestive heart failure: results from the Multisite STimulation in Cardiomyopathy (MUSTIC) Study. J Am Coll Cardiol 2002;40:111–8. [74] Bradley DJ, Bradley EA, Braughman KL, et al. Cardiac resynchronization and death from progressive heart failure: a meta-analysis of randomized controlled trials. JAMA 2003;289: 730–40. [75] Young JB, Abraham WT, Smith AL, et al. Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure: the MIRACLE ICD Trial. JAMA 2003;289:2685–94. [76] Cleland JG, Daubert JC, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005;352(15):1539–49. [77] Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 2002;346:877–83. [78] Moss AJ, Hall WJ, Cannom DS, et al. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators. N Engl J Med 1996;335:1933–40. [79] Ezekowitz JA, Armstrong PW, McAlister FA. Implantable cardioverter defibrillators in primary and secondary prevention: a systematic review of randomized, controlled trials. Ann Intern Med 2003;138:445–52.

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Nutritional Disorders in the Elderly Ian McPhee Chapman, MBBS, PhD Department of Medicine, University of Adelaide, Level 6, Eleanor Harrald Building, Royal Adelaide Hospital, North Terrace, 5000 Adelaide, Australia

There are probably no nutritional disorders that occur only in older people. In developed countries, certain nutritional disorders, particularly undernutrition, occur more commonly in older people. Other disorders require different approaches to those used in younger adults. This is particularly so for overweight and obesity, because weight loss in older people may have adverse effects. This article focuses on undernutrition, overnutrition and obesity, and deficiencies (absolute or relative) of vitamins and minerals that are particularly common or important in older people: calcium, vitamins D and B12, and folate.

Changes in appetite and food intake with increasing age On average, people become less hungry and eat less as they get older [1]. Healthy older persons are less hungry and more full before meals, consume smaller meals more slowly, eat fewer snacks between meals, and become satiated more rapidly after eating a standard meal than do younger persons [2,3]. Aging is associated with consumption of a less varied, more monotonous diet. Average daily energy intake decreases by up to 30% between 20 and 80 years [1]. Most of the age-related decrease in energy probably is a response to the decline in energy expenditure that also occurs as people get older. In many individuals, however, the decrease in energy intake is greater than the decrease in energy expenditure, so body weight is lost. This physiologic, age-related reduction in appetite and energy intake has been termed ‘‘the anorexia of aging’’ [3].

Supported by a project grant from the National Health and Medical Research Council of Australia. E-mail address: [email protected] 0025-7125/06/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.mcna.2006.05.010 medical.theclinics.com

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Changes in body weight with increasing age The results of large cross-sectional studies show that, on average, body weight and body mass index (BMI) increase throughout adult life until about age 50 to 60 years, after which they decline [4]. Although some of the decline in mean body weight after age 50 to 60 years is due to the premature death of obese people, there is evidence from longitudinal studies of a decrease in body weight after age 60 years. For example, in one 2-year prospective study, community-dwelling American men older than 65 years lost an average of 0.5% of their body weight per year, and 13.1% of the group had a weight loss of 4% or more per annum [5]. A substantial minority of older people has marked weight changes over time [5,6]. In one study [6], 17% of home-dwelling people in the United States who were older than 65 years lost 5% or more of their initial body weight over 3 years, whereas 13% gained 5% or more. There is evidence for interactive effects on health of body weight category and change in body weight, particularly adverse effects in already underweight people who lose weight.

Changes in body composition with increasing age With normal aging there is a progressive increase in fat and decrease in fat-free mass, which mainly is due to loss of skeletal muscle, with loss of up to 3 kg of lean body mass per decade after age 50 years. Consequently, at any given weight older people, on average, have substantially more body fat than do young adults. In one study, the mean body fat of 20-year-old 80-kg men was 15%, compared with 29% in 75-year-old men of the same weight [7]. The increase in body fat with aging is multifactorial in origin; decreased physical activity is a major cause, with contributions from reduced growth hormone secretion, declining sex hormone action, and reduced resting metabolic rate and thermic effect of food. Not only do older adults have more body fat than do young adults, it is in different places. A greater proportion of body fat in older people is intrahepatic, intramuscular, and intra-abdominal (versus subcutaneous) [8]; these changes are associated with increased insulin resistance, and, therefore, are likely to be associated with adverse metabolic outcomes [9]. Undernutrition in older people Prevalence Protein-energy malnutrition is common in the elderly. Studies in developed countries found that up to 15% of community-dwelling and home-bound elderly, between 23% and 62% of hospitalized patients, and up to 85% of nursing homes residents suffer from the condition [3].

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Adverse effects Protein-energy malnutrition is associated with impaired muscle function, decreased bone mass, immune dysfunction, anemia, reduced cognitive function, poor wound healing, delayed recovery from surgerydand ultimatelydincreased morbidity and mortality. Epidemiologic studies have demonstrated that protein-energy malnutrition is a strong independent predictor of mortality in elderly people, regardless of whether they live in the community [10] or in a nursing home [11], are patients in a hospital [12], or have been discharged from the hospital in the last 1 to 2 years [13]. The increased mortality in elderly people who have protein-energy malnutrition is increased further in the presence of other medical diseases (eg, renal failure, cardiac failure, cerebrovascular disease). For example, the 9-month mortality among patients older than 70 years (and who did not have cancer) who were admitted to a medical ward in Sweden was 44% in 41 malnourished patients who did not have cardiac failure, but 80% in 10 malnourished patients who had cardiac failure [12]. Two of the most common markers of undernutrition and increased risk for morbidity and mortality in older people are low body weight and loss of weight, particularly if unintentional. Low body weight in older people: what is too low? The relationship between mortality and body weight is a J-shaped curve, with increased mortality at low and high BMIs. For young adults, BMIs that are associated with the greatest life expectancy are in the range of 20 to 25 kg/m2 [14,15]. Most evidence suggests that the BMI that is associated with maximum life expectancy increases with age. The lower end of the range increases to about 22 to 23 kg/m2 and the upper end increases to 27 to 28 kg/m2 for people older than 65 years [16–18]. Below 22 to 23 kg/m2 there is a steady increase in risk for death, probably particularly at BMI values of less than 18.5 kg/m2 in women and 20.5 kg/m2 in men [15]. The deleterious effects of being underweight are amplified by increasing age [19]. Weight loss in older people Body weight tends to decrease after about age 60 years, and a loss of 5% or more of body weight over several years is not uncommon in older people. Numerous studies have shown that weight loss in the elderly is associated with poor outcomes (for review see [18]). The prospective Cardiovascular Health Study [6] studied 4714 home-dwelling subjects who were older than 65 years and did not have known cancer. In the 3 years after study entry 17% of the subjects lost 5% or more of their initial body weight. This group had significant increases in total (2.09
higher [95% CI, 1.67–2.62]) and riskadjusted mortality (1.67
higher [1.29–2.15]) over the following 4 years

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compared with the group that had stable weight. The increased mortality occurred irrespective of starting weight. In the Systolic Hypertension in the Elderly Program study [16], subjects who had a weight loss of 1.6 kg/y or more experienced a 4.9-fold greater death rate (95% CI, 3.5–6.8) than did those without significant weight change. The relation between increased mortality that was associated with weight loss was present even in the subjects who were heaviest at baseline (BMI R31 kg/m2) and was independent of baseline weight. Nevertheless, subjects with a low baseline weight (BMI !23.6 kg/m2) who lost more than 1.6 kg/y had a mortality of 22.6%, almost 20 times greater than the mortality of persons with a baseline BMI of 23.6 to 28 kg/m2 whose weight remained stable. Thus, weight loss by an older person of initially low body weight is associated with a particularly bad outcome, perhaps because such weight loss is more likely to be unintentional than is weight loss by overweight older people (see later discussion). This additive adverse effect is of concern, because the tendency for older people to lose weight is variable, with lean individuals probably most at risk [20]. There are many reasons why weight loss in older people has adverse effects. Weight loss can be a marker and consequence of illness, such as a malignancy, which itself is mainly responsible for the poor outcome. Such illnesses may be multiple, interactive, and difficult to detect. Inflammatory conditions are important causes, and act by way of cachectic effects of increased cytokines (see later discussion). Whatever the cause, the resulting weight loss and associated undernutrition can contribute further to adverse outcomes, because loss of body weight after the age of 60 years is disproportionately of lean body tissue, predominantly skeletal muscle. When excessive, this leads to sarcopenia (defined as muscle mass more than two standard deviations below the sex-specific young-normal mean), which is present in up to 6% to 15% of people who are older than 65 years [21]. Unlike the loss of fat tissue, the loss of skeletal muscle is associated with metabolic, physiologic, and functional impairments; disability, including increased falls; and increased risk for protein-energy malnutrition. In the National Health And Nutrition Examination Survey (NHANES) 111 study [22] older people who had marked sarcopenia (!5.75 kg skeletal muscle/m2) were 3.3 times (women) to 4.7 times (men) more likely to have physical disability than were those with low-risk skeletal muscle mass (O6.75 kg/m2). Causes of undernutrition in older people The causes of undernutrition in older people are usually multiple. Healthy aging is associated with a decline in energy (food) intake, the physiologic ‘‘anorexia of aging,’’ and a reduction in function of homeostatic mechanisms that work in younger people to restore food intake in response to anorectic insults. As an illustration of the latter, Roberts and colleagues [23] underfed young and old men by approximately 750 kcal/d for 21 days, during which time both groups of men lost weight. After the underfeeding

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period the men were allowed to eat ad libitum. The young men ate more than at baseline (before underfeeding) and quickly returned to normal weight, whereas the old men did not compensate, returned only to their baseline intake, and did not regain the weight that they had lost. Thus, older people are at an increased risk for developing undernutrition when pathologic factors that commonly are associated with aging supervene. The physiologic anorexia of aging The causes of the physiologic anorexia of aging are poorly understood. A list of factors that may contribute is given in Box 1. There is a strong correlation between impaired sense of smell and reduced interest in and intake of food. The senses of taste and smell deteriorate with age; in one study more than 60% of subjects aged 65 to 80 years, and more than 80% of subjects aged 80 years or older exhibited major reductions in their sense of smell, compared with less than 10% of those who were younger than 50 years [24]. Age-associated increases in the production or effect of satiating cytokines probably also contribute [25]. Cytokines are secreted in response to significant stress, often due to malignancy or infection, and act to decrease food intake and reduce body weight. Blockade of these cytokines (eg, tumor necrosis factor [TNF] in mice with TNF-producing sarcomas) significantly attenuates weight loss in high-stress conditions that are

Box 1. Factors that may contribute to the physiologic anorexia of aging Diminished sense of smell and taste Increased cytokine activity Alterations in gastrointestinal function Delayed gastric emptying Altered gastric food distribution Hormonal [98] Increase appetite/food intake Opioids: lower activity; not proven in humans Testosterone: lower activity with age Ghrelin: possible lower activity with aging (unproven) Decrease appetite/food intake Cocaine-amphetamine-related transcript: possible higher central levels (rodents) Cholecystokinin: higher circulating levels; higher cerebrospinal fluid levels; higher sensitivity to satiating effects Leptin situation complex: circulating levels higher in men but possible leptin resistance

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associated with cachexia. Circulating concentrations of the cytokines interleukin (IL)-1, IL-6, TNF-a, and C-reactive protein are increased in cachectic patients who have cancer or HIV/AIDS. Older people have increased circulating and monocyte concentrations of cytokines, and these levels are related inversely to skeletal muscle protein synthesis and positively to the rate of muscle tissue loss [26–28]. In The Framingham Heart Study, higher IL-6 and TNF-a production was associated with reduced muscle strength and increased mortality [28,29]. Pathologic anorexia and undernutrition in older people Protein-energy malnutrition is particularly likely to develop in the presence of other ‘‘pathologic’’ factors, many of which become more common with increased age (Box 2). Most are responsive to treatment, at least in part, so recognition is important. Older people are more likely to live alone than are young adults, and social isolation and loneliness have been associated with decreased appetite and energy intake in the elderly [30]. Elderly people tend to consume substantially more food (sometimes up to 50% more) during a meal when eating in the company of friends than when eating alone. The simple measure of having older people eat in company, rather than alone, may be effective in increasing their energy intake. Depression is a common problem in older people, and is present in 2% to 10% of community-dwelling older people and a much greater proportion of those who are in institutions [31]. Depression is more likely to manifest as reduced appetite and weight loss in the elderly than in younger adults, and is an important cause of weight loss and undernutrition in this group. Depression is the cause in 30% to 36% of medical outpatients and nursing home residents who lose weight [32,33]. Undernutrition per se, particularly if it produces folate deficiency, may worsen depression [34]. Treatment of depression is effective in producing weight gain and improving other nutritional indices [35]. Many older people no longer have their own teeth. Poor dentition and illfitting dentures may limit the type and quantity of food eaten. Complaints of problems with chewing, biting, and swallowing are common among nursing home residents, and those with dentures are more likely to have poor protein intake than are those with their own teeth [36]. The elderly often take multiple medications, which increases the risk for drug interactions that can cause anorexia. Diagnosis A detailed discussion of methods that are used to diagnose undernutrition in older people is beyond the scope of this article; there is no gold standard, and multiple methods have been used [18]. The most important thing is to be aware of the diagnosis. It is important to weigh older people at regular intervals, particularly those in nursing homes or other institutions, because weight loss, particularly unintentional loss of more than 5%, is a key

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Box 2. Pathologic causes of undernutrition in older people Social factors Poverty Inability to shop, prepare, and cook meals or to feed oneself Living alone/social isolation/lack of social support network Failure to cater to ethnic and other food preferences in institutionalized individuals Psychologic factors Depression Dementia/Alzheimer’s disease Alcoholism Bereavement Medical factors Cardiac failure Chronic obstructive pulmonary disease Infection Cancer Alcoholism Poor dentition Dysphagia Rheumatoid arthritis Malabsorption syndromes Gastrointestinal symptoms Dyspepsia Helicobacter pylori infection/atrophic gastritis Vomiting/diarrhea/constipation Parkinson’s disease Hypermetabolism (eg, hyperthyroidism) Medications: multiple

indicator. A BMI of less than 22 kg/m2 suggests undernutrition, which is particularly likely if the BMI is less than 18.5 kg/m2, even at weight stability. Various diagnostic instruments have been developed, which rely on differing combinations of anthropometric measures; questions regarding weight loss, food intake, and medications; and measurement of blood parameters. Reduced serum albumin, hematocrit, lymphocyte count, and serum folate are among the factors that were found to be associated with the risk for undernutrition and poor outcome [37]. Among the most widely used outpatient screening tools for undernutrition risk are the Mini Nutritional Assessment [38], the Functional Assessment of Anorexia Cachexia Therapy [39], and the Seniors in the Community Risk Evaluation for Eating

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and Nutrition tool [40]. Even the most simple of these tools can provide useful information; the Simplified Nutritional Appetite Questionnaire, for example, which includes four questions on appetite, timing of eating, frequency of meals, and taste, has a high sensitivity and specificity (both O75%) in predicting future 5% weight loss in older people [41]. Management Underlying causes should be identified and corrected where possible (see Box 2), particularly depression and problems with dentition. Adequate intake of vitamins and minerals should be ensured by supplements, including vitamin D and calcium, unless contraindicated. Target weight gains should be set and the intake of nutritional food increased if possible, by offering more food, improving the social setting of food intake (eg, eating in company not alone), and encouraging the older person to eat. If target weight gains are not achieved or if the deficiency is severe, protein and energy nutritional supplements should be added, which preferably provide at least 400 kcal/d. In undernourished older people, nutritional supplements were shown by meta-analysis of controlled trials to produce weight gain, to be mostly free of side effects, and to reduce mortality by up to 34% among patients in short-term hospital care (odds ratio, 0.66; CI, 0.49–0.90) [42,43]. The effects of supplements on function are less clear, although they may improve cognitive function [44]. These supplements are best ingested between meals, because this reduces the compensatory suppression of food at usual meal times [33,45]. Various forms of tube feeding may be required for severe undernutrition, particularly when swallowing is impaired or not possible. There may be a limited role for orexigenic drugs to promote weight gain in undernourished older patients, but study results are sparse [46]. Megestrol acetate is a progestational agent that increases appetite and has been shown to produce weight gain in cancer-related anorexia, HIV/AIDS, and other conditions that are characterized by increased cytokine activity, although weight is gained disproportionately as fat [46]. When megestrol, 800 mg/d, was administered in a placebo-controlled trial for 12 weeks to undernourished nursing home residents, there was no significant weight gain during that time, but there was a significant increase in weight in the 12 weeks after it was stopped [47]. Although usually well tolerated, megestrol can produce fluid retention, flushing, adrenal insufficiency, and an increased rate of deep vein thromboses. Testosterone levels are reduced in men and testosterone probably should be administered with megestrol in men. Dronabinol is a cannabis derivative, which can stimulate appetite, improve mood, and aid pain relief. Its effects are not well characterized in undernourished older people, and its use is associated with delirium and occasional nausea. The 6week administration of dronabinol, 2.5 mg twice daily, to older patients who had Alzheimer’s disease was associated with 0.5- to 1-kg greater weight gain than was placebo in one study [48]. It is hoped that the identification of

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specific causes of the anorexia of aging will enable the development of targeted treatments. Examples might include cholecystokinin antagonists or oral analogs of ghrelin.

Overnutrition and obesity in older people Prevalence A substantial number of older people in westernized countries are overweight by standard BMI criteria, and the prevalence of overweight and obesity is increasing. In 2000, 58% of Americans who were aged 65 years and older had a BMI of 25 kg/m2 or more [49], and the prevalence of obesity (BMI R30) in people in the United States who were older than 70 years increased 36% between 1991 and 2000, from 11.4% to 15.5% [50]. Consequences of obesity in older people Mortality The increase in the relative risk for death that is associated with being obese is not as great in older adults as it is in young adults. An assessment of 13 observational, prospective studies, in which nonhospitalized people who were older than 65 years were followed for at least 3 years [17], found an association between mortality and high BMI in only a few, and then at BMIs only above 27 to 28.5 kg/m2, with little or no increase in mortality at any BMI for people older than 75 years. Where an optimum BMI could be identified it usually was in the range of 27 to 30 kg/m2. Consistent with this, a combined analysis of the NHANES 1–111 (1974–2000) study results found no significant increase in mortality with any degree of overweight in people older than 70 years, and an increase in the relative risk for death in those between 60 and 69 years only when the BMI was at least 35 kg/m2 [51]. Nevertheless, the relative risk for mortality is still increased at high BMIs until about the age of 75 years, and because of the greater background death rate in older people, persons older than 70 years accounted for 25% of the excess deaths that were attributed to obesity in that NHANES analysis [49]. The causes of increased mortality are essentially the same as in younger adults: diabetes, hypertension, sleep apnea, cardiovascular disease, and an increased risk with obesity for developing certain cancers, including breast, uterus, colon, and prostate. Morbidity Obesity in older people is associated with increased rates of cataracts, mechanical urinary and bladder problems, sleep apnea, and other respiratory problems [4]. After the age of 65 years, more than 60% of people have symptomatic osteoarthritis (OA) [52], which commonly affects the hip and knee, and this is a major cause of disability. Excess weight hastens

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the development of knee OA [53], exacerbates the symptoms of lower limb OA, and makes surgical treatment more hazardous. Functional capacity and mobility are reduced significantly in obese older adults compared with lean older adults [54]. Compared with their nonobese counterparts, obese older people are less likely to be pain free. They have a lower quality of life, have greater limitations of physical function, and are more likely to be homebound. Obesity is predictive of a greater rate of future disability, declines in functional status [4], and an increased admission rate to nursing homes. Among women who were 65 years or older in the Nurses Health Study, a weight gain of 20 pounds or more over 4 years was associated with a reduction in reported physical functioning [55]. Increased fat mass seems to be the specific factor that is responsible for obesity-related disability [54]. In older people, obesity is associated with increased bone density in weight-bearing and nonweight-bearing bones. This combines with cushioning of falls that is provided by the extra fat stores, particularly around the hips (‘‘endogenous’’ hip protectors), to reduce fracture rates in older people [56]. Most studies show that when overweight older people intentionally lose weight they also lose bone [4,57]. Substantial unintentional weight loss in older people is associated with an increased risk for hip fracture [58], but it is not known whether the risk is increased in overweight people who intentionally lose weight. Management of obesity in older people Should overweight older people be advised to lose weight? This is a controversial question. The adverse effects of obesity, reduced life expectancy at high BMIs up to the age of 70 years (at least), and improvements in function that are associated with weight loss [55] must be balanced against the detrimental effects of weight loss on muscle mass and bone density, and the proven association between all-cause weight loss and increased mortality in older people, even those who are overweight initially. It could be that an older persondoverweight to a degree that reduces life expectancydmight be likely to die sooner if one attempted to lose weight and succeeded than if one remained weight stable. The key to this apparent paradox probably lies in the differing effects of intentional and unintentional weight loss by older people on mortality. Studies that demonstrated an association between weight loss and increased mortality in older people largely have examined all-cause weight loss, whether intentional or unintentional. There is little doubt that unintentional weight loss is not good for the elderly. Although some studies even found increased mortality in association with intentional weight loss [6], it is difficult to determine what proportion of weight loss that was labeled intentional really was unintentional. On balance, it seems that intentional weight loss by initially overweight older people has no significant effect [59,60] or even

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beneficial effects on mortality. In the U.S. National Health Interview Survey, for example, which followed 20,847 adults with a mean age of 54 years for 9 years, all-cause weight loss was associated with a significant increase in mortality, as in other studies [61]. Reported attempted weight loss, however, even if unsuccessful, was associated with a 24% reduction in mortality (Relative Risk [RR], 0.76; 95% CI, 0.64–0.9), as was successful intentional weight loss (RR, 0.76; 95% CI, 0.6–0.97). There was no interaction between weight loss intention and age in the effect on mortality, which was consistent with a prolongation of life by intended weight loss in older as well as young adults. Studies that involved predominantly younger adults have found that intentional weight loss can reduce mortality in those who have obesity-related health problems, such as type 2 diabetes, ischemic heart disease, and hypertension [62]. Although such studies have not been done in older people, available evidence suggests that it is safe to recommend weight loss to overweight older people who have obesity-related morbidities, particularly reduced mobility and function. This is the group that seems to have the most to gain. There are few, if any, indications for recommending weight loss to older people based on their weight alone. Weight loss measures in overweight older people Treatment options are reviewed in detail elsewhere [4]. There is limited information about the effectiveness and safety of weight loss treatments, particularly medications and surgery, in older people. Lifestyle interventions, which combine a reduced energy diet and exercise, are at least as effective in producing weight loss in people who are older than 60 years as in younger adults [4], and possibly more so [63]. The incorporation of an exercise component, particularly weight-bearing aerobic and resistance exercise, is important. Exercise reduces the percentage of weight lost as fat-free mass (essentially skeletal muscle) [64], otherwise about 25%; inhibits the regional loss of bone density that accompanies weight loss [65]; improves physical function by increasing muscle mass and fitness [66,67]; and reduces the risk for falls [68]. Multivitamin supplements, together with calcium (1000–1500 mg/d) and vitamin D (800–1000 IU/d) for bone protection (see later discussion), also should be taken. There is little reported experience with weight loss drugs, such as sibutramine and orlistat, in older people. Such drugs should be used with caution in older people, because of limited efficacy data, the possibility of interactions with other (multiple) medications, and potentially worse side effects. The few studies that have examined the outcomes of weight loss surgery in overweight people who were older than 60 years indicate that surgery produces major weight loss and a significant postoperative improvement in comorbidities, although both improvements are less than in younger patients, and the older patients have greater perioperative morbidity and mortality [4]. At this stage, these techniques probably should be restricted to selected older people who are disabled substantially by complications of obesity.

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Specific mineral and vitamin deficiencies The age-related reduction in energy intake, together with an increased dietary need for some vitamins and minerals, predisposes to the development of absolute or relative deficiencies in older people. Four of the most important are discussed below. Vitamin D Vitamin D deficiency causes osteomalacia, rickets, and myopathy, and is associated with reduced bone density, impaired mobility, an increased rate of falls and fractures, and probably an increased risk for developing cardiovascular disease, type 1 diabetes mellitus, rheumatoid arthritis, and certain cancers [69]. In ambulatory older people, mobility declines markedly at serum 25 hydroxyvitamin D levels of less than 40 pmol/L [70], and vitamin D supplementation reduced the rate of falls in nursing home residents, even those who were not deficient in vitamin D [71]. Treatment with vitamin D in dosages of 700 to 800 IU/d, with or without calcium, reduced the relative risk for hip and other nonvertebral fractures by 23% to 26% compared with calcium or placebo in ambulatory or institutionalized older persons [72,73]. Some authorities recommend vitamin D treatment for people with circulating 25 vitamin D levels of less than 70–80 nmol/L, because parathyroid hormone (PTH) starts to increase in compensation at levels of less than 80 nmol/L [74]. A plasma 25 vitamin D level of less than 40 nmol/L is widely considered to represent vitamin D deficiency that is in need of treatment [75]. Most circulating 25-hydroxyvitamin D comes from exposure of the skin to UV-B radiation in sunlight; the rest comes from the dietary intake of foods that are rich in vitamin D (predominantly oily fish), supplements, and vitamin D–fortified food. Because of dark skin pigmentation, aging, residence at high latitude, and short day length, dietary sources are required to contribute substantially to circulating vitamin D levels in some people, particularly during the winter. Dietary requirements are greater in older people because of reduced production in the skin, decreased sun exposure, agerelated thinning of skin, and other skin changes. Vitamin D production in the skindin response to any given period of sun exposuredat age 80 years is about half of what it was at age 18 years [76,77]. For that reason the recommended dietary reference intakes are higher for older adults; in the United States it is 10 mg (400 IU) for people 51 to 70 years of age and 5 mg (200 IU) for younger adults. The United States and Canada have mandatory vitamin D fortification of milk and Canada also requires it in margarine, whereas other countries have variable levels of nonmandatory fortification [69]. The United States also has high levels of use of vitamin D supplements, particularly in older women, increasing vitamin D intake by up to 2 to 3 mg/d. This gives the United States the highest dietary intake of vitamin D in the world, double that of the United Kingdom [78]. Even so, at 7 to 8 mg/d the

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mean intake for adults in the United States is still below the recommended dietary intake, and vitamin D deficiency remains common. Although dietary vitamin D intake remains stable with increasing age, and may even increase in women who are older than age 50 because of their increased use of supplements [69], vitamin D deficiency is more common in unsupplemented older adults than in young adults, largely because of decreased production in the skin. Low 25 vitamin D levels have been found in between 2% and 86% of postmenopausal women in the United States, and is particularly common among African Americans, persons who are house-bound or living in nursing homes, or persons who had a previous fracture [75,79,80]. Treatment Vitamin D therapy is safe, inexpensive, and easy to administer. The prevalence of vitamin D deficiency is so high among the institutionalized elderly that routine supplementation with dosages of 800 to 1000 IU/d without testing is being recommended and adopted increasingly. When vitamin D is measured because of a clinical suspicion of deficiency, vitamin D treatment probably should be started if the 25 vitamin D level is less than 60 nmol/L, or if it is 60 to 80 nmol/L with an otherwise unexplained elevation of PTH. The most effective form of replacement is oral cholecalciferol, which can be given in intermittent boluses at intervals of one to six months, in doses not usually totaling more than 50,000 IU per month or as 500 to 2000 IU/d. Calcium In older people, dietary calcium intake largely is important in the prevention and treatment of osteoporosis. In placebo-controlled studies, dietary calcium supplements had modest beneficial effects on bone density in older people, and form the basis of most osteoporosis-treatment regimens. Calcium treatment alone, in dosages of 1g/d, reduced fracture rates in postmenopausal women who did not have previous low-impact fractures [81], but it was not effective in the prevention of secondary fractures [82]. Guidelines for daily dietary intakes of calcium, developed with the aim of optimizing bone health, usually recommend higher intakes for older adults. An adequate daily calcium intake for Americans who are older than 51 years is believed to be 1200 mg [83]. Few older people achieve this intake without taking a calcium supplement; the median daily dietary intake for American men and women who are 60 years and older is approximately 600 mg [83]. One tablet per day of a supplement that contains 500 to 700 mg of elemental calcium usually is sufficient to achieve an adequate intake, whereas people with a low dietary intake should take two tablets. Adequate vitamin D status is essential for calcium uptake by the gut and bone formation and remodelling, so vitamin D deficiency should be identified and corrected in older people who take calcium, or vitamin D should be added routinely to calcium treatment.

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Vitamin B12 (cobalamin) deficiency Vitamin B12, together with vitamin B6 and folate, is integral to homocysteine and methylmalonate metabolism. Vitamin B12 deficiency is associated with increases in circulating homocysteine and methylmalonic acid concentrations, and supplementation with vitamin B12 or folate reduces homocysteine concentrations [84]. Vitamin B12 deficiency is more common in older people than in young adults. In the Framingham study, for example, 11.3% of elderly subjects had a serum vitamin B12 concentration of less than 258 pmol/L, together with elevated plasma homocysteine and methylmalonic acid levels, compared with 5.3% of younger adults [85]. In elderly people who are living in institutions the prevalence of deficiency may be as high as 30% to 40% [86]. Because the signs and symptoms of vitamin B12 deficiency often are subtle, there should be a low threshold for testing older people, in particular those who are malnourished, those who have a neurologic or neuropsychiatric presentation that is consistent with vitamin B12 deficiency, and those who are in institutions, including psychiatric hospitals [86]. Clinical effects of B12 deficiency in older people The most common clinical manifestations of vitamin B12 deficiency in older people are macrocytic anemia, subacute combined degeneration of the spinal cord, neuropathies, ataxia, glossitis, and possibly dementia [87], although vitamin B12 supplementation does not produce cognitive improvement consistently [86,87]. There is evidence that homocysteine damages blood vessel walls, and there is a significant association between increased plasma homocysteine levels and an increased risk for cardiovascular disease [88,89]. Results of meta-analyses are consistent with this connection being causal [89], but this has not been supported by intervention studies, so far confined to secondary prevention studies [84,90]. Numerous studies showed an association between reduced vitamin B12 levels, increased homocysteine levels, or both and impaired cognition, depression, and other neuropsychiatric disorders [87,91], and, more recently, reduced bone density and an increased rate of hip fractures [92]. Studies of supplementation with vitamin B12 and folate, however, have produced contradictory results, with improvements in some but not in others; there is some suggestion that treatment only may be successful if given early [93]. Therefore, the use of vitamin B12, folate, and other supplements for such indications is unproven. The increased prevalence of deficiency in the elderly is mainly due to an increased rate of two conditions that increase B12 requirements: foodcobalamin malabsorption and pernicious anemia, which account for approximately 60% to 70% and 15% to 20% of cases, respectively [86]. Malabsorption and other causes are more rare, as is true dietary insufficiency (intake !2.4 mg/d) [93], except in strict vegans. Nevertheless, vitamin B12 and folate deficiency coexist frequently in older people [93]. Food-cobalamin malabsorption syndrome is characterized by the inability to release

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vitamin B12 from intestinal transport proteins or food, despite normal absorption of unbound vitamin B12, such as crystalline vitamin B12 in supplements. Diagnosis requires a low serum vitamin B12 concentration, negative Schilling test, and adequate dietary intake (O2 mg/d) [86]. The most common predisposing factor is gastric atrophy, which is present in more than 40% of people who are older than 80 years. Numerous factors predispose to the development of gastric atrophy, including Helicobacter pylori infection, chronic alcoholism, bacterial overgrowth, long-term ingestion of metformin and antacids, and gastric bypass surgery for obesity [86]. Treatment Clinically apparent causes should be treated when possible (eg, stop metformin in an older person), but a reversible cause of vitamin B12 deficiency often is not found, so treatment with vitamin B12 usually is needed for life. The recommended daily intake of vitamin B12 is 2 to 5 mg in older adults [86].Vitamin B12 deficiency (!150 pmol/L) that is due to dietary deficiency is treated best initially with intramuscular (IM) vitamin B12 or at least 100 mg/d of oral vitamin B12. Food malabsorption is treated best with IM vitamin B12 or possibly high-dose oral vitamin B12 (eg, 500 mg/d), whereas pernicious anemia requires life-long IM therapy [86]. When folate deficiency coexists, vitamin B12 should be given with appropriate folate doses (see ‘‘folate deficiency’’), and it is reasonable to coadminister a multivitamin that contains folate in any case. Laboratory responses to treatment should be monitored; treatment with higher dosages of vitamin B12 and investigations for underlying causes should be undertaken if the response is not satisfactory. Folate deficiency Foods that are rich in folate include orange juice, dark green leafy vegetables, peanuts, strawberries, dried beans and peas, and asparagus. Unlike food folates, synthetic folic acid that is found in vitamin supplements and fortified foods does not need intestinal cleavage and is absorbed more readily. The recommended intake of folate and folic acid is 400 mg/d, with an upper limit of 1000 mg/d of synthetic folic acid, which in high doses could mask the features of coexistent vitamin B12 deficiency; this is a concern given the high rate of vitamin B12 deficiency in older people. Folate deficiency causes macrocytic anemia and increased homocysteine concentrations, and is associated with increased rates of colorectal cancer, and, possibly, cervical cancer, as well as cognitive impairment, depression, and dementia [94]. Interventional studies are needed to determine whether these associations are causal. Untreated anemia in older people is associated with increased morbidity and mortality, and folate deficiency contributes substantially to this problem [95]. The prevalence of folate deficiency among older people varies from 4% to 50%, depending on the population studied

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[94,96], and is particularly common among persons in institutions. Most folate deficiency is due to inadequate dietary intake (the older person living on ‘‘tea and toast’’); impaired use that is due to drugs (eg, methotrexate, anticonvulsants, sulfasalazine) or alcohol consumption is much less common. Folic acid fortification of grain became mandatory in the United States in 1998, since which time there has been a significant increase in blood and red cell folate concentrations and a corresponding reduction in the prevalence of folate deficiency [97]. Nevertheless, in the Framingham study, approximately 4% of subjects (mean age, 59 years) who were exposed to folate supplementation had less than acceptable red cell folate levels [97]. The prevalence is likely to be higher in older people, those living in institutions, and those living in countries without fortification. Treatment When folate deficiency is due to dietary insufficiency, attempts should be made to improve the diet by increasing the intake of fruit and vegetables because this is likely to have benefits in addition to increasing folate. Folic acid supplements are also indicated to ensure treatment success and are essential when the cause is not dietary. To avoid masking vitamin B12 deficiency, it should be excluded before starting treatment with folic acid, 0.5 to 5 mg/d; 0.5 mg/d will decrease plasma homocysteine levels reliably [94]. Because combined treatment with folic acid and vitamin B12 has additive effects in decreasing plasma homocysteine concentrations, which may be beneficial, it is reasonable to administer both to older people with a deficiency of only one, particularly if the homocysteine level is greater than 10 mmol/L, providing that the response to treatment is monitored. Summary Undernutrition is common in older people and has serious adverse effects. Weight loss and low body weight are key markers. Correctable causes, such as depression, are common and should be sought. Structured efforts to encourage food intake, together with nutritional supplements, often are of benefit. It is hoped that a better understanding of the underlying mechanisms will lead to targeted treatments. Overweight and obesity also are common in older people, and are associated with morbidity and impaired function. It is probably appropriate to recommend weight loss to obese older people who have associated comorbidities, particularly reduced mobility, but seldom, if ever, for increased weight alone. References [1] Wurtman JJ, Lieberman H, Tsay R, et al. Calorie and nutrient intakes of elderly and young subjects measured under identical conditions. J Gerontol 1988;43(6):B174–80.

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[2] Clarkston WK, Pantano MM, Morley JE, et al. Evidence for the anorexia of aging: gastrointestinal transit and hunger in healthy elderly vs. young adults. Am J Physiol 1997;272(1 Pt 2):R243–8. [3] Morley JE. Anorexia of aging: physiologic and pathologic. Am J Clin Nutr 1997;66(4): 760–73. [4] Villareal DT, Apovian CM, Kushner RF, et al. Obesity in older adults: technical review and position statement of the American Society for Nutrition and NAASO, The Obesity Society. Am J Clin Nutr 2005;82(5):923–34. [5] Wallace JI, Schwartz RS, LaCroix AZ, et al. Involuntary weight loss in older outpatients: incidence and clinical significance. J Am Geriatr Soc 1995;43(4):329–37. [6] Newman AB, Arnold AM, Burke GL, et al. Cardiovascular disease and mortality in older adults with small abdominal aortic aneurysms detected by ultrasonography: The Cardiovascular Health Study. Ann Intern Med 2001;134(3):182–90. [7] Prentice AM, Jebb SA. Beyond body mass index. Obes Rev 2001;2(3):141–7. [8] Beaufrere B, Morio B. Fat and protein redistribution with aging: metabolic considerations. Eur J Clin Nutr 2000;54(Suppl 3):S48–53. [9] Cree MG, Newcomer BR, Katsanos CS, et al. Intramuscular and liver triglycerides are increased in the elderly. J Clin Endocrinol Metab 2004;89(8):3864–71. [10] Campbell AJ, Spears GF, Brown JS, et al. Anthropometric measurements as predictors of mortality in a community population aged 70 years and over. Age Ageing 1990;19(2):131–5. [11] Morley JE, Silver AJ. Nutritional issues in nursing home care. Ann Intern Med 1995;123(11): 850–9. [12] Cederholm T, Jagren C, Hellstrom K. Outcome of protein-energy malnutrition in elderly medical patients. Am J Med 1995;98(1):67–74. [13] Sullivan DH, Walls RC, Lipschitz DA. Protein-energy undernutrition and the risk of mortality within 1 y of hospital discharge in a select population of geriatric rehabilitation patients. Am J Clin Nutr 1991;53(3):599–605. [14] Manson JE, Willett WC, Stampfer MJ, et al. Body weight and mortality among women. N Engl J Med 1995;333(11):677–85. [15] Calle EE, Thun MJ, Petrelli JM, et al. Body-mass index and mortality in a prospective cohort of US adults. N Engl J Med 1999;341(15):1097–105. [16] Somes GW, Kritchevsky SB, Shorr RI, et al. Body mass index, weight change, and death in older adults: the systolic hypertension in the elderly program. Am J Epidemiol 2002;156(2): 132–8. [17] Heiat A, Vaccarino V, Krumholz HM. An evidence-based assessment of federal guidelines for overweight and obesity as they apply to elderly persons. Arch Intern Med 2001;161(9): 1194–203. [18] Omran ML, Morley JE. Assessment of protein energy malnutrition in older persons, Part II: laboratory evaluation. Nutrition 2000;16(2):131–40. [19] Potter JF, Schafer DF, Bohi RL. In-hospital mortality as a function of body mass index: an age-dependent variable. J Gerontol 1988;43(3):M59–63. [20] Rumpel C, Harris TB, Madans J. Modification of the relationship between the Quetelet index and mortality by weight-loss history among older women. Ann Epidemiol 1993; 3(4):343–50. [21] Melton LJ III, Khosla S, Riggs BL. Epidemiology of sarcopenia. Mayo Clin Proc 2000; 75(Suppl):S10–2 [discussion S12–3]. [22] Janssen I, Baumgartner RN, Ross R, et al. Skeletal muscle cutpoints associated with elevated physical disability risk in older men and women. Am J Epidemiol 2004; 159(4):413–21. [23] Roberts SB, Fuss P, Heyman MB, et al. Control of food intake in older men. JAMA 1994; 272(20):1601–6. [24] Doty RL, Shaman P, Applebaum SL, et al. Smell identification ability: changes with age. Science 1984;226(4681):1441–3.

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[25] Yeh SS, Schuster MW. Geriatric cachexia: the role of cytokines. Am J Clin Nutr 1999;70(2): 183–97. [26] Roubenoff R, Harris TB, Abad LW, et al. Monocyte cytokine production in an elderly population: effect of age and inflammation. J Gerontol A Biol Sci Med Sci 1998;53(1):M20–6. [27] Toth MJ, Matthews DE, Tracy RP, et al. Age-related differences in skeletal muscle protein synthesis: relation to markers of immune activation. Am J Physiol Endocrinol Metab 2005; 288(5):E883–91. [28] Payette H, Roubenoff R, Jacques PF, et al. Insulin-like growth factor-1 and interleukin 6 predict sarcopenia in very old community-living men and women: The Framingham Heart Study. J Am Geriatr Soc 2003;51(9):1237–43. [29] Roubenoff R, Parise H, Payette HA, et al. Cytokines, insulin-like growth factor 1, sarcopenia, and mortality in very old community-dwelling men and women: The Framingham Heart Study. Am J Med 2003;115(6):429–35. [30] Walker D, Beauchene RE. The relationship of loneliness, social isolation, and physical health to dietary adequacy of independently living elderly. J Am Diet Assoc 1991;91(3): 300–4. [31] Evers MM, Marin DB. Mood disorders. Effective management of major depressive disorder in the geriatric patient. Geriatrics 2002;57(10):36–40 [quiz 41]. [32] Morley JE, Kraenzle D. Causes of weight loss in a community nursing home. J Am Geriatr Soc 1994;42(6):583–5. [33] Wilson MM, Vaswani S, Liu D, et al. Prevalence and causes of undernutrition in medical outpatients. Am J Med 1998;104(1):56–63. [34] Morris MS, Fava M, Jacques PF, et al. Depression and folate status in the US population. Psychother Psychosom 2003;72(2):80–7. [35] Thomas P, Hazif-Thomas C, Clement JP. Influence of antidepressant therapies on weight and appetite in the elderly. J Nutr Health Aging 2003;7(3):166–70. [36] Sahyoun NR, Otradovec CL, Hartz SC, et al. Dietary intakes and biochemical indicators of nutritional status in an elderly, institutionalized population. Am J Clin Nutr 1988;47(3): 524–33. [37] Fuhrman MP, Charney P, Mueller CM. Hepatic proteins and nutrition assessment. J Am Diet Assoc 2004;104(8):1258–64. [38] Guigoz Y, Lauque S, Vellas BJ. Identifying the elderly at risk for malnutrition. The Mini Nutritional Assessment. Clin Geriatr Med 2002;18(4):737–57. [39] Ribaudo JM, Cella D, Hahn EA, et al. Re-validation and shortening of the Functional Assessment of Anorexia/Cachexia Therapy (FAACT) questionnaire. Qual Life Res 2000; 9(10):1137–46. [40] Keller HH, McKenzie JD, Goy RE. Construct validation and test-retest reliability of the seniors in the community: risk evaluation for eating and nutrition questionnaire. J Gerontol A Biol Sci Med Sci 2001;56(9):M552–8. [41] Wilson MM, Thomas DR, Rubenstein LZ, et al. Appetite assessment: simple appetite questionnaire predicts weight loss in community-dwelling adults and nursing home residents. Am J Clin Nutr 2005;82(5):1074–81. [42] Milne AC, Avenell A, Potter J. Meta-analysis: protein and energy supplementation in older people. Ann Intern Med 2006;144(1):37–48. [43] Milne AC, Potter J, Avenell A. Protein and energy supplementation in elderly people at risk from malnutrition. Cochrane Database Syst Rev 2005;(2):CD003288. [44] Manders M, de Groot LC, van Staveren WA, et al. Effectiveness of nutritional supplements on cognitive functioning in elderly persons: a systematic review. J Gerontol A Biol Sci Med Sci 2004;59(10):1041–9. [45] Wilson MM, Purushothaman R, Morley JE. Effect of liquid dietary supplements on energy intake in the elderly. Am J Clin Nutr 2002;75(5):944–7. [46] Morley JE. Orexigenic and anabolic agents. Clin Geriatr Med 2002;18(4):853–66.

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[47] Yeh SS, Wu SY, Lee TP, et al. Improvement in quality-of-life measures and stimulation of weight gain after treatment with megestrol acetate oral suspension in geriatric cachexia: results of a double-blind, placebo-controlled study. J Am Geriatr Soc 2000;48(5):485–92. [48] Volicer L, Stelly M, Morris J, et al. Effects of dronabinol on anorexia and disturbed behavior in patients with Alzheimer’s disease. Int J Geriatr Psychiatry 1997;12(9):913–9. [49] Flegal KM, Carroll MD, Ogden CL, et al. Prevalence and trends in obesity among US adults, 1999–2000. JAMA 2002;288(14):1723–7. [50] Mokdad AH, Bowman BA, Ford ES, et al. The continuing epidemics of obesity and diabetes in the United States. JAMA 2001;286(10):1195–200. [51] Flegal KM, Graubard BI, Williamson DF, et al. Excess deaths associated with underweight, overweight, and obesity. JAMA 2005;293(15):1861–7. [52] Cicuttini FM, Spector TD. Osteoarthritis in the aged. Epidemiological issues and optimal management. Drugs Aging 1995;6(5):409–20. [53] Cicuttini FM, Baker JR, Spector TD. The association of obesity with osteoarthritis of the hand and knee in women: a twin study. J Rheumatol 1996;23(7):1221–6. [54] Jensen GL. Obesity and functional decline: epidemiology and geriatric consequences. Clin Geriatr Med 2005;21(4):677–87. [55] Fine JT, Colditz GA, Coakley EH, et al. A prospective study of weight change and healthrelated quality of life in women. JAMA 1999;282(22):2136–42. [56] Schott AM, Cormier C, Hans D, et al. How hip and whole-body bone mineral density predict hip fracture in elderly women: the EPIDOS Prospective Study. Osteoporos Int 1998;8(3): 247–54. [57] Ensrud KE, Fullman RL, Barrett-Connor E, et al. Voluntary weight reduction in older men increases hip bone loss: the osteoporotic fractures in men study. J Clin Endocrinol Metab 2005;90(4):1998–2004. [58] Langlois JA, Harris T, Looker AC, et al. Weight change between age 50 years and old age is associated with risk of hip fracture in white women aged 67 years and older. Arch Intern Med 1996;156(9):989–94. [59] Yaari S, Goldbourt U. Voluntary and involuntary weight loss: associations with long term mortality in 9,228 middle-aged and elderly men. Am J Epidemiol 1998;148(6):546–55. [60] Wannamethee SG, Shaper AG, Lennon L. Reasons for intentional weight loss, unintentional weight loss, and mortality in older men. Arch Intern Med 2005;165(9):1035–40. [61] Gregg EW, Gerzoff RB, Thompson TJ, et al. Intentional weight loss and death in overweight and obese US adults 35 years of age and older. Ann Intern Med 2003;138(5):383–9. [62] Fontaine KR, Allison DB. Does intentional weight loss affect mortality rate? Eat Behav 2001;2(2):87–95. [63] Wing RR, Hamman RF, Bray GA, et al. Achieving weight and activity goals among diabetes prevention program lifestyle participants. Obes Res 2004;12(9):1426–34. [64] Garrow JS, Summerbell CD. Meta-analysis: effect of exercise, with or without dieting, on the body composition of overweight subjects. Eur J Clin Nutr 1995;49(1):1–10. [65] Ryan AS, Nicklas BJ, Dennis KE. Aerobic exercise maintains regional bone mineral density during weight loss in postmenopausal women. J Appl Physiol 1998;84(4):1305–10. [66] Binder EF, Schechtman KB, Ehsani AA, et al. Effects of exercise training on frailty in community-dwelling older adults: results of a randomized, controlled trial. J Am Geriatr Soc 2002;50(12):1921–8. [67] Seguin R, Nelson ME. The benefits of strength training for older adults. Am J Prev Med 2003;25 (3)(Suppl 2):141–9. [68] Chang JT, Morton SC, Rubenstein LZ, et al. Interventions for the prevention of falls in older adults: systematic review and meta-analysis of randomised clinical trials. BMJ 2004; 328(7441):680. [69] Calvo MS, Whiting SJ, Barton CN. Vitamin D fortification in the United States and Canada: current status and data needs. Am J Clin Nutr 2004;80(6 Suppl):1710S–6S.

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[92] McLean RR, Jacques PF, Selhub J, et al. Homocysteine as a predictive factor for hip fracture in older persons. N Engl J Med 2004;350(5):2042–9. [93] Wolters M, Strohle A, Hahn A. Cobalamin: a critical vitamin in the elderly. Prev Med 2004; 39(6):1256–66. [94] Rampersaud GC, Kauwell GP, Bailey LB. Folate: a key to optimizing health and reducing disease risk in the elderly. J Am Coll Nutr 2003;22(1):1–8. [95] Arinzon Z, Fidelman Z, Peisakh A, et al. Folate status and folate related anemia: a comparative cross-sectional study of long-term care and post-acute care psychogeriatric patients. Arch Gerontol Geriatr 2004;39(2):133–42. [96] Salles-Montaudon N, Parrot F, Balas D, et al. Prevalence and mechanisms of hyperhomocysteinemia in elderly hospitalized patients. J Nutr Health Aging 2003;7(2):111–6. [97] Choumenkovitch SF, Jacques PF, Nadeau MR, et al. Folic acid fortification increases red blood cell folate concentrations in the Framingham study. J Nutr 2001;131(12):3277–80. [98] Chapman IM. Endocrinology of anorexia of ageing. Best Pract Res Clin Endocrinol Metab 2004;18(3):437–52.

Med Clin N Am 90 (2006) 909–923

Diabetes in the Elderly Graydon S. Meneilly, MD Department of Medicine, University of British Columbia, Room 3300, 950 West 10th Avenue, Vancouver, British Columbia V5Z 4E3, Canada

Numerous studies over the last decade have evaluated the incidence and prevalence of diabetes in the elderly. Although differing diagnostic criteria have been used, these studies consistently found an increased prevalence of diabetes in this age group (Fig. 1). The most recent health and nutrition survey found that the prevalence of diabetes is approximately 20% in Caucasians who are older than 75 years [1]. At least half of these patients are not aware that they have the disease. A substantially higher prevalence is seen in other ethnic groups, especially blacks, Hispanics, Native Indians, and Micronesians. It is clear that we are facing an epidemic of diabetes in the elderly in the twenty-first century.

Pathogenesis of type 2 diabetes in the elderly There clearly is a strong genetic predisposition to type 2 diabetes in elderly subjects [2]. Patients with a family history of diabetes are more likely to develop the illness as they get older. The prevalence is especially high in certain ethnic groups. In elderly identical twins that are discordant for type 2 diabetes, the nondiabetic siblings have evidence of abnormal glucose metabolism [3]. Several other factors contribute to a high prevalence of diabetes in the elderly [4]. Normal aging is characterized by progressive alterations in all aspects of glucose metabolism, including insulin secretion, insulin action, and hepatic glucose production [5,6]. These changes interact with a patient’s genetic background to increase the incidence of the disease with aging. Older

This work was funded in part by grants from the Canadian Diabetes Association and the Canadian Institutes of Health Research. The author has received unrestricted research grants in the past from Novo Nordisk, Servier, and Bayer, and currently is on advisory boards for Bayer and Glaxo Smith Kline. E-mail address: [email protected] 0025-7125/06/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.mcna.2006.05.011 medical.theclinics.com

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Fig. 1. Prevalence of diabetes in men and women in the U.S. population age at least 20 years, based on the third National Health and Nutrition Examination Survey. Diabetes includes previously diagnosed and undiagnosed diabetes defined by fasting plasma glucose of at least 126 mg/dL. age-std, age-standardized. (From Harris MI, Flegal KM, Cowie CC, et al. Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in US adults. The Third National Health and Nutrition Examination Survey, 1988–1994. Diabetes Care 1998;21:521; with permission.)

individuals who have a diet that is low in complex carbohydrates and high in fat, and who are inactive or have obesitydparticularly with a central fat distributiondare more likely to develop diabetes as they age. The presence of inflammation, as measured by C-reactive protein and other proinflammatory cytokines, is associated with the development of diabetes in the elderly [7–9]. Higher levels of adiponectin (an adipocytokine that increases insulin sensitivity) are associated with a reduced incidence of diabetes in the elderly [8]. There is evidence that higher testosterone levels in women and lower levels in men are associated with an increased risk for diabetes [10]. Finally, older people have multiple comorbidities and take multiple drugs that can alter glucose metabolism [11]. Thus, it is clear that genetic, environmental, and physiologic factors work in concert to result in a high prevalence of diabetes in the elderly. Middle-aged patients who have type 2 diabetes have a constellation of metabolic abnormalities, including resistance to insulin-mediated glucose disposal, impaired glucose-induced insulin secretion, and an increase in fasting hepatic glucose production [12]. It seems that diabetes in the elderly is metabolically distinct [13–16]. Older patients do not have an increase in fasting hepatic glucose output (Fig. 2); obese subjects have normal insulin secretion, but marked resistance to insulin-mediated glucose disposal (Fig. 3); lean subjects have a profound impairment in glucose-induced insulin secretion, but normal insulin action (see Fig. 3). These findings suggest that the therapeutic approach to older people who have diabetes should be different

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Fig. 2. Fasting hepatic glucose production in relation to fasting glucose levels in healthy elderly controls and elderly patients with diabetes. (From Meneilly GS, Diabetes in the elderly. In: Morley JE, van den Berg L, editors. Endocrinology of aging. Totowa (NJ): Humana Press; 2000; p. 183; with permission.)

than in younger subjects. Many endocrinologists recommend that middleaged patients be treated initially with drugs that stimulate insulin secretion and improve insulin sensitivity, on the assumption that most patients have multiple metabolic abnormalities. In obese elderly subjects, the principal defect is insulin resistance, so patients should be treated initially with drugs that enhance insulin sensitivity. In contrast, in lean subjects, the principal problem is an impairment in insulin secretion. Therefore,

Fig. 3. Insulin-mediated glucose disposal rates in healthy elderly controls and elderly patients with diabetes. (From Meneilly GS, Diabetes in the elderly. In: Morley JE, van den Berg L, editors. Endocrinology of aging. Totowa (NJ): Humana Press; 2000; p. 184; with permission.)

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patients should be treated with exogenous insulin or drugs that stimulate insulin secretion. Insulin-mediated vasodilation accounts for about 30% of normal glucose disposal. Insulin-mediated blood flow is impaired markedly in obese insulinresistant elderly patients who have diabetes [14]. Because angiotensinconverting enzyme inhibitors improve insulin sensitivity in elderly patients who have diabetes, this finding may have therapeutic relevance [17]. There is some evidence that autoimmunity may play a role in the impairment of glucose-induced insulin secretion that occurs in lean older patients who have diabetes [5]. In the future, measurements of autoimmune parameters, such as glutamic acid decarboxylase antibodies, may allow clinicians to predict which older people are likely to become insulin dependent. If therapies become available that can reverse this autoimmunity, these treatments may be useful in preventing b cell destruction. Uptake of glucose in the body occurs by way of noninsulin-mediated and insulin-mediated mechanisms [18]. Noninsulin-mediated glucose disposal is reduced in older people who have diabetes (Fig. 4) [19]. Several interventions, including glucagon-like peptide 1 (GLP-1), enhance noninsulin-mediated glucose uptake in the elderly. These agents may prove to be useful in the aged. Few studies have evaluated the molecular abnormalities in the elderly [20–22]. There is no difference in insulin receptor number or affinity, but there may be alterations in insulin receptor tyrosine kinase. There also may be alterations in the glucokinase gene, which is the glucose sensor for the b cell. Further studies are required to delineate the molecular abnormalities in this age group.

Fig. 4. Glucose effectiveness in elderly controls and patients with diabetes. (From Meneilly GS, Diabetes in the elderly. In: Morley JE, van den Berg L, editors. Endocrinology of aging. Totowa (NJ): Humana Press; 2000; p. 185; with permission.)

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Presentation and clinical features As a result of an increase in the renal threshold for glucose with age, older patients do not develop glucosuria until the plasma glucose is elevated markedly [23,24]. Additionally, because of impaired thirst mechanisms with age, older people often do not develop polydipsia. As a result, the classic symptoms of hyperglycemia often are not present in these patients, and the diagnosis is made based on routine blood tests or if the patient is admitted to the hospital for another illness. If symptoms are present, they tend to be nonspecific. Older people may present for the first time with a complication of their illness, such as a stroke or a heart attack. Finally, nonketotic hyperosmolar coma may be the first sign of diabetes in older patients, particularly those who reside in nursing homes. There are several unique syndromes that occur almost exclusively in older patients who have diabetes [5]. Diabetic amyotrophy is manifested by asymmetric and painful weakness of pelvic girdle muscles, and occurs primarily in older men. Diabetic neuropathic cachexia is a syndrome of peripheral neuropathy, depression, and weight loss. Painful limitation of the shoulder joints occurs frequently in older patients who have diabetes. Accidental hypothermia is more common in older people who have diabetes. A variety of infections, including malignant otitis externa, is more common in older patients. Urinary tract infections can result in papillary necrosis in older people who have diabetes. Few studies have evaluated the clinical features of diabetes in the elderly nursing home patient [5]. Compared with community subjects, elderly nursing home patients who have diabetes have a higher incidence of macrovascular complications, skin infections, and renal disease. Compared with other nursing home residents, these patients are more likely to have macrovascular complications as well as urinary and soft tissue infections. Complications Although diabetes is listed as the sixth leading cause of death among the elderly, it is a much more common contributor to morbidity and mortality in this age group, because it is a contributing factor to many deaths that are caused by cardiovascular disease. Older people who have diabetes have twice the mortality of age-matched controls who do not have diabetes [25]. The principal killer is macrovascular disease. The mortality of older people who have diabetes is related to the long-term variability of plasma glucose and to measures of glycemic control, such as Hemoglobin A1C (Hgb A1C). In a variety of longitudinal studies, diabetes is one of the strongest predictors of functional decline [5,26–30]. Older patients who have diabetes have a much poorer self-rated quality of life. They also use hospital days and outpatient services at twice the rate of older people who do not have diabetes [31].

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Vascular complications The risk for microvascular and macrovascular complications and heart failure is increased in old patients who have diabetes relative to age-matched controls [5,32–35]. The risk for these complications increases with the age of the patient and the duration of the diabetes. There is a strong correlation between Hgb A1C and the risk for events, which suggests that improved glycemic control may reduce the risk for these complications. The Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction Study found that intensive insulin therapy after myocardial infarction reduced mortality in older patients [36]. The risk for macrovascular events is increased further in these patients by the presence of other risk factors, including hyperlipidemia, smoking, and hypertension. Recent randomized control trials demonstrated that risk factor modification has a beneficial effect on the risk for macrovascular complications in these patients (see later discussion). It is not known whether interventions other than improved glycemic control reduce the risk for microvascular complications in this patient population. Further randomized studies are needed to demonstrate definitively the benefits of glycemic control on all vascular complications, and of risk factor modification on microvascular events. Hypoglycemia The risk that severe or fatal hypoglycemia will occur with oral agents or insulin increases exponentially with age [5]. There are several reasons for the increased frequency of hypoglycemia in this age group. Older patients have impaired secretion of counterregulatory hormones, particularly the most important counterregulatory hormone, glucagon [37]. They are unaware of the warning symptoms of hypoglycemia and have reduced awareness of the autonomic warning symptoms, even when they have been educated in this regard [38]. They also have impaired psychomotor performance during hypoglycemia that reduces their ability to take steps to return blood sugar to normal. To reduce the frequency of severe hypoglycemic events, every effort should be made to educate older people about warning symptoms of hypoglycemia. The use of oral agents or insulin that are associated with a reduced frequency of hypoglycemia in this age group should be encouraged (see ‘‘treatment goals’’). Cognitive function Older patients who have diabetes have a higher incidence of depression and reduced performance on a variety of neuropsychologic tests [39]. Results on these tests correlate closely with Hgb A1C, lipid values, and blood pressure; improved glycemic control results in an improvement in affective and cognitive function in this age group [39,40].

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The risk for vascular dementia is increased and Alzheimer’s disease may be increased in elderly patients [41,42], but it is not known if improved control of blood sugar in patients who have diabetes or attention to risk factors modification will reduce the risk for dementia in this age group. Further studies are needed to address this issue. Prevention of diabetes Impaired glucose tolerance occurs in 25% of older patients [1]. A substantial number of these patients develops diabetes. Recent studies suggest that interventions in patients who have impaired glucose intolerance will reduce the development of diabetes in the elderly. The diabetes prevention program showed that although metformin was not particularly effective in older patients, lifestyle interventions were effective in reducing the incidence of diabetes [43]. The Study To Prevent Non-Insulin–Dependent Diabetes Mellitus (STOP-NIDDM) study demonstrated that not only did the aglucosidase inhibitor acarbose reduce the incidence of diabetes in this age group, it also reduced the incidence of macrovascular events [44]. It is not known whether other therapeutic interventions, such as glitazones, have a beneficial effect on the development of diabetes in elderly patients who have impaired glucose tolerance. Efforts to prevent diabetes in this age group should be intensified to reduce the morbidity and mortality that are associated with full-blown diabetes in the elderly. Diagnosis and monitoring The American Diabetes Association recently revised the diagnostic criteria for diabetes [45]. These criteria are not adjusted for age. Older people who have undiagnosed diabetes have an increased rate of complications when compared with age-matched controls who do not have diabetes [5]. It has been suggested that there should be widespread screening for diabetes on the assumption that earlier intervention will reduce the risk for complications. Several potential screening tests have been suggested, including an oral glucose tolerance test, an Hgb A1C, and random glucose measurements, as well as questionnaires that determine the presence of risk factors for diabetes. Screening of the entire population is unlikely to be justified economically, but targeted screening has been suggested to be cost effective in the elderly [46]. Although no consensus has been reached, it is likely that in the near future questionnaires will be administered to all patients who are older than a certain age. People who score above a certain level, because of a constellation of risk factors, will have further testing performeddeither an oral glucose tolerance test or some combination of a random glucose and postprandial glucose or an Hgb A1C. Urine glucose testing is not reliable in the elderly because of the increased renal threshold for glucose with age. Glucose monitoring can be taught to

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older people easily, and it does not impact on their quality of life significantly. HgB A1C is the best measure of long-term control. Treatment goals It is generally agreed that blood glucose should be reduced in elderly patients to prevent symptomatic hyperglycemia. In most patients, this can be accomplished by reducing the fasting glucose to less than 10 mmol/L and the 2-hour postprandial sugar to less than 14 mmol/L. There are no data from randomized controlled trials similar to the Diabetes Control and Complications Trial or the United Kingdom Prospective Diabetes Study Project to demonstrate that improved glycemic control reduces the risk for long-term complications and minimizes the risks for harm in this age group [47,48]. Prospective studies indicate that improved control as measured by reduced Hgb A1C levels is associated with a reduced risk for vascular or other complications in older patients as well as improvements in neuropsychologic function. To put this in perspective, the average 80-year-old woman in North America has a life expectancy of approximately 9 years, but she can expect to spend most of that time with a major disability. In diabetic patients, the principal causes of disability relate to vascular events. Therefore, anything that reduces the risk for these complications is likely to improve function and have a major effect on quality of life. Some investigators have debated the cost effectiveness of improving glycemic control in older patients [5]. Suffice it to say that the assumptions underlying these analyses have been called into question. Ultimately, the only way to determine definitively that improved glycemic control is good for older people is to conduct appropriately powered randomized controlled trials. What should be the treatment guidelines for elderly patients who have diabetes? Recently, the European Union Geriatric Society, in association with the International Diabetes Federation, developed guidelines for the control of diabetes and its associated risk factors in older people (Tables 1 and 2) [49]. These guidelines must be individualized based on functional status and comorbidities. Postprandial hyperglycemia It was identified recently that fasting glucose is a poor predictor of outcome in older patients who have diabetes. Hgb A1C is better, but the best Table 1 Glycemic targets in older patients who have diabetes

Fasting blood glucose 2-h postmeal glucose Hgb A1

Healthy

Frail

!7.0 mM/L !10.0 mM/L !7.0%

!10.0 mM/L !14.0 mM/L !8.5%

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Table 2 Blood pressure and lipid targets in older people who have diabetes

Blood pressure LDL TG

Healthy

Frail

!140/!80 mm Hg !3.0 mM/L !2.3 mM/L

!150/!90 mm Hg

Abbreviations: LDL, Low Density Lipoprotein; TG, Triglyceride.

predictor of outcome in older patients who have diabetes is the postprandial glucose [50]. Only two small randomized trials (see ‘‘a-glucosidase inhibitors’’) have suggested that targeting postprandial glucose results in improved outcome in older patients. Further studies are needed in this regard; however, it is likely that in the near future the focus of glycemic control in older patients who have diabetes will be more on postprandial blood sugars rather than on preprandial blood sugars. Therapeutic options Treatment of older patients who have diabetes is difficult because they take multiple medications, have multiple diseases, and often have complex social situations that complicate their therapy. As a result, a team approach that involves nurses, dietitians, physicians, and other health care professionals is absolutely essential [5]. In general, older people are less aware of the implications of their disease and do not participate in educational programs; however, multidisciplinary programs in older patients result in improved glycemic control and better compliance with therapy [5,51]. The involvement of family members in therapeutic plans also improves the outcome. Older people often have visual difficulties. Therefore, it is essential that the print be large enough in educational materials. Nursing homes frequently have few guidelines for the management of older people who have diabetes, and the staff are uninformed about diabetes. Educational programs for nursing staff resulted in better outcomes for older patients who had diabetes. For elderly patients who have diabetes, risk factor modification is an important part of management. Calcium channel blockers, thiazide diuretics, Angiotensin II blockers, and angiotensin-converting enzyme inhibitors are effective antihypertensive agents in these patients, and reduce the risk for major cardiovascular events [52–57]. Several randomized controlled trials suggest that treatment with statins reduces the risk for vascular events and overall mortality in older patients who have diabetes [5,58–60]. Current guidelines for the management of hypertension and hyperlipidemia in the elderly patient with diabetes are shown (see Table 2).

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Diet Several agencies have given dietary guidelines for diabetes in older people, but there is little data to support these recommendations [5]. Older people seem to comply poorly with many dietary recommendations. Older patients benefit from weight loss, but rigorous diabetic diets do not improve outcome in older nursing home patients. Patients who have diabetes often are deficient in trace elements. Short-term studies involving supplementation of magnesium and zinc found improved glycemic control in these patients. Additionally, supplementation with antioxidant vitamins, such as vitamin C and vitamin E, may improve control.

Exercise Several randomized controlled trials evaluated the effect of exercise in older patients who had type 2 diabetes [5]. Although aerobic exercise has a limited impact on glycemic control, strength training significantly improves glycemic control [61,62].

Medication management a-Glucosidase inhibitors Several randomized controlled trials and one large postmarketing surveillance survey found that acarbose significantly reduced Hgb A1C and postprandial glucose levels in older patients who had type 2 diabetes [5]. A recent study compared miglitol with glyburide in older people who had diabetes and found that glyburide was more effective in reducing Hgb A1C [63]; however, patients who took glyburide had more hypoglycemic events, greater weight gain, and a higher incidence of cardiovascular events. The recent STOP-NIDDM study demonstrated that acarbose significantly reduced vascular events in an older patient population that had impaired glucose tolerance [64]. The major side effects of these drugs are gastrointestinal, but most patients are able to continue therapy with careful titration of the dosage. If larger randomized controlled trials that specifically target postprandial hyperglycemia demonstrate improved outcome in older patients who have diabetes or prediabetes, the use of these drugs will become more widespread. Metformin Although it has never been evaluated in randomized controlled trials, metformin is safe and effective in older patients who have diabetes. Most cases of lactic acidosis occur in patients who have abnormal renal function or heart failure or who are admitted to the hospital with a lactate-producing

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illness. Metformin is particularly useful because it increases insulin sensitivity, helps patients lose weight, and does not cause hypoglycemia when used alone. Thiazolindinediones Recent data suggest that these drugs are effective in improving glycemic control in older patients who have diabetes [65]. The risk for fluid retention is tripled in older patients who are treated with these drugs, so they should not be used in patients who have class 3 or 4 heart failure. All patients should be monitored carefully for fluid retention when these drugs are started. Sulfonylureas The elimination and absorption of glyburide is decreased with age, and the elderly seem to have greater insulin responses to the drug. This may explain the increased risk for severe or fatal hypoglycemia with glyburide in the elderly. The risk for hypoglycemia seems to be less with gliclazide and its extended release form as well as glipizide and glimepiride in this patient population [66–70]. These drugs should be used in preference to glyburide in the elderly. Other oral agents Nateglinide and repaglinide are short-acting insulin secretagogues that mimic normal postprandial insulin secretion and rapidly acting insulin analogs. These drugs are associated with a lower frequency of hypoglycemia in the aged than is glyburide [71]. Because they specifically target postprandial hypoglycemia, their use may become widespread if studies confirm the therapeutic relevance of this target. Insulin Older patients frequently make errors when they try to mix insulin [5]. The accuracy of insulin injections is improved when older people use premixed preparations, although the proportion of regular and long-acting insulin does not seem to affect glucose levels. Limited data suggest that basal-bolus insulin regimens are tolerated well by some elderly patients, and may improve control relative to conventional insulin regimens [72]. Hypoglycemia is more frequent in older people who are treated with one daily injection of Neutral Protamine Hagedorn (NPH), so two injections of NPH are preferred in most patients. Insulin glargine or detemir would seem to be the ideal therapy for elderly patients when multiple insulin injections are a problem, but there are no randomized controlled trials to support their use in the elderly.

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Other drugs Fluoxetine assists in weight loss and improves glycemic control in older people who have diabetes [73]. It should be considered for use in obese diabetic older patients who are depressed. There are ongoing studies that demonstrate that GLP-1 and its analogs improve glycemic control in older people who have diabetes and rarely result in hypoglycemia [74]. Use of these peptides likely will increase in the future. Erectile dysfunction is extremely common in elderly men who have diabetes, and phosphodiesterase inhibitors are safe and effective in this patient population [75–77]. Summary We are approaching an epidemic of diabetes in the elderly. This epidemic and its associated complications will have a significant impact on quality of life in this age group. Recent studies suggest that diabetes can be prevented in a large number of patients with appropriate interventions. It seems that diabetes in this age group is metabolically distinct. As a result, the approach to therapy in the elderly differs from that in younger patients. Unfortunately, we still have huge gaps in our understanding of the pathogenesis and treatment of diabetes in the aged, and further studies are needed urgently. References [1] Harris MI, Flegal KM, Cowie CC, et al. Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in US adults. Diabetes Care 1998;21:518–24. [2] Kahn CR. Banting Lecture. Insulin action, diabetogenes, and the cause of type II diabetes. Diabetes 1994;43:1066–84. [3] Vaag A, Henriksen JE, Madsbad S, et al. Insulin secretion, insulin action, and hepatic glucose production in identical twins discordant for non-insulin-dependent diabetes mellitus. J Clin Invest 1995;95:690–8. [4] Skarfors ET, Selinus KI, Lithell HO. Risk factors for developing non-insulin-dependent diabetes. A 10-year follow-up of men in Uppsala. BMJ 1991;303:755–60. [5] Meneilly GS, Tessier D. Diabetes in elderly adults. J Gerontol 2001;56A:M5–13. [6] Jackson RA. Mechanisms of age-related glucose intolerance. Diabetes Care 1990;13(Suppl 2): 9–19. [7] Barzilay JI, Abraham L, Heckbert S, et al. The relation of markers of inflammation to the development of glucose disorders in the elderly. Diabetes 2001;50:2384–9. [8] Kanaya AM, Harris T, Goodpaster BH, et al. Adipocytokines attenuate the association between visceral adiposity and diabetes in older adults. Diabetes Care 2004;27:1375–80. [9] Lechleitner M, Herold M, Dzien-Bischinger C, et al. Tumour necrosis factor-alpha plasma levels in elderly patients with type 2 diabetes mellitusdobservations over 2 years. Diabet Med 2002;19:949–53. [10] Oh J-Y, Barrett-Connor E, Wedick NM, et al. Endogenous sex hormones and the development of type 2 diabetes in older men and women: the Rancho Bernardo Study. Diabetes Care 2002;25:55–60. [11] Pandit MK, Burke J, Gustafson AB, et al. Drug induced disorders of glucose intolerance. Ann Intern Med 1993;118:529–39.

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[12] DeFronzo RA. Lilly Lecture 1987. The triumvirate: b-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes 1988;37:667–87. [13] Meneilly GS, Hards L, Tessier D, et al. NIDDM in the elderly. Diabetes Care 1996;19: 1320–5. [14] Meneilly GS, Elliott T. Metabolic alterations in middle-aged and elderly obese patients with type 2 diabetes. Diabetes Care 1999;22:112–8. [15] Meneilly GS, Elahi D. Metabolic alterations in middle-aged and elderly lean patients with type 2 diabetes. Diabetes Care 2005;28:1498–9. [16] Arner P, Pollare T, Lithell H. Different aetiologies of type 2 (non-insulin-dependent) diabetes mellitus in obese and non-obese subjects. Diabetologia 1991;4:483–7. [17] Paolisso G, Gambardella A, Verza M, et al. ACE inhibition improves insulin-sensitivity in aged insulin-resistant hypertensive patients. J Hum Hypertens 1992;6:175–9. [18] Best JD, Kahn SE, Ader M, et al. Role of glucose effectiveness in the determination of glucose tolerance. Diabetes Care 1996;19:1018–30. [19] Forbes A, Elliot T, Tildesley H, et al. Alterations in non-insulin-mediated glucose uptake in the elderly patient with diabetes. Diabetes 1998;47:1915–9. [20] McCarthy MI, Hitman GA, Hitchins M, et al. Glucokinase gene polymorphisms: a genetic marker for glucose intolerance in cohort of elderly Finnish men. Diabet Med 1993;10: 198–204. [21] Laakso M, Malkki M, Kekalainen P, et al. Glucokinase gene variants in subjects with lateonset NIDDM and impaired glucose tolerance. Diabetes Care 1995;18:398–400. [22] Obermaier-Kusser B, White MF, Pongratz DE, et al. A defective intramolecular autoactivation cascade may cause the reduced kinase activity of the skeletal muscle insulin receptor from patients with non-insulin-dependent diabetes mellitus. J Biol Chem 1989;264: 9497–504. [23] Gambert SR. Atypical presentation of diabetes in the elderly. Clin Geriatr Med 1990;6:721–9. [24] Morley JE, Kaiser FE. Unique aspects of diabetes mellitus in the elderly. Clin Geriatr Med 1990;6:693–702. [25] Sinclair AJ, Robert IM, Croxson SCM. Mortality in older people with diabetes mellitus. Diabet Med 1996;14:639–47. [26] Spiers NA, Matthews RJ, Jagger C, et al. Diseases and impairments as risk factors for onset of disability in the older population in England and Wales: findings from the Medical Research Council Cognitive Function and Ageing Study. J Gerontol 2005;60A:248–54. [27] Seeman T, Chen X. Risk and protective factors for physical functioning in older adults with and without chronic conditions: MacArthur studies of successful aging. J Gerontol B Psychol Sci Soc Sci 2002;57B:S135–44. [28] Wray LA, Ofstedal MB, Langa KM, et al. The effect of diabetes on disability in middle-aged and older adults. J Gerontol 2005;60A:1206–11. [29] Al Snih S, Fisher MN, Raji MA, et al. Diabetes mellitus and incidence of lower body disability among older Mexican Americans. J Gerontol A Biol Sci Med Sci 2005;60:1152–6. [30] Maggi S, Noale M, Gallina P, et al, for the ILS Group. Physical disability among older Italians with diabetes. The ILSA Study. Diabetologia 2004;47:1957–62. [31] Maciejewski ML, Maynard C. Diabetes-related utilization and costs for inpatient and outpatient services in the Veterans Administration. Diabetes Care 2004;27:B69–73. [32] Bertoni AG, Hundley WG, Massing MW, et al. Heart failure prevalence, incidence, and mortality in the elderly with diabetes. Diabetes Care 2004;27:699–703. [33] Mayfield JA, Reiber GE, Maynard C, et al. The epidemiology of lower-extremity disease in veterans with diabetes. Diabetes Care 2004;27:B39–44. [34] Nichols GA, Gullion CM, Koro CE, et al. The incidence of congestive heart failure in type 2 diabetes. Diabetes Care 2004;27:1879–84. [35] Gregg EW, Sorlie P, Paulose-Ram R, et al. Prevalence of lower-extremity disease in the US adult population over 40 years of age with and without diabetes. Diabetes Care 2004;27: 1591–7.

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[36] DIGAMI (DiabetesMellitus, Insulin Glucose Infusion in Acute Myocardial Infarction)Study Group.Prospective randomised study of intensiveinsulin treatment onlong term survivalafter acute myocardial infarction in patients with diabetes mellitus. BMJ 1997;314(7093):1512–15. [37] Meneilly GS, Cheung E, Tuokko H. Counterregulatory hormone responses to hypoglycemia in the elderly patient with diabetes. Diabetes 1994;43:403–10. [38] Thomson FJ, Masson EA, Leeming JT, et al. Lack of knowledge of symptoms of hypoglycaemia by elderly diabetic patients. Age Aging 1991;20:404–6. [39] Meneilly GS, Cheung E, Tessier D, et al. The effect of improved glycemic control on cognitive functions in the elderly patient with diabetes. J Gerontol 1993;48:M117–21. [40] Gradman TJ, Laws A, Thompson LW, et al. Verbal learning and/or memory improves with glycemic control in older subjects with non-insulin-dependent diabetes mellitus. J Am Geriatr Soc 1993;41:1305–12. [41] Janson J, Laedtke T, Parisi JE, et al. Increased risk of type 2 diabetes in Alzheimer disease. Diabetes 2004;53:474–81. [42] Beeri MS, Silverman JM, Davis KL, et al. Type 2 diabetes is negatively associated with Alzheimer’s disease neuropathology. J Gerontol A Biol Sci Med Sci 2005;60:471–5. [43] Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393–403. [44] Chiasson JL, Josse RG, Gomis R, et al, for The STOP-NIDDM Trial Research Group. Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance. JAMA 2003;290:486–94. [45] American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2005;28:S37–42. [46] Hoerger TJ, Harris R, Hicks KA, et al. Screening for type 2 diabetes mellitus: a cost-effectiveness analysis. Ann Intern Med 2004;140:689–99. [47] Diabetes Control and Complications Trial Research Group. The effect of intensive treatment on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977–86. [48] UK Prospective Diabetes Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes. Lancet 1998;352:837–53. [49] European Diabetes Working Party for Older People 2001–2004. Clinical guidelines for type 2 diabetes mellitus. Available at: http://www.euroage-diabetes.com. Accessed November 2003. [50] The DECODE Study Group. Glucose tolerance and cardiovascular mortality: comparison of fasting and 2 hour diagnostic criteria. Arch Intern Med 2001;161:397–405. [51] Braun A, Muller UA, Muller R, et al. Structured treatment and teaching of patients with type 2 diabetes mellitus and impaired cognitive functiondthe DICOF trial. Diabet Med 2004;21:999–1006. [52] Curb JD, Pressel SL, Cutler JA, et al. Effect of diuretic-based antihypertensive treatment on cardiovascular disease risk in older diabetic patients with isolated systolic hypertension. JAMA 1996;276:1886–91. [53] Tuomilehto J, Rastenyte D, Birkenha¨ger WH, et al, for the Systolic Hypertension in Europe Trial investigators. Effects of calcium-channel blockade in older patients with diabetes and systolic hypertension. N Engl J Med 1999;340:677–84. [54] Voyaki SM, Staessen JA, Thijs L, et al, for Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Follow-up of renal function in treated and untreated older patients with isolated systolic hypertension. J Hypertens 2001;19:511–9. [55] The Heart Outcome Prevention Evaluation Study Investigators. Effects of an angiotensinconverting-enzyme inhibitor, ramipril, on cardiovascular events in high risk patients. N Engl J Med 2000;342:145–53. [56] Julius S, Kjeldsen SE, Weber M, et al, for the VALUE trial group. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlopidine: the VALUE randomized trial. Lancet 2004;363:2022–30.

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[57] Dahlo¨f B, Devereux RB, Kjeldsen SE, et al, for the LIFE study group. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomized trial against atenolol. Lancet 2002;359:995–1003. [58] Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomized placebo-controlled trial. Lancet 2003;361:2005–16. [59] Shepherd J, Blauw GJ, Murphy MB, et al. PROSPER study group. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomized controlled trial. Lancet 2002;360:1623–30. [60] Colhoun HM, Betteridge DJ, Durrington PN, et al, on behalf of the CARDS investigators. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomized placebocontrolled trial. Lancet 2004;364:685–96. [61] Dunstan DW, Daly RM, Owen N, et al. High-intensity resistance training improves glycemic control in older patients with type 2 diabetes. Diabetes Care 2002;25:1729–36. [62] Iban˜ez J, Izquierdo M, Argu¨elles I, et al. Twice-weekly progressive resistance training decreases abdominal fat and improves insulin sensitivity in older men with type 2 diabetes. Diabetes Care 2005;28:662–7. [63] Johnston PS, Lebovitz HE, Coniff RF, et al. Advantages of alpha-glucosidase inhibition as monotherapy in elderly type 2 diabetic patients. J Clin Endocrinol Metab 1998;83:1515–22. [64] Chiasson JL, Josse RG, Gomis R, et al, for The STOP-NIDDM Trial Research Group. Acarbose prevention of type 2 diabetes mellitus: the STOP-NIDDM randomized trial. Lancet 2002;359:2072–7. [65] Rajagopalan R, Perez A, Ye Z, et al. Pioglitazone is effective therapy for elderly patients with type 2 diabetes mellitus. Drugs Aging 2004;21:259–71. [66] Rosenstock J, Corrao PJ, Goldberg RB, et al. Diabetes control in the elderly: a randomized, comparative study of glyburide versus glipizide in non-insulin-dependent diabetes mellitus. Clin Ther 1993;15:1031–40. [67] Brodows RG. Benefits and risks with glyburide and glipazide in elderly NIDDM patients. Diabetes Care 1992;15:75–80. [68] Tessier D, Dawson K, Tetrault JP, et al. Glibenclamide vs glicazide in type 2 diabetes of the elderly. Diabet Med 1994;11:974–80. [69] Drouin P, Standl E, , for the Diamicron MR Study Group. Gliclazide modified release: results of a 2-year study in patients with type 2 diabetes. Diabetes Obes Metab 2004;6:414–21. [70] Holstein A, Plaschke A, Eick-Hartwig E. Lower incidence of severe hypoglycaemia in patients with type 2 diabetes treated with glimepiride versus glibenclamide. Diabetes Metab Res Rev 2001;17:467–73. [71] Del Prato S, Heine RJ, Keilson L, et al. Treatment of patients over 64 years of age with type 2 diabetes. Diabetes Care 2003;26:2075–80. [72] Hendra TJ, Taylor CD. A randomized trial of insulin on well-being and carer strain in elderly type 2 diabetic subjects. J Diabetes Complications 2004;18:148–54. [73] Connolly VM, Gallagher A, Kesson CM. A study of fluoxetine in obese elderly patients with type 2 diabetes. Diabet Med 1994;12:416–8. [74] Meneilly GS, Greig N, Tildesley H, et al. Effects of 3 months of continuous subcutaneous administration of glucagon-like peptide 1 in elderly patients with type 2 diabetes. Diabetes Care 2003;26:2835–41. [75] Wagner G, Montorsi F, Auerbach S, et al. Sildenafil citrate (Viagra) improves erectile function in elderly patients with erectile dysfunction: a subgroup analysis. J Gerontol 2001;56A: M113–9. [76] Carson CC, Rajfer J, Eardley I, et al. The efficacy and safety of tadalafil: an update. BJU Int 2004;93:1276–81. [77] Tsujimura A, Yamanaka M, Takahashi T, et al. The clinical studies of sildenafil for the ageing male. Int J Androl 2002;25:28–33.

Med Clin N Am 90 (2006) 925–944

Assessment and Management of Chronic Pressure Ulcers in the Elderly Aime´e Dinorah Garcia, MD, CWSa,*, David R. Thomas, MDb a

Michael E. DeBakey VA Medical Center, Baylor College of Medicine, 2002 Holcombe ECL 110, Houston, TX 77030, USA b Division of Geriatric Medicine, St. Louis University, 1402 South Grand Boulevard, M238, St. Louis, MO 63104, USA

Pressure ulcers are a significant problem in today’s aging society. Although there are no concrete data on total costs, the United States cost of managing pressure ulcers is estimated to be $1.335 billion annually [1–3]. This cost is likely to rise given the alarming increases of an aging society, most notably in the oldest old, defined as individuals over the age of 80. In most nations of the world there have been major reductions in the prevalence of infectious and parasitic diseases, declines in infant and maternal mortality, and improved nutrition during the twentieth century [4]. Because of the overall improved nutrition and improved treatment of infections, the average life expectancy increased from 49.24 years in 1900 to 77.3 years in 2002 [5]. By the year 2030, it is expected that 20% of the population will be over the age of 65 [6]. Although health care is making tremendous strides in prolonging quantity of life, there are an ever increasing number of debilitated individuals with chronic comorbidities that put them at higher risk for skin breakdown. Health care providers are often unfamiliar with the scientific evidence, classification, and treatment of chronic wounds. A glossary is provided at the end of this article that defines common terms used in the field of wound care (Appendix). Medical conditions, such as peripheral vascular disease, diabetes mellitus, renal disease, obesity, and malnutrition, are associated with poor wound healing. Limited mobility caused by hip fractures, gait abnormalities, and progressive neurologic disorders that have a higher incidence in the elderly,

* Corresponding author. E-mail address: [email protected] (A.D. Garcia). 0025-7125/06/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.mcna.2006.05.018 medical.theclinics.com

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such as Alzheimer’s dementia and Parkinson’s disease, also place this population at higher risk. In addition, there are normal changes in aging skin that put these individuals at higher risk for skin breakdown, although the relationship between chronologic age and wound healing is highly debated. The relationship is more likely caused by pathologic changes in the skin rather than age itself [7]. Because of these cumulative factors, the elderly are especially susceptible to pressure ulcers. An important statistic to remember is that approximately 70% of pressure ulcers occur in individuals over the age of 70 years [8,9]. Although prevention of pressure ulcers is an important goal, in many elderly patients, once pressure ulcers develop, without vigilant and aggressive treatment they may become chronic. A chronic wound, such as a pressure ulcer, is defined as one that has failed to proceed through the orderly process of normal wound healing to produce anatomic and functional integrity. To understand what makes a wound falter into a state of chronicity, it is important first to understand the normal progression of wound healing.

Phases of wound healing The process of wound healing can be divided into four phases: (1) hemostasis, (2) inflammatory, (3) proliferative, and (4) maturation (Table 1). The phases overlap and are a continuous process. Each phase is mediated by cells that then impact the next phase of healing. In the hemostasis phase, platelets migrate into the wound bed to staunch the flow of blood. The platelets then release chemical mediators that call neutrophils to the wound bed in the inflammatory phase. Neutrophils have two important functions. They clear the wound of bacterial debris, and they help fight infection. Neutrophils are short-lived in the wound bed, and are extruded within the eschar. Monocytes are also recruited, and eventually mature into macrophages, Table 1 Phases of wound healing Phase

Cells involved

Activity

Hemostasis

Platelets

Inflammatory

Neutrophils Monocytes and macrophages

Proliferate

Fibroblasts

Maturation

Fibroblasts

Stop blood loss Release chemoattractants Kill bacteria Continue to kill bacteria Stimulate fibroblasts to release collagen Promote fibroblasts to transform into myofibroblasts Promote angiogenesis Lay down extracellular matrix Transform into myofibroblasts and contract wound edges Replacement of immature collagen with mature collagen (may take up to 2 y)

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which then take over the role of killing bacteria in the wound bed. Macrophages also stimulate fibroblasts to secrete collagen, promote transformation of fibroblasts to myofibroblasts, and stimulate angiogenesis [10]. The next phase of the healing cascade is the proliferative phase, which is characterized by the deposition of extracellular matrix. The components of the provisional extracellular matrix are fibrin, fibronectin, and hyaluronic acid [11,12]. Fibronectin, along with various growth factors, attracts fibroblasts to the matrix [13]. The role of the fibroblast is twofold: to lay down the collagen-based extracellular matrix, and to transform into myofibroblasts and contract the edges of the wound [14]. Another critical part of the proliferative phase is angiogenesis. Without an adequate blood supply, the newly formed granulation tissue cannot survive. The final phase of the healing cascade is the maturation phase. In this phase, the immature collagen type I, which was initially laid down by the fibroblasts, is replaced by mature collagen type III. The process can take up to 2 years. It is important to note that the integrity of the skin that is replaced by scar tissue is at best 70% to 80% of the surrounding tissue [15,16]. Because of the decrease in tensile strength, the area of scar tissue is always more susceptible to recurrent skin breakdown.

Risk factors for pressure ulcers There are numerous risk factors that put the elderly at higher risk for skin breakdown. These factors can be classified as intrinsic or extrinsic (Box 1). Intrinsic factors are those that influence architecture and integrity of the skin’s supporting and underlying structures [17]. They include limited mobility; comorbidities, such as diabetes, chronic obstructive pulmonary disease, congestive heart failure, malignancy, and renal dysfunction; poor nutrition; and aging skin. Extrinsic factors are those factors that influence tissue tolerance by impinging on the skin surface. They include pressure, friction, shear stress, and moisture [17–19]. In addition, federal surveyors are now inspecting long-term care facilities based on the new Tag F-314 guidelines, which outline the risk factors they believe are important in pressure ulcer development. Intrinsic factors Immobility Although the two groups of patients with the largest incidence of pressure ulcers are the elderly and spinal cord injury patient, any patient who is immobilized is at risk. Patients undergoing surgical procedures, those in braces or splints, and patients who require traction are all at increased risk [20–23]. The incidence of pressure ulcer development for patients undergoing hip fracture repair is 42% [24], and increases the cost of hospitalization by an

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Box 1. Risk factors for pressure ulcers Intrinsic Limited mobility Spinal cord injury Cerebrovascular accident Progressive neurologic disorders (ie, Parkinson’s, Alzheimer’s, multiple sclerosis) Immobilized patients (hip fracture patients in traction) Poor nutrition Anorexia Poor dentition Medications Poverty or lack of access to food Decreased sense of smell affecting taste Depression Dietary restrictions Comorbidities Diabetes mellitus Congestive heart failure Renal failure Malignancies Chronic obstructive pulmonary disease Aging skin Loss of elasticity Decreased cutaneous blood flow Decreased dermal-epidermal turnover Changes in dermal pH Flattening of rete ridges Loss of subcutaneous fat Disorganization of collagen fibrils: photoaging Accumulation of abnormal elastin: containing Extrinsic Pressure: Unrelieved pressure on any hard surface (ie, bed, wheelchair, stretcher) Friction: Dragging across sheets Agitation Pushing up in bed with heels (friction blisters) Shear: Sliding down in bed

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Moisture: Bowel or bladder incontinence Excessive sweating Trapped moisture in skin folds

average of $10,000 [1]. Among neurologically impaired patients, pressure ulcers occur at an annual rate of 5% to 8%, with a lifetime risk estimated to be 25% to 85% [25]. Quadriplegic patients have a higher risk than paraplegics. This is likely caused by the higher degree of reduced mobility and larger body area affected by altered perception in quadriplegic patients. The most common site is in the ischial region and can lead to complications, such as amputation of extremities and urinary or bowel diversions [26–29]. Approximately 57% to 60% of pressure ulcers occur in the hospital setting within the first 2 weeks of admission [30–32]. This time frame is logical given that patients requiring acute hospital admissions are likely to be bed bound until their medical condition is stabilized. In addition, the immediate time period surrounding acute hospitalization requires patients to be on stretchers for extended periods of time for diagnostic or therapeutic procedures, or transportation. A standard hospital mattress can generate pressures of 45 to 75 mm Hg [18], and stretchers increase risk because they do not have any type of pressure-reducing surface, and patients often do not get repositioned. In the long-term care setting, the incidence of pressure ulcers is approximately 13% to 24%, but the longer the patient stays in the nursing home, the greater the likelihood that a pressure ulcer develops [33]. Comorbidities There are numerous comorbid conditions that make the risk of pressure ulcer development greater and affect wound healing. Disease processes, such as congestive heart failure, cause significant tissue hypoxia, which can accelerate cell death. With diabetes mellitus, there are vascular, neuropathic, immune function, and biochemical abnormalities each contributing to the altered tissue repair [34]. Progressive neurologic disorders, such as dementia, can eventually lead to difficulty with mobility, bowel and bladder incontinence, altered sensory perception, and poor nutrition, all of which increase the risk of skin breakdown. Debilitating arthropathies can lead to wheelchair or bed confinement and patients with malignancies or who are terminal are likely to be in a catabolic state [35]. This is by no means a comprehensive list of all the factors that can play a role in the risk of pressure ulcer development. It is important to focus not only on the prevention or treatment of the pressure ulcer itself, but on the overall clinical picture that affects the healing process, or predisposes the patient to skin breakdown.

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Poor nutrition Of all the intrinsic factors that affect wound healing, one of the most important is poor nutrition. Severe protein-calorie malnutrition in humans alters tissue regeneration, the inflammatory reaction, and immune function [36]. Protein-calorie malnutrition has been reported in 15% of communitydwelling and home-bound elderly, up to 62% of hospitalized patients, and up to 85% of nursing home residents [37–40]. Poor nutrition has been associated with impaired wound healing [41]. One study in high-risk, malnourished patients found the relative risk of developing a pressure ulcer was 2.1 times greater (95% confidence interval) compared with normally nourished patients [42]. Malnourished patients are more likely to have postoperative complications, and have a higher overall risk for infection and increased mortality [43,44]. It is also important to recognize that although most believe obesity is a marker of overnutrition, elderly obese individuals are very likely to be nutritionally compromised [45]. There are numerous changes that occur as individuals age that can also predispose them to malnutrition and skin breakdown. These include poor dentition; decline in cognitive or functional status; depression; decreased sense of smell, which affects taste; anorexia secondary to chronic diseases; dysphagia; and poverty [46–50]. In addition, some of the dietary restrictions that clinicians impose on patients can make food unpalatable, and can create nutritional deficits because patients refuse to eat [51]. Given these numerous risk factors, and the high prevalence of malnutrition in the elderly community, every elderly patient considered to be at risk for pressure ulcer development should have a full nutritional assessment. Aging skin The skin is the largest organ system in the body, and provides multiple important functions including protection against entry of microorganisms; regulation of water loss; protection from UV radiation; and assistance with thermoregulation. It also plays a role in the immune, endocrine, and metabolic systems [52]. As with all other organ systems, there are changes that occur within the skin as an individual ages at all levels, including the epidermis and the dermis. These changes are a combination of intrinsic and extrinsic factors. Intrinsic changes include loss of elasticity, decreased cutaneous blood perfusion, decreased dermal-epidermal turnover, changes in dermal pH, flattening of rete ridges, and loss of subcutaneous fat. In addition, there is damage that occurs as a result of extrinsic aging on sun-exposed skin from long-standing environmental exposure and from UV radiation from sunlight, known as ‘‘photoaging’’ [53]. The damage caused by photoaging occurs mostly in the dermal connective tissue and is characterized by disorganization of collagen fibrils and the accumulation of abnormal elastin-containing material [54,55]. Environmental factors, such as tobacco use, also play a significant role in damage to the skin and in delayed wound healing [56,57].

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Extrinsic factors The extrinsic factors that can lead to the formation of pressure ulcers are pressure, friction, shear, and moisture [17]. Pressure By definition, a pressure ulcer develops when there is unrelieved pressure between an external surface and underlying structures, often over a bony prominence. Damage occurs when external pressure exceeds capillary closing pressure obstructing blood flow to tissue and causing local ischemia [58,59]. The amount of pressure required to compress dermal vessels in the arteriolar limb of the capillary bed is 32 mm Hg [60]. There is an inverse relationship, however, between duration and intensity of pressures and the amount of time to tissue death [61]. Also, as individuals age, there is a decrease in lean body mass and an increase in total body fat, but a decrease in subcutaneous fat [51]. This loss of subcutaneous fat leads to more pronounced bony prominences that are less protected against external pressures. Friction Friction is caused by the abrasion of one surface against another, such as when a patient is dragged across the sheets, or an agitated patient is restless and develops ‘‘sheet burn’’ [62]. Patients can also develop friction blisters on the heels when they push themselves up in the bed using only the heels against the sheets. Although friction does not directly cause pressure ulcers, it contributes by stripping the stratum corneum and making the skin more susceptible to pressure ulcers [63]. Shear Shear is caused by gravity pushing down on the body, and friction between the patient and the surface [62,64]. It occurs when a force is applied parallel to the soft tissues. This force causes the dermal blood vessels to be stretched and angulated, and compromises tissue perfusion [65,66]. This leads to tissue ischemia, and is another factor is making the skin more susceptible to pressure ulcers [67]. Also, as a consequence of aging, there is thinning of the epidermis, which is primarily caused by flattening of the rete pegs. This thinning makes the aged epidermis less resistant to shearing forces [68]. Moisture Moisture has been identified in the literature as a perspiration, bowel or bladder incontinence, or drainage from fistulas or wounds, which leads to skin maceration. There are several studies that suggest fecal and urinary incontinence increase the risk of pressure ulcer development fivefold [69], but when each risk factor was looked at independently, fecal incontinence was

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found to be a much more important factor in causing skin breakdown, which can lead to pressure ulcer formation [70]. This is likely caused by the bile acids and enzymes in feces. As per the Tag F-314 guidelines, it is also important to consider the maceration from urine and stool that make the skin more susceptible to friction and shear, and the irritation to the skin, which can cause dermatitis. This dermatitis may be difficult to distinguish from a partial-thickness pressure ulcer [71]. Dermatitis caused by incontinence likely occurs in the area where an incontinence brief or underpad is used, and typically presents with significant erythema, scaling, itching, papules, weeping, and eruptions [72]. F-Tag 314 risk factor guidelines In addition to the risk factors outlined and discussed in the previous section, the new federal guidelines for nursing home surveyors, Tag F-314, outlines other risk factors that increase a resident’s susceptibility to develop or not to heal pressure ulcers. These risk factors include, but are not limited to
Medical conditions, as listed previously, but including thyroid disease
Drugs, such as steroids that may affect wound healing
Impaired diffuse or localized blood flow (eg, generalized atherosclerosis or lower-extremity arterial insufficiency)
Resident refusal of some aspects of care and treatment
Cognitive impairment
A healed ulcer (the history of a healed pressure ulcer and its stage, if known, is important, because areas of healed stage III or IV pressure ulcers are more likely to have recurrent breakdown) [73–75]. Risk assessment Every patient entering an acute, subacute, or long-term care facility needs to be assessed for pressure ulcer risk. The most widely used tools for pressure ulcer risk assessment are the Norton, Braden, Gosnell, and Waterlow Scales [75–78]. Of these scales, the most widely used are the Braden Scale and the Norton Scale in the United States, and the Waterlow Scale in the United Kingdom [79]. The first scale developed for pressure ulcers was the Norton Scale in 1962 [76]. The original Norton score assessed risk based on five factors: (1) physical condition, (2) mental condition, (3) activity, (4) mobility, and (5) incontinence. The maximum score for the Norton Scale was 20, with a minimum score of 5. The patient was considered to be at risk for a pressure ulcer if the score was %14. The tool has now been modified and is called the Norton Plus Pressure Ulcer Scale. The modified scale uses the original Norton Scale score, then makes deductions for comorbidities, such as diabetes, hypertension, low hemoglobin and hematocrit, albumin level !3.3 mg/dL, fever of O99.6 F, five or more medications, and change in mental status to confused

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or lethargic in the last 24 hours. Each of these factors results in the deduction of one point from the original Norton score. A score of 10 or less is considered high risk [76]. The Braden Scale was first introduced in 1987 and is the scale most frequently used in research, and along with the Norton scale is recommended by the American Agency for Health Care Research and Quality for predicting pressure ulcer risk [80,81]. The scale is composed of six subscales: (1) sensory perception, (2) activity, (3) mobility, (4) nutrition, (5) moisture level, and (6) friction and shear. The maximum score on the tool is 23, and a score of 16 or less indicates a high risk of pressure ulcer development in the general population, but is 18 or less in the elderly or dark-skinned individuals [77,82,83]. In the Gosnell Scale, there are five parameters that are assessed: (1) mental status, (2) continence, (3) mobility, (4) activity, and (5) nutrition. In addition, evaluation of the patient includes vital signs; skin appearance; 24-hour fluid balance; interventions, which are defined as all devices, measures, or nursing care activity being used for the purpose of pressure sore prevention; and medications. The minimum score on the scale is 5, and the maximum is 20. The higher the score, the higher the risk of pressure ulcer development [75,83]. The Waterlow Scale is based on the Norton Scale, but is considered to be more comprehensive. The Waterlow Scale consists of eight items: (1) build and weight for height, (2) visual assessment of the skin in the area at risk, (3) sex and age, (4) continence, (5) mobility, (6) appetite, (7) medication, and (8) special risk factors. The highest and lowest scores of each item vary. For instance, the scores for mobility range from 0 to 5; scores for appetite range from 0 to 3. Patients scoring 10 to 14 are identified as being at risk for pressure ulcer formation. A score of 16 or above is the usual cutoff point for at-risk patients in clinical studies [78,83]. The use of any risk assessment tool in the prediction of pressure ulcer risk must be in combination with good clinical judgment. It is important to know that although the sensitivity and specificity is high, the positive predictive value of the most widely used scales, the Braden and Norton Scales, is around 37% [84]. Even with the use of these tools, and proper use of interventions, patients can develop pressure ulcers. Also, there are problems with risk assessment. These include lack of assessment altogether, and lack of proof that identification and development of care plan reduces the risk of pressure ulcers. There are patients who develop pressure ulcers despite proper assessment and preventions being put into place. This may be caused by a catabolic state in patients who are severely ill [85]. The Tag F-314 guidelines for pressure ulcers note that some residents may have risk factors for developing pressure ulcers, such as diabetic neuropathy, frailty, cognitive impairment, and undernutrition. The guidelines recognize that some of these factors are not modifiable, and some take time to modify. Some pressure ulcers are unavoidable based on the patient’s underlying diagnosis and overall

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medical state. Evidence from published data suggests that many of the known risk factors for the pressure ulcer development cannot be modified by current treatments [86]. This being said, a pressure ulcer cannot be considered unavoidable if proper preventive strategies have not been used.

Assessment of pressure ulcers Once a pressure ulcer occurs, it is critical properly to assess the extent of skin breakdown. The first step is to determine the stage of the pressure ulcer. The staging system currently used was created by Shea in 1975 [58] and adapted by the National Pressure Ulcer Advisory Panel (NPUAP) in 1989 [87]. It is currently being revised to define the stages more clearly and to include the definition of unstageable pressure ulcers and deep tissue injury. In this system, pressure ulcers are divided into four stages depending on the level of tissue breakdown. Stage 1 is defined as nonblanchable erythema of intact skin. This can be especially difficult to determine in individuals with dark skin pigmentation; the parameters were broadened to include skin temperature, pain, and tissue consistency. Stage 2 is defined as partial-thickness skin loss involving epidermis, dermis, or both. The ulcer is superficial and presents clinically as an abrasion, blister, or shallow crater. Stage 3 is full-thickness skin loss involving damage to, or necrosis of, subcutaneous tissue that may extend down to, but not through, underlying fascia. The ulcer presents clinically as a deep crater with or without undermining of adjacent tissue. Stage 4 is full-thickness skin loss with extensive destruction; tissue necrosis; or damage to muscle, bone, or supporting structures (eg, tendon, joint, capsule). Undermining and sinus tracts also may be associated with stage 4 pressure ulcers. An unstageable pressure ulcer is described as tissue destruction in which the actual depth of tissue loss is obscured by slough (yellow, tan, gray, green, or brown) or eschar (tan, brown, or black) in the wound bed. It may also present as a blood-filled blister. The NPUAP guidelines further state that until enough slough or eschar is removed to expose the base of the wound, the true depth and stage cannot be determined. Stable (dry, adherent, intact without erythema or fluctuance) eschar on the heels serves as the body’s natural (biologic) cover and should not be removed. In the longterm care setting, there is an issue with documentation of wounds with eschar on the minimum data set. As per Tag F-314 guidelines, if eschar and necrotic tissue are covering and preventing adequate staging of a pressure ulcer, the Resident Assessment Instrument user’s manual version 2 instructs the assessor to code the pressure ulcer as a stage IV [71]. This is clearly an issue, because there is no way to determine the level of tissue injury if eschar is present. Until the system of documentation is changed, this flaw remains. Deep tissue injury is a term proposed by NPAUP to describe a unique form of pressure ulcers. These ulcers have been described by clinicians for many

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years with such terms as ‘‘purple pressure ulcers,’’ ‘‘ulcers that are likely to deteriorate,’’ and ‘‘bruises on bony prominences’’ [88]. NPAUP’s proposed definition is ‘‘A pressure-related injury to subcutaneous tissues under intact skin. Initially, these lesions have the appearance of a deep bruise. These lesions may herald the subsequent development of a Stage III-IV pressure ulcer even with optimal treatment’’ [89,90]. The definition of this type of injury is important because although it presents as a discoloration or bruising of the skin, it can rapidly progress, and may mistakenly be attributed to poor care. It is important to note that once a pressure ulcer has been staged, it cannot be back-staged. For example, once a pressure ulcer has been determined to be a stage 4, it remains a stage 4 to closure. A pressure ulcer can progress forward in level of tissue involved, such as a stage 2 ulcer deteriorating to a stage 4. Reverse staging suggests that ulcers heal from the bottom up, anatomically regaining the missing tissues. Such healing does not occur biologically: full-thickness wounds heal by scar and contraction and never regain more than 70% of their original tensile strength. Scar tissue is dynamic and relatively ischemic, making it more prone to future ulceration [90]. Unfortunately, in the long-term care setting, the minimum data set currently requires the staff to identify the stages of pressure ulcers by describing depth in reverse order from deepest to lesser stages to describe the healing or improvement of a pressure ulcer. This is by definition reverse staging. Until this system is revised, the staff completing the minimum data set is required to follow current documentation procedures. Once staging of the pressure ulcer has been determined, it is important completely and consistently to document the wound. By following an organized system of evaluation, the clinician can systematically evaluate the wound. This gives the clinician an indication as to whether the ulcer occurred in relation to an acute event, such as recent hip surgery, or if it has been present for a prolonged period of time, indicating an underlying process affecting wound healing. There has been no consensus on exact method of documentation, but the following components are frequently found in most methods of documentation and provide a thorough assessment of the patient’s wound (Fig. 1). 1. The first step is to determine the type of ulcer, how long it has been present, and in what setting it occurred. 2. The patient should always be assessed on the same side, and the anatomic location of the wound should be noted. 3. Although there are various ways to measure a wound, measurement of area and volume is fast and reliable, requires no special equipment, and is inexpensive [91]. The ulcer is documented as length  width  depth in centimeters. Depth is determined at the area of the wound bed that is deepest, without a tract. 4. The next step is to describe the wound bed. A commonly used method is the red-yellow-black system. Each component is described in percentages,

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Algorithm for Documentation of a Wound* Determination of length of time wound has been present, type of wound and in what setting the wound occurred

Where is the wound located (anatomic description)?

Measurement in centimeters (length x width x depth)

How much granulation tissue vs. yellow slough vs. necrotic tissue/eschar? (describe in )

Is there an odor to the wound bed? (Make sure the wound has been cleansed thoroughly before assessing odor)

Describe the periwound tissues (viable, macerated, inflamed, hyperkeratotic)

Is there undermining or tunneling present? (if undermining is present, document using the clock method)**

* although clinical assessment should be done by clinical staff on every dressing change, documentation of the wound with these components should be done on a weekly basis. ** example of undermining documentation: 3.5cm of undermining at 3 o'clock.

Fig. 1. Algorithm for documentation of a wound.

with red indicating amount of granulation tissue, yellow indicating the amount of slough present, and black being necrotic tissue or eschar. This system is easy to teach, but has been criticized because it is too simplistic, and it is difficult to qualify and quantify [91,92]. The type and level of exudate is important. Common descriptors of drainage are serous, serosanguinous, sanguinous, or purulent. 5. The presence or absence of odor in the wound should be noted. This can only be determined once the wound is thoroughly cleaned, because many of the dressings used can cause an odor in the wound bed. 6. The periwound tissues should be assessed and described. Some terms used to describe the periwound tissues are viable, macerated, inflamed, or hyperkeratotic. 7. The presence or absence of undermining should be noted. Undermining is a separation of the tissues between the surface and the subcutaneous tissues. It must be assessed by using a cotton-tipped applicator and going around the wound edges like the face of a clock. The patient’s head is 12 o’clock and the patient’s feet are at 6 o’clock. A systematic evaluation around the wound determines all levels of undermining. It is

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imperative that undermining be assessed and properly treated with gentle packing, or abscess formation can occur should the skin surface close without complete filling in of dead space. Excessive packing can cause damage and necrosis to underlying tissues. Re-evaluation of the wound should be done by the staff or caregiver on every dressing change, but formal documentation of the wound should be done at least weekly [93]. Clinicians can assess healing by using the NPUAP pressure ulcer scale for healing (PUSH tool) [94]. The PUSH tool consists of three parameters: (1) length  width, (2) exudate amount, and (3) tissue type. A total score is assigned based on each of the parameters, and helps to track the healing of the wound over time. The final parameter of pressure ulcer assessment is pain. Pain may be one of the factors leading to the development of pressure ulcers, such as a patient with back pain who refuses to get out of bed, or may occur as a result of the pressure ulcer, especially as the level of tissue damage deepens. Management of chronic wound pain should include a thorough evaluation of pain origin. Some factors that can contribute to pain in pressure ulcers include therapeutic maneuvers, such as debridements; bacterial colonization; arterial insufficiency; contractures; and peripheral neuropathy. In addition, the manifestation of pain has multiple factors, including cognitive, psychosocial, and nutritional factors, which further add to pain perception [95]. Patients with pressure ulcers should be assessed frequently for pain and adequately treated. Management of pressure ulcer The management of pressure ulcers can be divided into components: (1) pressure relief, (2) debridement, (3) management of bacterial load, and (4) selection of a topical dressing. Each component is critical if wound healing is to be achieved. Pressure relief There is no doubt that unrelieved pressure is the main component of pressure ulcer formation; a cornerstone of management is pressure relief. There are numerous techniques that can be used to decrease pressure to an affected site. Among these are increasing mobility through physical therapy and repositioning the patient while in bed or while up in a chair. The US Agency for Health Care Policy and Research recommends that any individual in bed who is assessed to be at risk for developing pressure ulcers should be repositioned at least every 2 hours if consistent with overall patient goals, and a written schedule for systematically turning and repositioning the individual should be used [96]. For those patients who are at high risk and are up in a chair, repositioning should occur every hour. The turning schedules that were developed in the past, however, do not take into account the modern

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pressure-reducing devices, both for beds and for chairs, which may allow turning intervals to be decreased without increasing risk of pressure ulcer development. Specialty mattresses are classified by Centers of Medicare and Medicaid Medicare into three groups, and patients must meet clinical criteria before reimbursement is provided: group 1 (static overlays and replacement mattresses); group 2 (low-air-loss beds, alternating pressure, and powered or nonpowered overlays or mattresses); and group 3 (air-fluidized beds). Most surfaces are pressure reducing, but do not decrease pressure below capillary closing pressure of 32 mm Hg; patients continue to require repositioning every 2 hours to allow for tissue recovery [97]. The only true pressure-relieving surface is the air-fluidized bed, which is used for patients after flap surgeries and for patients who have no turning surfaces. In terms of chairs or wheelchairs, there are specialty cushions that also reduce pressure and help decrease risk of pressure ulcers. Debridement The goal of debridement is to remove devitalized tissue from the wound bed. It can be achieved through several means including sharp, mechanical, enzymatic, autolytic, and biologic. Debridement is important in wound management for several reasons including decreasing bacterial load, increasing the effectiveness of topical antimicrobials, improving the bacterial activity of leukocytes, shortening the inflammatory phase of wound healing, decreasing the energy requirement of the body for wound healing, eliminating the physical barrier to wound healing, and decreasing wound odor [98]. Sharp debridement is achieved through use of a scalpel or scissors. It is a selective form of debridement, because the clinician is only removing the devitalized tissue. It is the fastest form of debridement, but should only be performed by individuals who are trained and comfortable with proper debridement techniques. Mechanical debridement is a nonselective form of debridement, which includes wet-to-dry, whirlpool therapy, pulsatile lavage, or wound irrigation [99]. Enzymatic debridement is achieved through use of proteolytics, fibrinolytics, and collagenases. It is a slower method of debridement but is appropriate for patients who cannot tolerate sharp debridement, in settings where sharp debridement is not available, or in patients in whom sharp debridement is not an option [100]. Autolytic debridement uses the body’s own endogenous enzymes to liquefy necrotic tissue. It is achieved through the use of an occlusive dressing, which traps the wound fluid under the dressing [100–102]. It is the most conservative method of wound debridement, and is the least painful, but is contraindicated in infected wounds. The final method of debridement is biologic. This is achieved through the use of sterile maggots. Maggots only consume necrotic tissue, and they secrete a variety of antibacterial substances and granulation tissue growth-enhancing substances, which are beneficial for wound healing [103,104]. The main

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limitation of biologic debridement is access to the sterile larvae, and the resistance of patients to this form of therapy. Management of bacterial load Every wound has bacteria, but not all wounds are infected. It becomes necessary to manage the bacterial load when the bacteria reach critical colonization, which is defined as 1  105 colonies [105]. At this point, the bacteria affect the body’s ability to heal. Clinically, there may be increased drainage, odor, surrounding erythema, pain, warmth, or simply a wound that has failed to progress despite adequate removal of necrotic tissue and maintenance of a moist wound environment. The time frame is usually a lack of progression after 14 days of therapy. There is no need to treat with systemic antibiotic therapy unless there are signs of cellulitis. Topical therapies include silver dressings, cadexomer iodine, hydrogen peroxide, povidone-iodine, diluted sodium hypochlorite solution, and chlorpactin. None of these treatments should be used longer than 14 days, because they can be toxic to healthy tissues. Topical dressings The choice of topical dressing is geared toward managing fluid balance in the wound bed and maintaining a moist wound environment. There are five categories of dressings from which to choose, each of which has benefits and drawbacks: (1) films, (2) hydrogels, (3) hydrocolloids, (4) alginates, and (5) foams. Films are occlusive dressings, which can be used for autolytic debridement. Because they do not allow fluid to evaporate, they trap fluid underneath the dressing and can lead to maceration of underlying skin. Films can be applied to the sacral area to reduce shear effect, but should not be used for skin tears because their high adherence can tear the skin when the dressing is removed. Hydrogels are hydrophilic polymers that provide moisture to the wound bed and are ideal for wounds that have a good granulation bed and require only a moist environment to promote healing. They come in gel form, sheets, or saturated gauze. They can cause maceration of surrounding tissues if placed outside of the wound bed, and most require a secondary dressing. Hydrocolloid dressings are adherent dressings that have a low moisture vapor permeability rate and do not allow fluids to evaporate. This dressing promotes autolytic debridement. Because it is occlusive, it should not be used in an infected wound. Hydrocolloid dressings can also lead to hypergranulation. Alginate dressings are made from seaweed and are absorbent. It should be used in wounds that are moderately exudative, because if it dries in the wound it can cause damage to the tissue. The last type of dressing is foam. They are made from polyurethane foam and are very absorbent. The adhesive used on this type of dressing is not as tacky as films; they are less likely to damage fragile skin, such as in skin tears on elderly patients. Foams may or may not require a secondary dressing.

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Summary Pressure ulcers remain a complex and costly problem to the health care system. As the population ages, a greater number of individuals will be at high risk for developing pressure ulcers. An understanding of the physiologic changes that occur with aging skin is important in preventing and treating chronic wounds. Risk factor assessment and modification, when possible, can help to reduce the development of pressure ulcerations. Although the goal continues to be prevention, once a pressure ulcer does occur, a systematic and comprehensive approach to assessment and treatment is necessary to reduce healing times. Appendix Glossary of wound care terms Chronic wound: a wound, induced by various causes, whose progression through the phases of wound healing is prolonged or arrested due to underlying conditions Debridement: the removal of necrotic tissue, foreign material, and/or debris from a wound bed Epithelialization: regeneration of the epidermis across a wound surface Eschar: thick, leathery necrotic tissue; devitalized tissue Exudate: mixture of fluid, protein and cells Friction: Surface damage caused by skin rubbing against another surface. Granulation: formation or growth of small blood vessels and connective tissue in a full-thickness wound Induration: Abnormal firmness of tissue with a definite margin Maceration: softening of tissue by soaking in fluids; the skin can be described as white, friable, overhydrated and sometimes wrinkled Moist wound healing: the process of managing the wound exudate to create an environment that is conducive to healing Non-blanching erythema: lack of tissue color change from red to blanching when light pressure is applied Shear: Force parallel to the body surface; trauma is caused by tissue layers sliding against each other and results in disruption or angulation of blood vessels Undermining: tissue destruction to underlying intact skin along wound margins References [1] Bergstrom N, Allman RM, Alvarez OM, et al. Treatment of pressure ulcers. Clinical Practice Guideline No. 15. AHCPR publication 95–0652. Rockville (MD): Agency for Health Care Policy and Research, Public Health Service; 1994.

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[2] Miller H, Delozier J. Cost implications of the pressure ulcer treatment guideline (Contract No. 282–91–0070). Columbia (MD): Center for Health Policy Studies; 1994. [3] Xakellis GC, Fratz R. The cost of healing pressure ulcers across multiple health care settings. Adv Wound Care 1996;9:18–22. [4] Kinsella K, Velkoff VA. US Census Bureau, Series P95/01–1: An aging world: 2001. Washington: US Government Printing Office; 2001. [5] Arias E. United States life tables. Natl Vital Stat Rep 2004;53(6):1–38. [6] US Census Bureau. Population projections program, population division. Washington: US Census Bureau; 2000. [7] Thomas DR. Age-related changes in wound healing. Drugs Aging 2001;18:607–20. [8] Barbenel JC, Jordan MM, Nicol SM, et al. Incidence of pressure sore in the Greater Glascow Health Board area. Lancet 1977;2:548–50. [9] Thomas DR. Issues and dilemmas in the prevention and treatment of pressure ulcers. J Gerontol 2001;56A:M328–40. [10] Werner S, Grose R. Regulation of wound healing by growth factors and cytokines. Physiol Rev 2003;83:835–70. [11] Clark RAF, Lanigan JM, DellaPelle P, et al. Fibronectin and fibrin provide a provisional matrix for epidermal cell migration during wound reepithelialization. J Invest Dermatol 1982;79:264–9. [12] Greiling D, Clark RAF. Fibronectin provides a conduit for fibroblast transmigration from collagenous stroma into fibrin clot provisional matrix. J Cell Sci 1997;110:861–70. [13] Postlethwaite AE, Keski-Oja J, Balian G, et al. Induction of fibroblast chemotaxis by fibronectin. J Exp Med 1981;153:494–9. [14] Desmouliere A, Geinoz A, Gabbiani F, et al. Transforming growth factor beta-1 induces alpha-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J Cell Biol 1993;122:103–11. [15] Levenson SM, Geever EF, Crowley LV, et al. The healing of rat skin wounds. Ann Surg 1965;161:293–308. [16] Madden JW, Peacock EE Jr. Studies on the biology of collagen in wound healing rate of collagen synthesis and deposition in cutaneous wounds of the rat. Surgery 1968;64: 288–94. [17] Braden B, Berstrom N. A conceptual schema for the study of the etiology of pressure sores. Rehab Nursing 2000;25:105–10. [18] Livesley NJ, Chow AW. Infected pressure ulcers in elderly individuals. Clin Infect Dis 2002; 35:1390–6. [19] Cannon BC, Cannon JP. Management of pressure ulcers. Am J Health Syst Pharm 2004;61: 1895–907. [20] Hoshowsky V, Schramm C. Intra operative pressure sore prevention: an analysis of bedding materials. Res Nurs Health 1994;17:333–9. [21] Kemp MG, Keithley JK, Smith DW, et al. Factors that contribute to pressure ulcers in surgical patients. Res Nurs Health 1990;13:293–301. [22] Lindgren M, Unosson M, Kranz A-M, et al. Pressure ulcer risk factors in patients undergoing surgery. J Adv Nurs 2005;50:605–12. [23] Baumgarten M, Margolis D, Berlin JA, et al. Risk factors for pressure ulcers among hip fracture patients. Wound Repair Regen 2003;11:96–103. [24] Unosson M, Ek A-C, Bjurulf P, et al. Influence of macro-nutrient status on recovery after hip fracture. J Nutr Environ Med 1995;5:23–34. [25] Bansal C, Scott R, Stewart D, et al. Decubitus ulcers: a review of the literature. Int J Dermatol 2005;44:805–10. [26] Correa GI, Fuentes M, Gonzalez X, et al. Predictive factors for pressure ulcers in the ambulatory stage of spinal cord injury patients. Spinal Cord 2006; Epub ahead of print:1–6. [27] Krause JS. Skin sores after spinal cord injury: relationship to life adjustment. Spinal Cord 1998;36:51–6.

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[28] Vidal J, Sarrias M. An analysis of the diverse factors concerned with the development of pressure sores in spinalcord injured patients. Paraplegia 1991;29:261–7. [29] Lehman CA. Risk factors for pressure ulcers in the spinal cord injured in the community. SCI Nurs 1995;12:110–4. [30] Peterson NC, Bittman S. The epidemiology of pressure sores. Scand J Plast Reconstr Surg Hand Surg 1971;5:62–6. [31] Morrison S. Monitoring decubitus ulcers: a monthly survey method. Quart Rev Bull 1984; 10:112–7. [32] Guralnik JM, Harris TB, White LR, et al. Occurrence and predictors of pressure ulcers in the National Health and Nutrition Examination Survey follow-up. J Am Geriatr Soc 1988; 36:807–12. [33] Brandeis GH, Morris JN, Nash DJ, et al. The epidemiology and natural history of pressure ulcers in elderly nursing home residents. JAMA 1990;264:2905–9. [34] Greenhalgh DG. Wound healing and diabetes mellitus. Clin Plast Surg 2003;30:37–45. [35] Manley MT. Incidence, contributory factors, and costs of pressure sores. S Afr Med J 1978; 53(6):217–22. [36] Young ME. Malnutrition and wound healing. Heart Lung 1988;17:60–7. [37] Visvanathan R. Under-nutrition in older people: a serious and growing global problem!. J Postgrad Med 2003;49:352–60. [38] Morley JE, Thomas DR. Anorexia and aging: pathophysiology. Nutrition 1999;15: 499–503. [39] Thomas DR, Zedrowski CD, Wilson MM, et al. Malnutrition in subacute care. Am J Clin Nutr 2002;75:308–13. [40] Compan B, di Castri A, Plaze JM, et al. Epidemiological study of malnutrition in elderly patients in acute, sub-acute and long-term care using the MNA. J Nutr Health Aging 1999;3:146–51. [41] Thomas DR. The role of nutrition in prevention and healing of pressure ulcers. Clin Geriatr Med 1997;13:497–510. [42] Thomas DR, Goode PS, Tarquine PH, et al. Hospital-acquired pressure ulcers and risk of death. J Am Geriatr Soc 1996;44:1435–40. [43] Dempsey DT, Mullen JL, Buzby GP. The link between nutritional status and clinical outcome: can nutritional intervention modify it? Am J Clin Nutr 1988;47(2 Suppl):352–6. [44] Detsky AS, Baker JP, O’Rourke K, et al. Predicting nutrition-associated complications for patients undergoing gastrointestinal surgery. JPEN 1987;11:440–6. [45] Chernoff R. Dietary management for older subjects with obesity. Clin Geriatr Med 2005;21: 725–33. [46] Kagansky N, Berner Y, Koren-Morag N, et al. Poor nutritional habits are predictors of poor outcome in very old hospitalized patients. Am J Clin Nutr 2005;82:784–91. [47] Pearson JM, Schlettwein-Gsell D, Brzozowska A, et al. Life style characteristics associated with nutritional risk in elderly subjects aged 80–85 years. J Nutr Health Aging 2001;5: 278–83. [48] Wilson MM, Vaswani S, Liu D, et al. Prevalence and causes of undernutrition in medical outpatients. Am J Med 1998;104:56–63. [49] Morley JE, Kraenzle D. Causes of weight loss in a community nursing home. J Am Geriatr Soc 1994;42:583–5. [50] Mathey MF, Zandstra EH, de Graaf C, et al. Social and physiologic factors affecting food intake in elderly subjects: an experimental comparative study. Food Qual Pref 2000;11: 397–403. [51] Wauters AD. Nutrition and hydration. In: Sheffield PA, Smith AP, Fife CE, editors. Wound care practice. Flagstaff (AZ): Best Publishing; 2004. p. 471–502. [52] Kaminer MS, Gilchrest BA. Aging of the skin. In: Hazzard WR, Bierman EL, Blass JP, et al, editors. Principles of geriatric medicine and gerontology. 3rd edition. New York: McGraw-Hill Publishing; 1994. p. 411–42.

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[53] Fisher GJ, Wang ZQ, Datta SC, et al. Pathophysiology of premature aging induced by ultraviolet light. N Engl J Med 1997;337:1419–28. [54] Bernstein EF, Chen YQ, Kopp JB, et al. Long-term sun exposure alters the collagen of the papillary dermis: comparison of sun-protected and photoaged skin by Northern analysis, immunohistochemical staining, and confocal laser scanning microscopy. J Am Acad Dermatol 1996;34:209–18. [55] Lavker RM. Cutaneous aging: chronologic versus photoaging. In: Gilchrest BA, editor. Photoaging. Cambridge (MA): Blackwell Science; 1995. p. 123–35. [56] Silverstein P. Smoking and wound healing. Am J Med 1992;931A:22S–4S. [57] Smith J, Fenske N. Cutaneous manifestations and consequences of smoking. J Am Acad Dermatol 1996;45:717–32. [58] Shea J. Pressure sores: classification and management. Clin Orthop 1975;12:89–100. [59] Ennis JE, Sarmiento A. The pathophysiology and management of pressure sores. Orthop Rev 1973;11:25–34. [60] Landis EM. Micro-injection studies of capillary blood pressure in human skin. Heart 1930; 15:209. [61] Kosiak M. Etiology of decubitus ulcers. Arch Phys Med Rehabil 1961;42:19–29. [62] Pieper B. Mechanical forces: pressure, shear and friction. In: Bryant R, editor. Acute and chronic wounds: nursing management. 2nd edition. St. Louis: Mosby Publishing; 2000. p. 221–64. [63] Myers BA. Pressure ulcers. In: Wound management principles and practice. Upper Saddle River (NJ): Prentice Hall; 2004. p. 260–96. [64] Reichel SM. Shearing force as a factor in decubitus ulcers in paraplegics. JAMA 1958;166: 762–3. [65] Reuler JB, Cooney TG. The pressure sore: pathophysiology and principles of management. Ann Intern Med 1981;94:661–6. [66] Longe RL. Current concepts in clinical therapeutics: pressure sores. Clin Pharm 1986;5: 669–81. [67] Maklebust J. Pressure ulcers: etiology and prevention. Nurs Clin North Am 1987;22: 359–77. [68] Chung JH, Yano K, Lee MK, et al. Differential effects of photoaging vs. Intrinsic aging on the vascularization of human skin. Arch Dermatol 2002;138:1437–42. [69] Lowthian P. Underpads in the prevention of decubiti. In: Kenedi RM, Cowden JM, Scales JT, editors. Bedsore biomechanics. Baltimore: University Park Press; 1976. p. 141–5. [70] Maklebust J, Sieggreen M. Pressure ulcers: guidelines for prevention and management. 3rd edition. Springhouse (PA): Springhouse; 2001. [71] CMS Manual System. Appendix PP, Tag F314. Guidance to surveyors for long term care facilities. Baltimore: Department of Health and Human Services 2004. [72] Lyder C. Perineal dermatitis in the elderly: a critical review of the literature. J Gerontol Nurs 1997;23:5–10. [73] Ayello EA, Braden B. How and why to do a pressure ulcer risk assessment. Adv Skin Wound Care 2002;15:125–32. [74] Bergstrom N, Braden BA. A prospective study of pressure sore risk among institutionalized elderly. J Am Geriatr Soc 1992;40(8):747–58. [75] Gosnell SJ. An assessment tool to identify pressure sores. Nurs Res 1973;22:55–9. [76] Norton D, McLaren R, Exton-Smith AN. An investigation of geriatric nursing problems in hospital. London: National Corporation for the Care of Old People [now Centre for Policy on Ageing]; 1962. [77] Bergstrom N, Braden BJ, Laguzza A, et al. The Braden Scale for predicting pressure sore risk. Nurs Res 1987;36:205–10. [78] Waterlow J. Pressure sores: a risk assessment card. Nurs Times 1985;81:49–55. [79] Pancorbo-Hidalgo PL, Garcia-Fernandez FP, Lopez-Medina IM, et al. Risk assessment scales for pressure ulcer prevention: a systematic review. J Adv Nurs 2006;54:94–110.

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[80] Ayello EA, Braden B. How and why to do pressure ulcer risk assessment. Adv Skin Wound Care 2002;15:125–32. [81] Defloor T, Grypdonck MFH. Pressure ulcers: validation of two risk assessment scales. J Clin Nurs 2005;14:373–82. [82] Bergstrom N, Braden BJ. Predictive validity of the Braden Scale among black and white subjects. Nurs Res 2002;51:398–403. [83] Jalali R, Rezaie M. Predicting pressure ulcer risk: comparing the predictive validity of 4 scales. Adv Skin Wound Care 2005;18:92–7. [84] Smith DM, Winsemius DK, Besdine RW. Pressure sores in the elderly: can this outcome be improved? J Gen Intern Med 1991;6:81–93. [85] Hagisawa S, Barbenel J. The limits of pressure sore prevention. J R Soc Med 1999;92:576–8. [86] Thomas D. Are all pressure ulcers avoidable? JAMA 2001;2:297–301. [87] National Pressure Ulcer Advisory Panel. Staging report. Available at: www.npuap.org/ positn6.html. Accessed April 1, 2006. [88] Ankrom M, Bennett R, Sprigle S, et al. Pressure-related deep tissue injury under intact skin and the current pressure ulcer staging systems. Adv Skin Wound Care 2005;18(1):35–42. [89] Deep tissue injury. Available at: www.npuap.org/DOCS/DTI.doc. Accessed April 1, 2006. [90] Zulkowski K, Langemo D, Posthauer ME, et al. Coming to consensus on deep tissue injury. Adv Skin Wound Care 2005;18:28–9. [91] Goldman RJ, Salcido R. More than one way to measure a wound: an overview of tools and techniques. Adv Skin Wound Care 2002;15:236–43. [92] Maklebust J. Pressure ulcer assessment. Clin Geriatr Med 1997;13:455–81. [93] Brem H, Lyder C. Protocol for the successful treatment of pressure ulcers. Am J Surg 2004; 188:9S–17S. [94] Thomas DR, Rodeheaver GT, Bartolucci AA, et al. Pressure ulcer scale for healing: derivation and validation of the PUSH tool. Adv Wound Care 1997;10:96–101. [95] Popescu A, Salcido R. Wound pain: a challenge for the patient and the wound care specialist. Adv Skin Wound Care 2004;17:14–22. [96] Agency for Health Care Policy and Research. Pressure ulcers in adults: prediction and prevention. Clinical Practice, Guideline Number 3. AHCPR Publication No. 92–0047. Rockville (MD): Agency for Health Care Policy and Research; 1992. [97] Clark M. Repositioning to prevent pressure sores-what is the evidence? Nurs Standard 1998;13:58–60. [98] Myers BA. Debridement. In: Wound management principles and practice. Upper Saddle River (NJ): Prentice Hall; 2004. p. 65–87. [99] Singhal K, Reis G, Kerstein MD. Options for nonsurgical debridement of necrotic wounds. Adv Skin Wound Care 2001;14:96–103. [100] Maklebust J. Using wound care products to promote a healing environment. Crit Care Nurs Clin North Am 1996;8:141–58. [101] Rodeheaver GK, Baharestani NM, Brabec ME, et al. Wound healing and wound management: focus on debridement. Adv Wound Care 1994;7:32–6. [102] Kernstein MD. Moist wound healing: the clinical perspective. Ostomy Wound Manage 1995;41:37S–43S. [103] Mumcuoglu KY. Clinical applications for maggots in wound care. Am J Clin Dermatol 2001;2:219–27. [104] Thomas S, Andrews AM, Hay NP, et al. The anti-microbial activity of maggot secretions: results of a preliminary study. J Tissue Viability 1999;9:127–32. [105] Stotts NA, Wipke-Tevis D. Co-factors in impaired healing. Ostomy Wound Manage 1996; 42:44–53.

Med Clin N Am 90 (2006) 945–966

Elders with Epilepsy Nancy S. Collins, MDa,*, Rita A. Shapiro, DOb,c, R. Eugene Ramsay, MDd,e a

Department of Neurology, Rosalind Franklin University of Medicine and Science/Chicago Medical School, 3333 Green Bay Road, North Chicago, IL 60064, USA b Geriatrics-Neurology Service, North Chicago Veterans Affairs Medical Center, 3001 Green Bay Road, North Chicago, IL 60064, USA c Departments of Neurology, Medicine, and Psychiatry and Behavioral Sciences, Rosalind Franklin University of Medicine and Science/Chicago Medical School, 3333 Green Bay Road, North Chicago, IL 60064, USA d Departments of Neurology and Psychiatry, University of Miami e International Center for Epilepsy, 1150 NW 14th Street, Suite 410, University of Miami, Miami, FL 33136-2115, USA

Introduction Why is it important to learn about epilepsy in elders? Because, as this article will highlight, compared with younger individuals, older patients who have epilepsy have different (1) incidence and prevalence, (2) causes, (3) clinical presentation, (4) prognosis, and (5) treatment responsiveness or sensitivity to antiepileptic medications. The cellular mechanisms of epilepsy still are not known and until recently, understanding and treating epilepsy in elders generated little interest. Over the last 10 to 15 years, an increasing number of investigators have been working to understand the mechanisms, manifestations, and management of epilepsy in elders and to generalize their findings so that epilepsy in elders can be more easily prevented, recognized, diagnosed, and treated. The paradox, as the reader will appreciate by the end of this article, is that the incidence of epilepsy in elders is more common than in younger adults but often goes unrecognized. It is attributable to more structural or symptomatic causes than in younger individuals and thus often is associated with brain lesions. The manifestations of epilepsy are often more subtle than in younger individuals and thus go unrecognized for prolonged periodsdsometimes * Corresponding author. Department of Neurology, Rosalind Franklin University of Medicine and Science/Chicago Medical School, 3333 Green Bay Road, North Chicago, IL 60064. E-mail address: [email protected] (N.S. Collins). 0025-7125/06/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.mcna.2006.06.002 medical.theclinics.com

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as long as weeks, and even months and years in many of these patients. Seizures in elders recur more often but tend to be more treatable than in younger individualsdthat is, epilepsy is more responsive and patients are more sensitive to antiepileptic drugs, but less tolerant to the side effects of these drugs. Definitions and classifications of seizures Definitions relating to seizures Some common terms and definitions relating to seizures and epilepsy are helpful to establish common foundations about the nature of seizures, types of seizures, classification schemes, and descriptive terminology. Seizure: a brief episode of prolonged uncontrolled abnormal brain electrical activity that produces behavioral consequences [1]. Another definition: discrete clinical events that reflect a temporary physiologic dysfunction of the brain, characterized by excessive and hypersynchronous discharge of cortical neurons. There are many different types of seizures, each with its own characteristic behavioral and electroencephalographic changes [2]. Seizures may be provoked, or situation related, as in temporary medical conditions, such as metabolic disturbances (eg, hypoglycemia or hyponatremia), medications (eg, clozapine, bupropion), medical withdrawal (eg, benzodiazepines), or substance abuse (eg, alcohol, cocaine). Provoked seizures almost always are generalized tonic-clonic seizures (Table 1). In these cases it is expected that the seizures will go away when the causative circumstance is corrected, and the term epilepsy is not used [1,3]. Symptomatic unprovoked seizure or acute symptomatic seizure: seizures precipitated by an acute insult to the central nervous system (CNS). These seizures usually have an identified or suspected cause [4]. The cause may be identified by imaging wherein the MRI is much more sensitive than CT in detecting possible focal abnormalities [3]. Status epilepticus (SE): seizures recurring frequently enough to produce a fixed and enduring epileptic condition. Epilepsy: a condition characterized by two or more unprovoked seizures or two or more seizures from a known or suspected cause [1]. Consciousness: refers to the degree of awareness or responsiveness of the patient to externally applied stimuli [2]. Responsiveness: refers to the ability of the patient to carry out simple commands of willed movement [2]. Awareness: refers to the patient’s contact with events during the period in question and its recall [2]. Ictal: refers to signs and symptoms present during seizure [2]. Postictal: refers to events after the seizure. For example, after complex partial seizures there are often several minutes of postictal confusion. Another type of postictal event seen after some complex partial seizures is

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Todd paralysis, which is a brief period (defined as !48 hours) of transient paralysis following the seizure, generally occurring on one side of the body. This event may also affect speech and vision depending on the seizure focus. (See later discussion and Table 1 for classification and description of seizure types). Automatisms: defined as more or less coordinated adapted involuntary motor activities occurring during the state of clouding of consciousness either in the course of or after an epileptic seizure. The automatism may be simply a continuation of an activity that was going on when the seizure occurred, or, conversely, a new activity developed in association with the ictal impairment of consciousness [2]. Aura: is that portion of the seizure that occurs before consciousness is lost and for which memory is retained afterwards. Classification of seizures The current classification of seizures was developed in 1981 from the International League Against Epilepsy and termed the International Classification of Seizures [2]. Final approval for the proposed revision is in process. The scheme is based on where in the brain the seizure originates and how it spreads. The classification recognizes two broad categories of seizures: partial and generalized (see Table 1). In addition to the descriptions detailed in Table 1, clinical clues can help in discriminating the two types of partial seizures in which the patient may stare off and have alteration in consciousness (that is, discriminating between partial complex seizures and absence seizures, both of which have a blank stare and altered consciousness.) Clinically, complex partial seizures sometimes are preceded by an aura, may have automatisms, usually are followed by a period of postictal confusion, and sometimes are followed by a focal Todd paralysis. Absence seizures begin in childhood, have no aura and no postictal confusion, and are followed by immediate resumption of normal alertness and activities. This pattern is an important clinical clue, particularly in younger patients who have seizures emanating from the temporal lobes. Definitions relating to elderly The term elderly typically has been linked to retirement age, which is usually conceived as being age 65. Many older adults continue to be healthy, however, with preserved independent functional status in their later years. Conversely, much earlier in life medical disorders can develop that increase the incidence of cerebrovascular disease and epilepsy (hypertension, dyslipidemia, and diabetes mellitus) and thus younger individuals who have chronic medical problems may present with poor functional status, be considered frail, and reside in nursing homes. A classification has suggested

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Table 1 Classification and description of seizures Type of seizure

Description

Subtypes

I. Partial

Those that arise in A. Simple part of one cerebral partial hemisphere and are seizures accompanied by focal electroencephalographic abnormalities

Description

Subtypes

Description

Those in which consciousness is preserved

Depending on where in the cerebral cortex the seizure originates, the clinical manifestations will be congruent.

1. With motor symptoms

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1. There would be jerking of the area of the body referable to that cortical region 2. With 2. If originates in the somatosensory somatosensory cortex or special sensory areas, there or special would be sensory symptoms sensory referable to that cortical region symptoms (such as numbness over that area of the body or unusual smells, visual distortions, etc, depending on cortical localization) 3. If originates in the areas of cortex 3. With subserving autonomic sensations, autonomic there would be congruent symptoms symptoms (such as rising epigastric sensation, piloerection, etc, depending on localization) 4. With psychic 4. If originates in the areas of cortex symptoms subserving psychic symptoms, there would be congruent symptoms (such as ‘‘de´ja` vu’’ etc, depending on localization)

B. Complex partial seizures

Those seizures in which the first clinical and electroencephalographic manifestations indicate simultaneous involvement of both cerebral hemispheres from the beginning

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II. Generalized

C. Partial seizures that evolve to become secondarily generalized A. Absence seizures

The simple partial seizure preceding 1. Complex the complex partial seizure is often partial the ‘‘aura’’ or warning the patient seizures experiences before progressing to beginning a complex partial seizure as simple Depending on where in the cerebral partial cortex the seizure originates, the seizures and clinical manifestations will be progressing to congruent impairment of consciousness 2. Complex Depending on where in the cerebral partial cortex the seizure originates, the seizures with clinical manifestations will be impairment of congruent consciousness at the onset Those that begin as a partial seizure and then spread to involve both cerebral hemispheres Those in which consciousness is impaired

Formerly termed ‘‘petit mal’’ seizures. These seizures are characterized by sudden onset, interruption of ongoing activities, blank stare, lasting for a few seconds, with immediate return to normal activities. There is no postictal confusion. The EEG demonstrates, during the seizure: 3 cycles per second generalized spike and wave pattern

(continued on next page) 949

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Table 1 (continued) Type of seizure

Description

Subtypes

Description

B. Atypical absence seizures

These are more difficult to clinically identify; patients are usually mentally retarded. The onset and offset of the clinical manifestations of the seizure are more difficult to determine. The EEG during the seizure shows 1.5 to 2.5 cycles per second generalized spike and wave (‘‘slow spike and wave’’) pattern These have sudden, brief, shock-like contractions that may be generalized or confined to face or trunk or extremity These have repetitive clonic jerking of affected areas of body These have muscular contraction fixing the trunk, neck, and limbs in some strained position Formerly termed ‘‘grand mal’’ characterized by tonic, then clonic movements and then postictal confusion 1. During the tonic phase, respiratory muscles involved result in stridor, a cry or moan; trunk and extremity muscles involved result in fall to ground, patient lies rigid, cyanosis; sphincter muscles involved result in urinary incontinence 2. During the clonic phase, respiratory muscles involved result in small gusts of grunting respirations, trunk and extremity muscles involved result in clonic movements 3. During the postictal phase, the clinical manifestations are deep respirations and slow return consciousness These are characterized by sudden diminution in tone. The areas of the body involved determine the severity of the clinical manifestations. If fragmentary: head drop or dropping of arms; If axial: patient falls to the ground (‘‘drop attacks’’)

et al

G. Atonic seizures

Description

COLLINS

C. Myoclonic seizures D. Clonic seizures E. Tonic seizures F. Tonic clonic seizures

Subtypes

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subdivisions based on progressive 10-year epochs: the ‘‘young-old’’ (65–74 years), ‘‘middle-old’’ (75–84 years), and ‘‘oldest–old’’ (85 years and older), and subclassification of these groups as ‘‘healthy,’’ ‘‘with multiple medical problems,’’ or ‘‘frail’’ [5]. These proposed subdivisions may help with research and prognosticating outcomes and therapeutic successes and take into account factors related to chronologic age, disease burden, and physiologic decline (frailty) [5].

Incidence/prevalence Elders compose the fastest-growing segment of the population in the United States; estimates suggest that by the first part of the twenty-first century 20% of the population will be older than 65 years [6]. By 2025, in many developed countries, the proportion of the population older than 60 years will be more than 30% [5]. Several epidemiologic studies over the last l0 to 15 years have revealed that elders experience the highest incidence and prevalence of seizure disorders in developed countries [5]. Hauser and colleagues [4] found that by the age of 70 the incidence of epilepsy is almost double that of children, and over the age of 80 it is more than three times the rate in childhood. According to Hauser [7], incidence at age 50 years is w28/100,000/year, incidence at 60 years is w40/100,000/year, and incidence at 75 years is 139/100,000/year [7]. Likewise, the prevalence of epilepsy is 1% for individuals over the age of 60 and increases with advancing age [8]. The greatest prevalence is in elders over age 85, the most rapidly increasing population group in the United States [7]. In some groups of high-risk individuals, such as nursing home residents, the prevalence of epilepsy exceeds 5% [9]. To underscore the frequency of seizures in elders, studies show the recurrence rate is reported to be anywhere from 40% to greater than 90% after first seizure if the seizures go untreated [3,4,10,11]. As this article emphasizes, however, all of these figures are likely conservative given that underdiagnosis and misdiagnosis of seizures in elders are common [10,11].

Cause The most common identifiable cause of epilepsy in elders is cerebrovascular, accounting for up to 40% to 50% of cases [3,11]. A substantial number of epilepsy cases can be attributable to other causes, including Alzheimer disease, brain tumors, and head trauma [11,12]. Unfortunately, even with the advent of sophisticated imaging techniques, as many as 25% to 40% of new epilepsy cases in the elderly have no obvious underlying cause [4,12]. Ramsey and colleagues [11] documented in their Veterans Administration Cooperative Study (VACS) #428 that 24.6% of the patients in that study were classified as having seizures of unknown cause, but that

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most of those same patients displayed risk factors for cerebrovascular disease, such as hypertension (67%), cerebral infarction (34.1%), arteriosclerosis (14.9%), head trauma (6.9%), and hemorrhage (1.7%). In most cases, post-stoke epilepsy occurs within 3 months to 1 year after the vascular event, although epilepsy attributed to stroke has been report to develop 3 to 14 years later [13].

Clinical presentation The most common seizure type presenting in younger patients is the generalized tonic-clonic seizure. Ramsay and coworkers [14] found that approximately two thirds of patients less than 40 years of age present with tonic-clonic seizures. This percentage declines to 54% for ages 40 to 64 years and 40% in patients aged 65 and older [14]. The most common seizure types in elders are partial seizures, either simple (consciousness is preserved) or complex partial (consciousness is impaired), which is to be expected because so many of these seizures in adults reflect focal brain pathology. Of the two types of partial seizures, complex partial seizures are even more common in older adults than simple partial seizures [3,11,15]. Partial seizures can and do secondarily generalize in 25.9% of these patients [11]. Indeed, in an elderly patient presenting with a generalized tonic-clonic seizure, the likely scenario is one in which, even though the secondarily generalized convulsion was what was witnessed, the patient likely had an unrecognized partial-onset seizure first [3]. In the VACS #428, Ramsay and colleagues [16] found 38.3% were complex partial seizures, 27.1% were generalized tonic-clonic seizures, 14.3% were simple partial seizures, and 12.8% were generalized tonic-clonic and partial seizures. Although generalized tonic-clonic seizures are easily recognized, the diagnosis becomes challenging because the symptomatology of simple and complex partial seizures can be subtle. In particular, the classic features of complex partial seizures observed in younger adults usually are not present in older patients. Young adults who have complex partial seizures typically experience an aura first followed by a disturbance of consciousness, or stare and behavioral arrest followed by limb and orofacial automatisms. The postictal period of confusion usually is brief, lasting 5 to 15 minutes. These manifestations are typical of seizures emanating from mesiotemporal brain areas (Table 2) [11]. In contrast, an older patient’s seizure focus is likely to be extratemporal, most often in the frontal lobe. Older patients have a lower incidence of psychic symptoms, while more commonly presenting with simple motor or sensory symptoms. Auras also are much less common and, when present, may manifest in a nonspecific way, such as dizziness. In general, elderly patients do not exhibit automatisms; consequently, a disturbance of consciousness

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Table 2 Clinical features of epilepsy

Incidence Location of focus Incidence of generalized seizures Symptomatic because of structural lesion, such as stroke Automatisms Postictal confusion duration Likelihood of recurrence Response to epileptic drugs

Elders

Teens and young adults

High Frontal, parietal Low

Low Temporal High

More

Less

Less Very long

More Brief

More Good

Less Variable

with a blank stare or brief gaps in conversation or periods of confusion may be the only manifestation of a complex partial seizure. One of the most striking differences between older and younger adults is the length of the postictal confusional state, which may last for hours, days, or even l to 2 weeks in older patients compared with minutes in younger adults (see Table 2). The absence of specific symptoms may undermine an epilepsy diagnosis. Data from the VACS #428 revealed that epilepsy was a diagnostic consideration after initial evaluation by a primary care physician or internist for only 73.3% of patients who were ultimately diagnosed with epilepsy [11]. Initial diagnoses included altered mental status (41.8%), confusion (37.5%), blackout spells (29.3%), memory disturbance (17.2%), syncope (16.8%), dizziness (10.3%), and dementia (6.9%). The mean time to diagnosis was l.7 years [11]. The reasons for diagnostic difficulty in elderly patients include:
The infrequent occurrence of generalized tonic-clonic seizures (only 21%–25.9%) [4,11].
Most are partial complex seizures and in this population are often subtle and prolonged. Their presentation resembles other causes: delirium; dementia; transient ischemic attack (TIA); hypoperfusion syndromes, such as congestive heart failure, cardiac arrhythmias, orthostatic hypotension, or vasodepressor episodes; metabolic dysfunction, such as hypoglycemia, hyponatremia, or sepsis; and adverse drug effects.
Often (at least 30% of the time) patients are unaware of their seizures [13].
Electroencephalograms (EEGs) often are nonspecific, showing focal or generalized slowing in this population, or are even normal (31%) [17].
Interictal epileptiform activity is present in only 26% to 38% of initial EEGs of patients ultimately diagnosed with seizures [11,18,19].

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Few seizures after stroke (only 10% to 20%) and few cerebral tumors (10% to 20%) have interictal epileptiform activity on EEG [10].
Frequent presence of comorbid disorders, such as hypertension, diabetes, TIA, cardiac disease, and medication toxicity, which, because of their co-occurrence, can confound the diagnosis [11,17] and can delay the diagnosis of seizures in these patients for almost 2 years [11]. In fact, on average, elderly patients who have seizure disorders take five to seven medications other than an antiepileptic drug [17,18,20,21]. Status epilepticus Of critical importance is the clinical presentation of types of SE that occur in elders. Generalized convulsive (tonic-clonic) SE, or grand mal seizures, are easily recognized and should be treated as a medical emergency. As the seizure progresses, however, the clinical manifestations become less obvious, and overt, convulsive status may evolve into subtle status. The mortality and morbidity rates are significantly higher in older than in younger adults, particularly in those 80 years of age and older. Most older patients have no prior history of seizures or SE before onset of SE [12]. The most common type of SE in elders is partial with secondary generalization followed in incidence by partial and then by generalized tonic-clonic. Generalized convulsive (tonic-clonic) SE has a high mortality, increasing to 50% or higher in those over age 80 [22]. Nonconvulsive SE is not recognized easily. It is also termed ‘‘ictal stupor’’ or ‘‘epileptic twilight state.’’ Patients present with confusion, personality change, slow mental ideation, mild to moderate clouding of consciousness, or even psychosis. These patients often are diagnosed erroneously with newonset dementia or change in mental status attributed to other medical or psychiatric conditions, and can only be diagnosed by concurrent EEG. These patients may be in nonconvulsive status for days and weeks at a time. Nonconvulsive SE can be subcategorized into:
Absence status, in which the EEG shows generalized rhythmic spike and wave abnormalities.
Complex partial status, in which the EEG shows focal rhythmic spike and wave abnormalities. The prognosis depends on the underlying cause of the seizure and generally is favorable, particularly if the patient is not critically ill or comatose [23]. In these patients who are not critically ill the recommendation is for conservative treatment with oral benzodiazepines. If critically ill, there is evidence to suggest aggressive treatment with IV antiepileptic drugs (AEDs) could worsen the prognosis (possibly related to the underlying cause of the seizures or comorbid conditions) [23]. Subtle generalized SE also is not easily recognized. It is the most severe clinical stage of generalized convulsive SE. The patient is in a coma and

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the EEG shows severely abnormal brain activity. There may be subtle trunk or extremity myoclonus, facial twitching, or nystagmoid eye movements. The prognosis of patients who have subtle generalized SE, contrary to those who have nonconvulsive SE, is dismal. It is considered the most severe clinical stage of generalized convulsive SE [24]. In all forms of SE, bedside EEG often has a pivotal role in uncovering the disorder and optimizing treatment.

Diagnostic evaluation A thorough history, examination, neuroimaging, and EEG are indicated in the diagnostic evaluation. If collectively the results are inconclusive, then prolonged inpatient EEG video monitoring is recommended. History A thorough history from the patient and observers is important, particularly because the patient may be unaware of the seizures. Seizures are, by their nature, paroxysmal, unpredictable, and usually stereotyped from patient to patient. Focal paroxysmal transient deficits in language, memory, motor, or sensory testing can occur not only with TIAs and such syndromes as transient global amnesia but also as the first manifestation of partial seizures (aura) or more commonly after a seizure (postictal Todd paralysis). By history, the description can help with seizure recognition and localization of the potential focus, which may be further supported by examination and imaging findings. Examination Findings on physical examination, with particular emphasis on cardiovascular and neurologic examinations, aid in the differential diagnosis, although in this population patients often have co-occurring diagnoses (seizures and cardiovascular problems). Checking blood pressure and assessing for arrhythmia or orthostatic hypotension can be helpful. A tilt table test can be helpful diagnostically in this population, particularly if it reproduces exactly the reported stereotyped symptoms. As stated above, findings on examination of focal deficits in language, memory, motor, or sensory testing can occur not only with TIAs and such syndromes as transient global amnesia but also as the first manifestation of partial seizures (aura) or, more commonly, afterward (postictal Todd’s paralysis). Neuroimaging Neuroimaging is essential in the evaluation, particularly in older patients whose seizures are often attributable to structural abnormalities. For nonemergent evaluation of recurrent seizures MRI is the imaging procedure of

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choice. The administration of gadolinium in these patients is helpful for better detection of tumors and infections [15]. As with EEG, there are nonspecific age-related changes seen on MRI that should not be overinterpreted. Electroencephalography EEG is an essential element to look for interictal epileptiform discharges that are potentially epileptogenic from the electrographic standpoint and when present confirm the likelihood of epilepsy. As mentioned earlier, however, the data show that EEGs are often nonspecific in showing focal or generalized slowing in this population or are even normal (31%) [17]. In fact, interictal epileptiform activity is present in only 26% to 38% on initial EEGs of patients ultimately diagnosed with seizures [11,18,19]. Few seizures after stroke (only 10% to 20%) and few cerebral tumors (10% to 20%) have interictal epileptiform activity on EEG [10], making it difficult in many cases to confirm the likelihood of seizures using routine EEG. Later discussion shows how further EEG testing can be of high yield and confirm the diagnosis of epilepsy. Inpatient electroencephalogram video monitoring The history, EEG, and MRI can be helpful to confirm the diagnosis but can be nonspecific also. In these cases, further diagnostic workup using inpatient video EEG monitoring is recommended. This tool is profoundly underused in the elderly population. Studies have shown that patients older than 60 years constitute less than 10% of admissions to epilepsy monitoring units [25]. Findings from several series have shown that prolonged EEG video monitoring leads to a definitive diagnosis of seizures versus nonepileptic events in most elderly patients having a mean length of stay of 3 to 4 days [13,25]. Studies [13,25,26] have shown more than half of patients over 60 who were monitored with prolonged inpatient video EEG ultimately were diagnosed with nonepileptic events (such as pseudo-seizures often from conversion disorder, cardiac events, TIA, syncope, movement disorders, and sleep disorders). This occurrence is important because most elderly patients undergoing video EEG monitoring who ultimately were diagnosed with nonepileptic events were taking anticonvulsant medications on admission, putting them at unnecessary risk for side effects and drug interactions [15]. Also, 25% of elderly patients who have nonepileptic events (as is seen in younger patients who undergo prolonged video EEG monitoring) experience epileptic events [26], emphasizing the importance of recognizing the frequency of this cooccurrence of nonepileptic and epileptic events in these same patients for appropriate therapeutic interventions for each. Further data reinforcing the use of prolonged EEG monitoring are found in Ramsay and coworkers’ VACS #428 [11]. Ambulatory several-day EEG

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was used for prolonged monitoring (rather than inpatient video EEG) in a subset of elder patients who had seizures whose routine EEG was normal (n ¼ 9) or slow (n ¼ 14). For the 9 initially normal EEGs extended EEG results with ambulatory monitoring resulted in 6 (66.7%) normal, 1 (11.1%) slow, and 2 (22.2%) epileptiform. For the 14 initially slow EEGs extended EEG results with ambulatory monitoring resulted in 0 (0%) normal, 4 (28.6%) slow, and 10 (71.4%) epileptiform. In summary, published evidence underscores the importance and high yield of extended prolonged EEG monitoring in elders who have nonspecific spells suspected but heretofore unconfirmed to be seizures.

Prognosis Epilepsy, by definition, consists of recurrent seizures or the tendency to have recurrent seizures. Young adults, particularly those who have epilepsies that are not associated with focal lesions, may only have a 15% to 30% chance of a recurrent seizure in the next several years [3]. In contrast, new-onset seizures in the elderly have a high risk for recurrence because of the increased presence of risk factors for cerebrovascular disease. As stated earlier in this article, studies show the recurrence rate in patients over 60 is reported to be anywhere from 40% to greater than 90% after first seizure if the seizures go untreated [3,4,10,11]. Epilepsy is a chronic illness that has prominent interactions with a person’s social, vocational, and psychological function. The presence of depression in elderly patients who have epilepsy is strongly correlated with low subjective quality of life [12,27,28]. Depression may be the most common psychiatric illness in older adults who have epilepsy [12,27], and depression is strongly associated with quality of life and function in people who have epilepsy [12,27,28]. Results from the few studies of depression and epilepsy indicate that the prevalence of depression ranges from 20% to 55% in adult patients who have recurrent seizures [12]. Depression also seems to be strongly associated with poor subjective health status or quality of life, independent of seizure frequency [27]. The severity of depression and the occurrence of adverse events because of antiepileptic drugs seem to be the strongest predictors of low subjective quality-of-life health status in patients who have refractory seizures [12,27], which is not related at all to the frequency of seizures [27,28]. If seizures and depression remain untreated and unrecognized in this population, seizures continue to occur and depression and quality of life deteriorates. Unrecognized and untreated seizures also can lead to falls, injury, and potential medical complications of a prolonged seizure. These individuals may be treated erroneously for conditions they do not have, exposing them to unnecessary additional medications and risks of adverse effects of polypharmacy. Medication adherence can be optimized by efforts that include

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education for patients and caregivers, dispensement systems including medication boxes and reminders, and other supportive and monitoring plans. Medication treatment responsiveness, sensitivity, and adverse effects Once elders are diagnosed with epilepsy and can tolerate a drug, the outcome for seizure control is favorable, particularly with less comorbid disease burden (R. Eugene Ramsay, MD, personal communication, 2006) [11]. Successful antiepileptic drug treatment of any patient who has a seizure disorder, including elders, requires a combination of efficacy and tolerability. Aging has a considerable influence on pharmacokinetic and pharmacodynamic processes; this is an important consideration in the choice of drug and dose adjusting in elders. Age-related pharmacokinetic alterations include decreased plasma protein binding, increased volume of distribution (for lipophilic drugs only), reduced activity of drug-metabolizing hepatic pathways (particularly those involving the CYP enzymes), decreased renal drug clearance, and prolonged elimination half-life [29]. In general, lower dosages of AEDs are needed for seizure control and for avoiding adverse effects or toxicity side effects in the elderly. The good news regarding treatment with AEDs in the elderly population, particularly those who have lower comorbid disease burden, is that despite the symptomatic cause of new-onset seizures in the elderly, seizures often are readily controlled [11,17]. Although elderly patients are more often seizure free at lower serum AED concentrations, they also tend to have adverse effects at lower drug concentrations [11]. In this age group, therefore, issues of tolerability, lack of drug interactions, and good cognitive profiles are important considerations in selection of an agent. Many of the first-generation, older AEDs (such as phenytoin, carbamazepine, valproic acid, and barbiturates) have characteristics that make them less than ideal agents for this population because of their pharmacokinetics, pharmacodynamics, and drug–drug interactions. The older AEDs tend to be more difficult to manage because of such characteristics as nonlinear pharmacokinetics, high protein binding, and the ability to induce or inhibit their metabolism or that of other drugs (Table 3). In fact, in the widely respected study by Birnbaum and coworkers [30] investigators examined sequential serum total phenytoin concentrations in 56 nursing home residents receiving constant phenytoin doses and found highly variable phenytoin levels within each individual patient despite constant dosing over time (Fig. 1). Note in Fig. 1 some study participants had minimal variability, but most had large (two- to threefold or greater) differences in total phenytoin concentrations when taking the same dose over time. Phenytoin concentrations ranged from subtherapeutic to toxic within some individuals. From a clinical standpoint, the high variability of total phenytoin concentrations demonstrates the riskiness of changing doses based on one serum level. Also, because phenytoin is highly protein bound, it is suggested that measuring free phenytoin levels may be

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Table 3 Pharmokinetic characteristics of AEDs

Nonlinear pharmacokinetics High protein binding (O90%) Mostly metabolized by the liver Induces or inhibits liver metabolism Mostly renal clearance Multiple formulations

Older AEDs

Newer AEDs

Phenytoin, (carbamazepine, valproic acid less so) Phenytoin, valproic acid, carbamazepine Phenytoin, valproic acid, carbamazepine, phenobarbital Phenytoin, valproic acid, carbamazepine, phenobarbital None

Gabapentin

Phenytoin, valproic acid, carbamazepine, phenobarbital

Tiagabine Lamotrigine, oxcarbazepine, tiagabine Lamotrigine, oxcarbazepine, topiramate (high doses) Gabapentin, topiramate, levetiracetam, pregabalin Lamotrigine, gabapentin, levetiracetam, oxcarbazepine, topiramate

From Birnbaum AK. The pharmacology of AED’s pertaining to the treatment of the elderly in chronic care facilities. Geriatrics 2005;(Suppl):13–6.

more useful than total phenytoin levels if using this drug in the older population [21,30]. Drugs that are cleared by the kidneys are desirable because this results in fewer drug–drug interactions. None of the older AEDs are more than 50%

Fig. 1. Variability of serum phenytoin levels within individual nursing home patients despite unchanged dosing. Total phenytoin concentrations for 56 elderly nursing home residents. Each X represents a single total phenytoin measurement; circles represent serum drawn after administration of phenytoin by gastric tube. The lines connect the values for a given patient. (From Birnbaum A, Hardie NA, Leppik IE, et al. Variability of total phenytoin serum concentrations within elderly nursing home residents. Neurology 2003;60:555–9; with permission.)

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renally cleared, whereas some of the newer drugs, such as gabapentin, levetiracetam, and pregabalin, are almost l00% renally cleared and exhibit fewer or no drug–drug interactions [21] (See Table 3; Box 1). Highly renally metabolized medications do require dose adjustments, particularly because renal function decreases with age. Dose adjustments in renally metabolized drugs should be based on the estimated or measured creatinine clearance. Serum creatinine level cannot be relied on as a marker for renal function because it largely depends on muscle mass and tends to decrease with age, and a creatinine value in the normal range may underestimate true renal function [31]. Selected second-generation, newer AEDs (such as gabapentin, lamotrigine, topiramate, and levetiracetam) are being recognized by epilepsy experts as preferred treatment of seizure disorders in the older patient because some appear to be better tolerated, some have less-sedating cognitive profiles, and many have less-significant interactions with other medications or metabolic considerations (Table 4) [11,17,18]. They have not been on the market as long as the older AEDs, however, and only a few headto-head double-blind studies for efficacy and tolerability have been published in this population. In the few double-blind head-to-head trials in elders of older versus newer AEDs, even though the patients on the newer AEDs are shown to

Box 1. Hepatic and renal interactions of antiepileptic drugs Hepatic metabolism/high interaction potential Phenytoin Carbamazepine Valproate Primidone Phenobarbital Hepatic metabolism/low interaction potential Lamotrigine Oxcarbazepine Zonisamide Topiramate Renal clearance/low interaction potential Gabapentin Levetiracetam Pregabalin Courtesy of R. Eugene Ramsay, MD, Miami, FL.

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definitively drop out of the studies significantly less often than the those taking the older AEDs, the drop-out rates are high in both groups and are predominantly because of high rates of adverse side effects in both groups [16,32,33]. These clinical trial findings of high drop-out rates because of adverse side effects to the AEDs has led to the recommendation to start AEDs at low doses in this population and slowly increase the doses incrementally to achieve seizure control. More double-blind trials are needed before final rankings for AEDs can be made [32]. There have been several studies examining the relationship between AED therapy and falls and fractures [29]. A study of nearly 8000 elderly community-dwelling women found that the risk for any fall was increased by 175% in women taking AEDs even after controlling for other risk factors, including seizure diagnosis [29]. Studies have shown that patients taking phenytoin have a threefold risk for any non-vertebral fracture. For non-hip fractures, the increase in risk among phenytoin users was even higher (odds ratio 3.74) [29]. Over the past 2 years, more evidence has been accumulating that several of the older AEDs are associated with osteoporosis and osteopenia [34], particularly those that induce the cytochrome P 450 enzyme system in the liver (phenobarbital, phenytoin, and carbamazepine). Emerging data suggest that valproic acid, an inhibitor of the cytochrome P 450 system, may also affect bone negatively [34]. Few studies have evaluated the effect of the newer medications on bone, although one study focused on gabapentin, lamotrigine, topiramate, and vigabatrin and found no significant abnormalities [34]. More studies are needed. Mechanisms are speculated but no single theory explains all the reported findings and there may be multiple mechanisms [34]. Calcium and vitamin D supplementation are recommended to be given with older AEDs [34]. Epidemiologic surveys indicate that the prevalence of AED use is increased in elderly people, particularly those in chronic care facilities. Approximately 10% of elderly nursing home residents take one or more AEDs, and 1.6% of the community-dwelling population takes one or more AEDs [21,29]. Despite the toxicity and potential bone damage associated with the older AEDs, these drugs tend to be used more often in nursing home residents as first-line therapy [9,21,29,35]. Phenytoin is the most commonly prescribed older AED [9,21,35], despite the multiple adverse effects related to its use. A study by Garrard and colleagues [35] on AED use in nursing homes found the most frequently used were phenytoin (52%), valproic acid (19%), gabapentin (17%), and carbamazepine (11%). When stratified for seizure or epilepsy indication, phenytoin, carbamazepine, and phenobarbital were used by most of the residents [21,29,35]. In this study [35], 14% of residents received a combination of at least two AEDs, phenytoin with phenobarbital being the most common combination [29,35]. This finding is important because concomitant medications can alter the absorption, distribution, and metabolism of AEDs, thereby increasing the risk for toxicity or seizure frequency.

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Table 4 Specific AEDs for the elderly AED

Advantages

Disadvantages

Phenytoin

Once daily Inexpensive

Phenobarbital

Once daily Very inexpensive Linear kinetics

Carbamazepine

Good efficacy Twice daily Linear kinetics

Valproate

Twice daily No ataxia

Gabapentin

No drug interactions Renal excretion Few side effects

Lamotrigine

Nonsedative Twice daily Linear kinetics

Oxcarbazepine

Rapid titration Monotherapy indication No interactions Rapid titration Linear kinetics No interactions Linear kinetics Weight loss

Nonlinear kinetics Ataxia Peripheral neuropathy Osteopenia Osteoporosis Sedation Depression Peripheral neuropathy Osteopenia Osteoporosis Some cognitive effects Some somnolence Hyponatremia Osteoporosis Osteopenia Weight gain Hair loss Cognitive effects Tremor Thrombocytopenia Osteoporosis Osteopenia Low efficacy Three daily doses Somnolence Weight gain Expensive Slow titration Expensive Drug rash, particularly in combination with valproate Hyponatremia Expensive

Levetiracetam

Topiramate

Zonisamide

Once daily Linear kinetics Long half-life Cognitively well tolerated Weight loss

Behavioral adverse events Expensive Cognitive/behavioral side effects Renal stones Weight loss Acidosis Expensive Renal stones Weight loss Expensive

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Table 4 (continued ) AED

Advantages

Disadvantages

Tiagabine

Generally well tolerated Few side effects Twice daily No drug interactions Linear kinetics Renal excretion

Encephalopathy Knee buckling

Pregablin

Weight gain Pedal edema

Courtesy of R. Eugene Ramsay, MD, Miami Florida.

A study by Lackner and colleagues [20,29] examined AED use in nursing homes. In 4291 residents in nursing homes, they found that residents were taking AEDs along with possible interfering agents, including antidepressants (18.9%), antipsychotics (12.7%), benzodiazepines (22.4%), thyroid supplements (l4%), antacids (8%), calcium channel blockers (6.9%), warfarin (5.9%), and cimetidine (2.5%). Moreover, they were taking an average of five medications in addition to their AEDs.

Future directions As more clinical experience accrues with newer AEDs in elders, the potential benefit versus possible unforeseen risks will emerge as greater numbers of patients receive these medications. Additionally, more head-to-head comparisons of new and old AEDs and studies addressing special populations or comorbidities, such as the oldest old or elders who have dementia, higher disease burden, behavioral or affective disorders, or pain syndromes, will direct choices of first-line, second-line, and possible combinations of AEDs. As discussed in this article, many elders in chronic care institutions are on AEDs. For clinicians treating these patients, the mounting evidence of significant medication toxicity and serious adverse effects on bone health with older AEDs will help in choosing alternative medication regimens using newer AEDs in nursing home residents and in community-dwelling elders. Future head-to-head double-blind studies in both these populations using the newer AEDs are eagerly awaited. No studies have examined AED withdrawal in this population, possibly because most seizures in this population are related to symptomatic (ie, structural, usually vascular) causes and thus these patients are presumed high risk for recurrence of seizures after AED withdrawal. Data on recurrent seizure rates in elders who have epilepsy who are withdrawn from AEDs will be helpful. Because interest in bone health and vitamin D levels has grown, future information about the effects of new agents on bone density may be forthcoming and important.

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Considering the value elders place on quality of life and functional status, newer studies may more comprehensively address the functional and social aspects of treatment with the newer AEDs. The goal in this population is always to preserve functional status and maintain quality of life while improving epilepsy identification and management. In the rare elder who has medically refractory epilepsy, there are a few reports relating to temporal lobectomy outcomes of older patients undergoing temporal lobectomies from comprehensive epilepsy centers. For example, postsurgical outcomes were reported by Boling and coworkers [36] on 18 patients, and Cascino and colleagues [37] reported on 8 patients 50 years of age or older. Generally they found a trend toward lower rate of seizure freedom in older patients compared with younger adults. Meaningful seizure frequency reduction was found without any significant morbidity or mortality differences between the young and the older populations. This finding suggests that elders who have seizures that are medically intractable and have precise localization of a seizure focus are appropriate surgical candidates for temporal lobectomy and have a favorable prognosis. Although more studies are needed, older adults should not be excluded from surgical consideration based solely on age. Rather, exclusion criteria should be similar to those for younger patients. In the future, patients over age 60 who have seizures that are medically intractable should be referred to comprehensive epilepsy centers to assess for candidacy for this procedure. In medically refractory elders who have epilepsy, there is some post-marketing data on vagal nerve stimulation (VNS). Sirven and coworkers [38] showed that in 45 adults over age 50, VNS reduced seizure rates with prolonged seizure-free periods and improved quality of life. Side effects were mild and transient and there were no reported incidents of bradycardia, syncope, or arrhythmia [15]. Patients who have medically refractory seizures therefore should not be excluded from VNS based solely on age. More studies are needed, but data show VNS offers an alternative that avoids complications from drug interactions and cognitive side effects while giving the patient some aspect of control and alleviating concerns of compliance [15]. There are few controlled studies underway using deep brain stimulation for epilepsy in adults and results are not yet available [39]. Controversies currently exist as to the proper target for localization of epileptogenicity. If deep brain stimulation ultimately shows therapeutic benefit, this may be another avenue for intervention in the population of elders who have medically refractory epilepsy. In elders who have epilepsy, the mainstay of treatment will likely remain medications. As stated earlier in the article, current treatment of most elders who have epilepsy is with older AEDs with known associated morbidity (high medication toxicity likelihood and potential bone damage). The future for most elders who have epilepsy is bright, however. In general, elders who have epilepsy, particularly those who have lower comorbid disease burdens, are responsive to AEDs with good seizure control. The newer AEDs

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promise lower drug–drug interactions, better pharmacokinetic and pharmacodynamic profiles, fewer side effects, and higher likelihood of efficacy. With slow and careful titration until seizures are controlled these patients will enjoy decreased seizure frequency and greater quality of life.

Summary Why is it important to learn about epilepsy in the elderly? The answers are many. As this article has highlighted, compared with younger individuals epilepsy is more common and the causes are more structural and symptomatic than in younger patients (particularly stroke). The clinical presentation is different in the elderly. The diagnosis is more difficult and often delayed. The most common seizures are simple partial and complex partial seizures, which are more often extratemporal in location. Confusion and memory problems are common presenting symptoms and postictal deficits often are prolonged. The prognosis for epilepsy in the elderly generally is favorable for seizure control, but if untreated, depression and quality of life suffer and seizures frequently recur. Seizures respond well at lower serum concentrations of antiepileptic drugs but these patients are also more sensitive (less tolerant) to side effects at lower doses than younger adults.

References [1] Faught E. Epidemiology and drug treatment of epilepsy in elderly people. Drugs Aging l999;15(4):255–69. [2] Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia 1981;22:489–501. [3] Bergey G. Initial treatment of epilepsy: special issues in treating the elderly. Neurology 2004; 63(suppl 4):S40–8. [4] Hauser A, Annegars J, Kurland L. Incidence of epilepsy and unprovoked seizures in Rochester Minnesota 1935–1984. Epilepsia 1993;34(3):453–68. [5] Leppik I. Introduction to the international geriatric epilepsy symposium. Epilepsy Res 2006; 68S:S1–4. [6] Butler R. Ageing: the challenge of the twenty-first century medicine. In: Rowan AJ, Ramsay RE, editors. Seizures and epilepsy in the elderly. Boston: Butterworth-Heinemann; 1997. p. 3–5. [7] Hauser A. Epidemiology of seizures in the elderly. In: Rowan AJ, Ramsay RE, editors. Seizures and epilepsy in the elderly. Boston: Butterworth-Heinemann; 1997. p. 7–20. [8] Hauser A, Annegars J, Kurland L. Prevalence of epilepsy in Rochester Minnesota: 1940– 1980. Epilepsia 1991;32:429–45. [9] Schachter SC, Cramer G, Thompson G, et al. An evaluation of antiepileptic drug therapy in nursing facilities. J Am Geriatr Soc 1998;46(9):ll37–41. [10] Stephen L, Brodie M. Epilepsy in older people. Lancet 2000;355:1441–6. [11] Ramsey E, Rowan J, Pryor F. Special considerations in treating the elderly patient with epilepsy. Neurology 2004;62(Suppl 2):S24–9. [12] Cloyd J, Hauser W, Towne A, et al. Epidemiological and medical aspects of epilepsy in the elderly. Epilepsy Res 2006;68S:S39–48.

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[32] [33]

[34] [35] [36] [37] [38] [39]

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Van Cott A. Epilepsy and EEG in the elderly. Epilepsia 2002;43(Suppl 3):94–102. Ramsey E, Pryor F. Epilepsy in the elderly. Neurology 2000;55(Suppl 1):S9–14. LaRoche S, Helmers S. Epilepsy in the elderly. Neurologist 2003;9(5):241–9. Rowan A, Ramsay R, Collins J, et al. Cooperative Study Group VA. New onset geriatric epilepsy: a randomized study of gabapentin, lamotrigine, and carbamazepine. Neurology 2005;64:l868–73. Bergey G. Minimizing misdiagnoses in epilepsy in the elderly. In: Epilepsy later in life: managing the unique problems of seizures in the elderly. Geriatrics 2005;(Supp):3–47. Ramsey E, Rowan J, Pryor F, et al. VA Cooperative Study Group 428. Seizures in the older patient: demographics, diagnosis, and treatment. Epilepsia 2000;41(Suppl 7):S172–3. Drury I, Beydoune A. Interictal epileptiform activity in elderly patients with epilepsy. Electroencephalogr Clin Neurophysiol 1998;106:369–73. Lackner T, Cloyd J, Thomas L, et al. Antiepileptic drug use in nursing home residents: effect of age, gender and co medication on patterns of use. Epilepsia 1998;39:1083–7. Birnbaum A. The pharmacology of AED’s pertaining to the treatment of the elderly in chronic care facilities. Geriatrics 2005;(Suppl):13–6. DeLorenzo R. Clinical and epidemiological study of status epilepticus in elders. In: Rowan AJ, Ramsay R, editors. Seizures and epilepsy in elders. Newton, MA: Butterworth-Heinemann; 1997. p. 191–205. Treiman D, Walker M. Treatment of seizure emergencies: convulsive and non-convulsive status epilepticus. Epilepsy Res 2006;68S:S77–82. Treiman D, DeGiorgio C, Salisbury S, et al. Subtle generalized convulsive status epilepticus. Epilepsia 1984;25:653. Drury I, Selwa L, Shuh L. Value of inpatient diagnostic CCTV-EEG monitoring in the elderly. Epilepsia 1999;40(8):1100–2. Kellinghaus C, Loddenkemper T, Dudley D, et al. Non-epileptic seizures of the elderly. J Neurol 2004;251:704–9. Gilliam F. Optimizing health outcomes in active epilepsy. Neurology 2002;58(Suppl 5):S9–20. Gilliam F, Hecimovic H, Sheline Y. Psychiatric co morbidity, health, and function in epilepsy. Epilepsy Behav 2003;4(Suppl. 4):S26–30. Perucca E, Berlowitz D, Birnbaum A, et al. Pharmacological and clinical aspects of antiepileptic drug use in elders. Epilepsy Res 2006;68S:S49–63. Birnbaum A, Hardie N, Leppik I, et al. Variability of multiple total phenytoin serum concentrations in elderly nursing home residents. Neurology 2003;60:555–9. Semla TP, Rochon PA. Pharmacotherapy. In: Pompei P, Murphy JB, et al, editors. Geriatric review syllabus: a core curriculum in geriatric medicine. 6th edition. New York: Fry Communications; 2006. p. 74. Leppik I, Brodie M, Saetre E, et al. Outcomes research: clinical trials in elders. Epilepsy Res 2006;68S:S71–6. Brodie J, Overstall P, Giorgi L. The UK Lamotrigine Elders Study Group. Multicentre, double blind, randomized comparison between lamotrigine and carbamazepine in elder patients with newly diagnosed epilepsy. Epilepsy Res 1999;37:1–7. Pack A, Gidal B, Vazquez B. Bone disease associated with antiepileptic drugs. Cleve Clin J Med 2004;71(Suppl 2):S42–8. Garrard J, Harms S, Hardie N. Antiepileptic drug use in nursing home admissions. Ann Neurol 2003;54:75–85. Boling W, Andermann F, Reutens D, et al. Surgery for temporal lobe epilepsy in older patients. J Neurosurg 2001;95:242–8. Cascino G, Sharbrough F, Hirschorn K, et al. Surgery for focal epilepsy in the older patient. Neurology 1991;41(9):l415–7. Sirvin J, Sperling M, Naritoku D, et al. Vagus nerve stimulation therapy for epilepsy in older adults. Neurology 2000;54:1179–82. Gallo B. Epilepsy, surgery, and elders. Epilepsy Res 2006;68S:S83–6.

Med Clin N Am 90 (2006) 967–982

The Older Cancer Patient Heidi K. White, MD, MHSa,b,*, Harvey J. Cohen, MDa,b,c a

Geriatrics Division, Duke University School of Medicine, 3502 Bluezone, Box 3003, Durham, NC 27710, USA b Geriatric Research, Education, and Clinical Center, Veterans Affairs Medical Center, 508 Fulton Street, Durham, NC 27705, USA c Center for the Study of Aging and Human Development, Geriatrics Division, Duke University Medical Center, Box 3003, Durham, NC 27710, USA

Introduction Cancer is a common problem in the older adult population and the second leading cause of death for both men and women. More than half of cancers occur in adults over the age of 65 years. The biologic, psychologic, and social aspects of the aging process must be considered for optimal screening, diagnosis, and treatment to occur in this population. The growing number of older adults facing a cancer diagnosis in conjunction with other acute and chronic conditions makes it imperative for primary care physicians, geriatricians, oncologists, surgeons, radiation oncologists, and virtually all specialists to consider the merits of geriatric assessment and treatment for optimal management. Of course cancer is not one disease but many. Rather than address even a short list of common cancers, this article focuses on aspects of the aging process that impact cancer development, progression, and treatment, along with principles that can be applied to the care of older patients who have cancer.

Principles of aging in the care of older adult patients who have cancer Understanding what makes the older adult patient who has cancer different from the middle-aged patient who has cancer, apart from comorbid

* Corresponding author. Geriatrics Division, Duke University School of Medicine, 3502 Bluezone, Box 3003, Durham, NC 27710. E-mail address: [email protected] (H.K. White). 0025-7125/06/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.mcna.2006.05.017 medical.theclinics.com

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illness, which can be a burden in both groups, is an important place to start conceptualizing appropriate care for this group of individuals (Table 1). Decreasing homeostatic reserve Aging results in a steady decline in physiologic reserve capacity in most organ systems and dysregulation in others. These changes are related to the passage of time and are not the result of disease processes but do increase the vulnerability to disease. These changes generally are imperceptible at rest or in the individual’s steady state but become apparent under stress of the system. Important changes that result in decreased reserve capacity include impaired glucose tolerance, decreased FEV1 and FVC, decreased creatinine clearance and glomerular filtration rate, decreased muscle mass (sarcopenia), decreased bone mass, decreased brain blood flow and impaired autoregulation of blood flow, decreased dark adaptation of vision, decreased odor detection, and loss of high-frequency auditory tones, to name only a few. An example of decreased bone marrow reserve is evident in higher rates of neutropenia among older patients treated with full-dose chemotherapeutic regimens for non-Hodgkin lymphoma [1]. As aging advances the loss of reserve capacity progresses and becomes evident even in a steady state; this advanced stage of absent reserves and dysregulation is being defined as the syndrome of frailty. Heterogeneity in aging Despite these predictable age-related changes that decrease reserve capacity and increase the vulnerability of older adults to progressively Table 1 Selected aspects of aging and their impact on older adults who have cancer Aging process

Impact on older adult patient who has cancer

Decreasing homeostatic reserve


Decreased ability to tolerate cancer treatment without adverse events or complications
Assessment is needed to measure functional reserves (eg, creatinine clearance, cognitive screening)
Assessment parameters other than chronologic age will best characterize an individual patient’s ability to undergo cancer-specific treatment with acceptable levels of toxicity, and quality of life (eg, comorbidities, functional status)
A particular patient may exhibit adequate reserves in some organ system and more limited reserves in others
Prolonged recovery and rehabilitation
Increased sensitivity to drug effects
Potential for poor drug absorption, higher peak concentrations, and prolonged half-life because of altered excretion
Increased sensitivity to toxicity of drugs (eg, higher rates of neutropenia, higher rates of mucositis)

Heterogeneity

Declining adaptability Altered pharmacokinetics

Altered pharmacodynamics

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smaller and smaller stresses, there is an amazing degree of heterogeneity that is evident in the aging population. This heterogeneity is most evident when comparing older adults to one another but it is also evident in the variability of age-related changes within organ systems of a given individual. For example, in the Baltimore Longitudinal study glomerular filtration rate on average declined 1 mL/min/y. But as many as 30% of individuals experienced no decline, whereas others experienced a decline of up to 2 mL/min/y [2]. In addition to presumed genetic differences that influence aging rates, behavioral factors, such as diet and exercise, play an important role. Slowing of the adaptive response Older adults adapt more slowly to environmental stressors. Aging has been defined as a progressive loss of adaptability of an individual organism as time passes. This loss is compellingly demonstrated in the marathon records by age group published by the US Corporate Athletic Association [3]. By this listing men aged 30 to 34 currently hold the best time of 2:19:04; however, the record for men aged 65 to 99 is 3:26:38, more than an hour longer. Although it is great news that men of this age are capable of completing marathons at a pace that would outdo many younger marathon runners, clearly older men do not possess the same degree of adaptability in this sport. In a perhaps more immediately relevant example, a slower (less vigorous) adaptive response may explain in part the increased susceptibility with age of normal tissues to chemotherapy. Mucosa, hemopoietic cells, the heart, and the nervous system are more susceptible to chemotherapy. For example, in patients who have cancer of the colon age is an independent risk factor for the development of mucositis induced by fluorinated pyrimidines [4]. Alterations in pharmacokinetics and pharmacodynamics of antineoplastic therapy Aging has a profound impact on the pharmacokinetics and pharmacodynamics of antineoplastic therapy [5]. Pharmacokinetics is what the body does to the drug in terms of absorption, distribution, metabolism, and excretion. With increasing age absorption may be reduced by decreased gastrointestinal motility, decreased secretion of gastric enzymes, and mucosal atrophy. Drug distribution is a function of body composition and the concentration of plasma proteins. In older adults body fat increases and water content decreases; this translates into a larger volume of distribution for fatsoluble drugs and reduced volume of distribution for water-soluble drugs, which lead to changes in peak concentration and alterations in half-life. Metabolism mainly occurs in the liver and is not affected strongly by aging processes but can be altered by surgical stress and illness [6,7]. Excretion is most affected by the gradual decline in glomerular filtration rate.

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Pharmacodynamics refers to what the drug does to the body, primarily referring to alterations in sensitivity that may lead to adverse events. For example, the plasma concentration of midazolam at which 50% of patients will be nonresponsive to the stimulus of verbal command decreases steadily with patient age [8]. It is more difficult to study pharmacodynamics because of the confounding effects of pharmacokinetics, which may appear to increase sensitivity when in actuality drug levels are elevated above typical levels because of alterations in distribution, metabolism, or excretion. The geriatrics adage, ‘‘start low, go slow,’’ means start with a low dosage and advance the dosage slowly. This simple yet effective approach has become a mainstay for avoiding problems because of altered pharmacokinetics and pharmacodynamics. It may not be as applicable for cancer-specific treatment as it is for symptom-specific treatment, however, because lower dosages of chemotherapy may rob older adults of the benefits of desired treatment effects while minimizing toxicity.

Aging biology in the development of cancer The biologic basis of cancer development is multidimensional. Disruption of genetic integrity is a cornerstone of this process. Alterations in the cellular environment also are important. These factors lead to the multistep process of cellular changes that result in neoplasia. The relationship between cancer biology and aging biology is beginning to unfold. The general increase in frequency of cancer with age makes the relationship between aging and cancer biology somewhat intuitive, but not all cancers increase in incidence with age. The incidence of breast, colon, and prostate cancers increase with age, whereas cervical cancer does not. The influence of aging on cancer biology remains uncertain. Some cancers appear more aggressive in advanced age, such as acute myelogenous leukemia, Hodgkin disease, and non-Hodgkin lymphoma, whereas other cancers, such as breast and prostate cancer, may become more indolent with advanced age. The linkage between aging and cancer biology may differ by cancer type and is influenced by environmental exposures and lifestyle choices. At a basic level aging provides the necessary time for chemical mutagens, radiation, and free radicals to promote genetic damage and aged cells may be more susceptible to these carcinogens. Cellular senescence is an important link between aging and cancer. This theory holds that nonmalignant cells have a finite replicative potential that is governed largely by telomere shortening. Telomeres, specialized regions of reiterative DNA at the ends of chromosomes, gradually shorten with successive replicative cycles. This shortening leads to the accumulation of senescent cells with age. Malignant cells overcome telomere shortening by upregulating production of telomerase [9]. Research regarding this linkage between aging and cancer is quickly accelerating our understanding of the interplay between cancer biology and aging biology, but other linkages

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are coming to light also, such as decreased ability to repair DNA, oncogene activation or amplification, decreased tumor suppressor gene activity, microenvironment alterations, and decreased immune surveillance [10].

Comprehensive geriatric assessment for patients who have cancer Because chronologic age is not an adequate indicator of response to cancer treatment and tolerance of toxicity, other factors need to be identified that characterize a ‘‘functional age,’’ assist in developing the most appropriate treatment plan, and further our understanding of what factors do influence outcomes. In the last 10 years there has been a growing recognition of the potential for comprehensive geriatric assessment (CGA) to improve the care of older adults who have cancer [11]. The International Society of Geriatric Oncology recommends the use of CGA in the evaluation of older patients who have cancer to detect unaddressed problems and improve functional status and, possibly, survival [12]. Components of the geriatric assessment are outlined in Table 2 along with screening tools, examples of detailed test components, and additional resources. CGA is ‘‘a multi disciplinary evaluation in which the multiple problems of older adults are uncovered, described, and explained, if possible, and in which the resources and strengths of the person are catalogued, need for services assessed, and a coordinated care plan developed to focus interventions on the person’s problems’’ [13]. Geriatric assessment has been studied in various settings that include specialized hospital units, hospital consultation services alone or with outpatient followup, clinic-based services, and in-home assessments. CGA has been shown to have positive effects on various health outcomes, such as prevention of disability progression, reduction of fall risk, rates of hospitalization, and nursing home admission. CGA is most effective when programs have control over implementation of recommendations and extended followup. Meta-analyses have suggested an impact on mortality [14,15], but more recent multi-institutional randomized controlled trials show no impact on mortality [16,17]. The results of studies of cost-effectiveness have been varied but generally favorable [17,18]. Specific trials of geriatric assessment outcomes in the oncologic setting are lacking. Some studies have suggested promise for the approach, however. One study using hospital inpatient geriatric care units for older adults who have cancer has shown improvements in psychologic status and pain management compared with usual care [19]. Another approach that has been implemented successfully has been to use primarily self-report components [20,21]. A pilot study of CGA by Extermann and colleagues in older women with breast cancer identified multiple undiagnosed problems [22]. Several studies indicate that when important predictors of mortality, such as cancer stage at diagnosis and age, are controlled, the burden of comorbid

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Table 2 Comprehensive geriatric assessment Dimension Medical Nutrition Vision Hearing

Urinary incontinence Comorbidities Medications

Cognitive

Affective Functional status

Detailed assessment

Resources

Height, weight, serum albumin, cholesterol ‘‘Describe any visual limitations.’’ ‘‘Do you have any trouble with your hearing?’’ Finger rub test Observed standing up, ambulation, and sitting down Screening questions

BMI, Mini Nutritional Assessment

Dietician, speech therapist

Snellen Eye Chart Audioscope

Ophthalmologist, optometrist Audiologist

Timed Get Up and Go [58], measured gait speed Urodynamic testing, urinalysis and urine culture Activity, severity, stability Ask patient to explain regimen, reason for each drug, and potential adverse effects Mini Mental Status Exam

Physical therapist, medically supervised exercise programs Urologist, gynecologist, geriatrician Primary care physician, specialists Pharmacist Primary care physician

Geriatric Depression Scale Koenig Depression Screen Katz ADL and IADL scale

Psychiatrist, psychologist, social worker Physical therapist, occupational therapist, speech therapist

Review of systems, medical record Review medication by having the patient bring all medication bottles to the visit ‘‘Do you have any memory or thinking problems?’’ Get permission to ask the same question of family members, Minicog Clinical observation, ‘‘Do you often feel sad or blue?’’ ADL

Neuropsychological testing, referral to geriatrician, psychiatrist, neurologist

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Mobility/balance

Screen

Social support

Economic

Advance directives

‘‘Do you have the financial resources to meet your current and future needs?’’ Home safety checklist ‘‘Do you have an advanced directive?’’

Detailed assessment of caregiver involvement and extended social support Health insurance Drug coverage

Social worker, home health services, hospice

Home visit

Occupational therapist, physical therapist, home health nurse Social worker

Detailed discussion

Social worker

Abbreviations: ADL, activities of daily living; BMI, body mass index; IADL, instrumental activities of daily living. Adapted and modified from Balducci L, Extermann M. Management of cancer in the older person: a practical approach. Oncologist 2000;5:224–37 and Reuben DB. Geriatric assessment in oncology. Cancer 1997;80:1311–6.

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Do you need help using the bathroom, bathing, dressing eating? IADL ‘‘Can you use the telephone, pay your bills, shop, drive a car?’’ ‘‘Who would help you in an emergency?’’

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illness is an important predictor of mortality [23,24]. Specific comorbidities, especially depression and cognitive impairment, are under-recognized in the oncology setting [25,26]. Comorbidity and functional status are independent predictors in older adult patients who have cancer and both need to be assessed [27]. Traditional oncologic measures of function, such as Karnofsky and Eastern Cooperative Oncology Group, are incomplete predictors in the elderly [27,28]. Ultimately, CGA should evaluate not only comorbidities and functional status but also stages or states of aging along with functional and coping (psychosocial) reserves that accurately predict therapeutic outcomes and improve outcomes through tailored treatment strategies. In this vein CGA may be used to recognize frailty, a developing concept of a phenotype that is strongly predictive of falls, disability, hospitalization, and mortality [29]. This phenotype is not synonymous with comorbidity or disability. Comorbidity is likely causative and disability should be considered an outcome. Frailty is attributable to underlying processes of aging and may be particularly useful in uncovering limited or absent reserve capacity associated with advanced aging. Recognizing older adults who appear stable and functional but have limited ability to recover from the stressors associated with cancer treatment may be extremely helpful in tailoring treatment plans [30]. At present there are competing definitions of frailty. Balducci and colleagues define frailty as one or more of the following: dependence in at least one activity of daily living (ADL), three or more serious comorbid conditions, and one or more geriatric syndromes [31]. Fried and colleagues define frailty by the presence of three of the following criteria: involuntary weight loss R10% of body weight over 1 year, fatigue, weakness (grip strength), slow walking speed, and low physical activity [29]. To date it seems that few specialists caring for older patients who have cancer use CGA on a regular basis, despite a general acknowledgment that age alone is not an adequate means of making treatment decisions [32,33]. This lack of assessment may be in large part because of a perceived impracticality of adopting a potentially time-consuming procedure with still unclear benefits for patient care. Cancer specialists are beginning to do the hard work of determining how to make CGA practical in usual care settings, however. There are several potential answers to this dilemma. Using primarily self-report components may optimize data gathering while minimizing staff time, but this may be less practical for more impaired individuals or diverse patient populations with limited literacy or English proficiency. Using hospital inpatient geriatric care units for older adults who have cancer may be a viable option in locations where these are available. In academic settings cancer specialists may be able to work in conjunction with geriatricians to manage more complicated older adult patients who have cancer. Also, cancer specialists should consider partnering with other clinical professionals in the implementation of CGA. Nurses, social workers, and midlevel practitioners can and should be part of the geriatric assessment process. A team approach to care has already been implemented to bring

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together the various cancer specialists to ensure that treatment modalities, including chemotherapy, radiation, and surgery, are implemented seamlessly; such programs can incorporate geriatric assessment into this team management framework. Screening tools may be another way of limiting time commitments, reserving full-blown CGA to those most likely to benefit from it. Screening tools may be informal, such as the screening questions outlined in Table 2. Alternatively, the Vulnerable Elders Survey 13 (VES-13) represents a formal means of predicting functional decline and death that also may be a viable screening tool (Fig. 1) [34]. The incorporation of CGA into clinical trials is of critical importance if we are to better delineate which patients with functional and cognitive limitations are appropriate for specific treatment regimens. This methodology will allow for comparison of patient characteristics across studies. Tailoring treatment CGA also can facilitate the process of tailoring treatment for individual patients (Table 3). The information collected should be used to establish goals of care; direct cancer-specific and symptom-specific treatment in light of comorbidities, functional status, psychological and social resources; and begin or review advanced planning (eg, living will, health care power of attorney, use of feeding tube). Cancer-specific treatment When carefully selected, older adult patients who have cancer undergoing the range of cancer treatment modalities experience similar responses to those seen in younger patients. Surgeons have been able to select carefully older adults who successfully undergo curative and palliative surgical procedures. Careful preoperative assessment, management of comorbidities, appropriate anesthesia management, and meticulous postoperative care have produced outcomes similar to those experienced by younger patients [35]. Radiation therapy is successful in older adults who have cancer and has developed its technical specificity for curative and palliative application with improved tolerability for older adults. Hormonal therapy is effective in older adult patients who have cancer of the breast, uterus, and prostate. With the advent of effective supportive therapy for the toxicity associated with chemotherapy more physicians have been willing to extend this treatment option to older patients, even those with some functional limitations and comorbidities. Growth factors, such as granulocyte colony-stimulating factor, modify or eliminate immunosuppressant effects. Cytoprotective agents, such as dexrazoxane, modify the cardiotoxic effects of doxorubicin. Newer antiemetics and improved techniques of chemotherapy administration also have opened the door of effective treatment to a wider range of older adult patients who have cancer. Important studies, such as the recent study of

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Fig. 1. Vulnerable Elders Survey. A score of 4 or more is associated with a four times greater risk for death or functional decline over 2 years among community-dwelling elders. (Adapted from Saliba D, Elliott M, Rubenstein LZ, et al. The Vulnerable Elders Survey: a tool for identifying vulnerable older people in the community. J Amer Geriatr Soc 2001;49(12):1691–9; with permission.)

adjuvant chemotherapy for lymph node–positive breast cancer, are confirming that older adults are just as likely to benefit from chemotherapy as younger adults [36]. It is important that older adults are allowed to make treatment decisions with explanations of all reasonable treatment options, including forgoing cancer-specific treatment. To make fully informed decisions they need

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Table 3 CGA-based cancer treatment plan Treatment type

Components

Cancer-specific treatment

Surgery Chemotherapy Hormonal therapy Radiation therapy Example: pain relief Medication, exercise, heat/cold, alternative therapies (eg, acupuncture), relaxation techniques, nerve blocks Dietary support Exercise prescription Support groups Address advance directives Periodically review goals of care

Symptom-specific therapy

Supportive therapy

End-of-life care

information regarding likely outcomes, adverse effects, and a description of the usual experience of treatment participation (frequency and length of procedures, usual recovery period, and so forth). If the treating physician is aware of functional limitations, cognitive impairment, or limitations of social support through the process of CGA, this allows for a more productive discussion of treatment options with the ability to anticipate and plan for how these issues may impact the treatment process and outcomes. For example, older adults who have cognitive impairment are at increased risk for developing delirium during hospitalization. Recognizing this potential complication can allow for interventions, such as family members staying with the patient around the clock, to be anticipated and planned. Many older adults rely heavily on close family members to assist them in treatment decisions. The physician can facilitate this process by inviting and encouraging the patient to bring family members to appointments. Treatment goals should be established clearly between the physician and patient. These goals should be reassessed periodically depending on factors that may precipitate change, such as a lack of response to therapy or a significant change in functional status. Communication helps to ensures that the goals of care are reflected in the course of treatment [37]. Symptom-specific treatment Whether or not patients decide to undergo cancer-specific treatment, symptom-specific treatment should be part of the treatment plan from diagnosis until death. Cancer specialists are becoming more and more adept at recognizing and treating cancer-related and treatment-related symptoms [38]. For example, fatigue is a particularly common symptom, especially in advanced stages of cancer. Treatment modalities include education, exercise, treatment of anemia, antidepressants, and psychostimulants.

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Pain is a common symptom experienced from early to late stages of cancer. Pain should be systematically assessed. Options include a visual descriptor scale containing a set of numbers with words representing different levels of pain. A visual analog scale typically uses a 10-cm line marked ‘‘no pain’’ on the left and ‘‘worst possible pain’’ on the right. The pain thermometer is a visual scale that allows patients to place their pain on a vertical scale that resembles a thermometer. The Faces pain scale provides a series of faces depicting various degrees of facial grimacing. Perhaps most frequently, patients are asked without a visual device such as those just described to rate their pain on a scale of 0 to 10, with 0 being no pain and 10 being the worst possible pain. The American Geriatrics Society guidelines for persistent pain management are helpful in developing a comprehensive treatment plan that is based on anticipatory treatment of pain with scheduled dosing rather than dosing as needed. This topic is addressed thoroughly elsewhere in this volume. Depression is fairly common among older adults who have chronic illness. Rates in patients who have cancer have been estimated at 17% to 33% [39,40]. Women who have severe illness, poor functional status, and advanced cancer are most at risk [40,41]. Multiple validated screening tools are available and should be used routinely, given the high prevalence of depression among patients who have cancer [42–44]. Treatment options include antidepressants, counseling, and electroconvulsive therapy. Supportive care Efforts currently are underway to assess the impact of diet and exercise prescriptions on the trajectory of functional decline and quality of life in newly diagnosed older adult patients who have cancer. Such efforts signal an acknowledgment of the motivation among patients who have cancer to make lifestyle changes and the potential for supportive interventions in addition to cancer-specific and symptom-specific treatments to improve the functional status and quality of life [45,46]. In another study, older patients who had cancer who also had mouth or tooth problems making it hard for them to eat experienced lower quality of life, poor emotional health, lower levels of physical functioning, and greater pain than patients without these problems [47]. This study emphasizes the impact that comorbid conditions can have on patients who have cancer, especially if they are not optimally identified and treated. In addition to comprehensive medical care, psychosocial interventions for the patient and caregiver can be extremely important. Supportive care needs to continue long term for cancer survivors who report a greater degree of disability than their counterparts without a history of cancer [48]. Psychosocial support is extremely important for the patient who has cancer, because the psychosocial demands of the illness course make an independent contribution to survival outcomes [49]. Support also should be

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available for the caregiver, because despite the many benefits of caregiving, such as greater intimacy, satisfaction, and gaining meaning and purpose in life, there are also substantial mental, physical, social, and economic costs [50]. End-of-life care End-of-life care should begin as early as possible in the course of a lifethreatening illness. An important initial step is asking about advanced directives, such as living will and health care power of attorney. If patients are unfamiliar with such documents, their usefulness should be explained and written information provided. It is important for patients to understand that choosing a less aggressive treatment plan does not mean they will forgo the involvement of a physician. The phrase ‘‘nothing more can be done’’ should not be used; physicians need to convey a willingness to stay involved with care and symptom management up until the moment of death [51]. Ideally the patient’s goals should be elicited at every stage of treatment and should be reflected in the course of treatment that is provided [37]. Endof-life care is thoroughly covered elsewhere in this volume.

The emergence of geriatric oncology Although 61% of new cases of cancer occur among the elderly they represent only 32% of participants in phase II and III clinical trials [52]. When comorbidities are controlled, age remains a strong predictor of whether or not a patient who has cancer will be offered a clinical trial, but when offered older adults respond with willingness to participate at similar rates [53]. Physicians may have good reasons for not offering clinical trials to older adults, such as protocol requirements that are onerous and not easily appreciated on enrollment, treatment-specific issues, including toxicity, and older patients’ medical and cognitive characteristics that may not exclude them but will hinder compliance with study requirements [54]. Insufficient enrollment of older adults in clinical trials is only one example of the inadequacies of current research to meet the needs of this growing population of patients who have cancer. There is an urgent need for further research at the interface of aging and cancer [55]. The lack of sufficient research makes it difficult to answer many of the questions that arise about cancer in older adults. Geriatric oncology represents a viable means of meeting the clinical and research needs of older adults who have cancer [56]. With the help of the John A. Hartford Foundation, gero-oncology training programs have been initiated and leaders are beginning to call for a new subspecialty of gero-oncology. Given the magnitude of the issue of appropriately caring for a growing number of older adults who have cancer, this seems to be a prudent course to pursue [57].

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Summary Providing effective and tolerable cancer treatment for the growing number of older adult patients who have cancer will require an understanding of the role of aging, comorbidity, functional status, and frailty on treatment outcomes. The incorporation of CGA into the care of older patients who have cancer will ensure that the heterogeneity of this population is considered in the development of treatment plans. It also may improve outcomes by identifying and optimally treating comorbid conditions and functional impairments. Optimal treatment of the older adult patient who has cancer starts with careful delineation of goals through conversation. The treatment plan should be comprehensive and address cancer-specific treatment, symptom-specific treatment, supportive treatment modalities, and end-of-life care.

References [1] Balducci L, Repetto L. Increased risk of myelotoxicity in elderly patients with Non-Hodgkin Lymphoma: The case for routine prophylaxis with colony-stimulating factor beginning in the first cycle of chemotherapy. Cancer 2004;100(1):6–11. [2] Lindeman RD, Tobin J, Shock NW. Longitudinal studies on the rate of decline in renal function with age. J Am Geriatr Soc 1985;33:278–85. [3] United States Corporate Athletic Association. Marathon Records by Age Group. Available at http://www.uscaa.org/marathon/records.htm. Accessed April 15, 2006. [4] Jacobson SD, Cha S, Sargent DJ, et al. Tolerability, dose intensity and benefit of 5FU based chemotherapy for advanced colorectal cancer (CRC) in the elderly. Proc Am Soc Clin Oncol 2001;20:384a, abstract 1534. [5] Wasil T, Lichtman SM. Clinical pharmacology issues relevant to the dosing and toxicity of chemotherapy in the elderly. Oncologist 2005;10:602–12. [6] O’Mahoney MS, George G, Westlake H, et al. Plasma aspirin esterase activity in elderly patients undergoing elective hip replacement and with fractured neck of femur. Age Ageing 1994;23:338–41. [7] Wynne HA, Cope LH, Herd B, et al. The association of age and frailty with paracetamol conjugation in man. Age Ageing 1990;19:419–24. [8] Jacobs JR, Reves JG, Marty J, et al. Aging increases pharmacodynamic sensitivity to the hypnotic effects of midazolam. Anesth Analg 1995;80:143–8. [9] Blasco MA. Telomeres and human disease: ageing, cancer and beyond. Nat Rev Genet 2005; 6:611–22. [10] Cohen HJ. Oncology and aging: general principles of cancer in the elderly. In: Hazzard WR, Blass JP, Halter JB, et al, editors. Principles of geriatric medicine and gerontology. 5th edition. New York: McGraw-Hill; 2003. p. 673–5. [11] Balducci L, Extermann M. Management of cancer in the older person: a practical approach. Oncologist 2000;5:224–37. [12] Extermann M, Aapro M, Bernabei R, et al. Use of comprehensive geriatric assessment in older cancer patients: recommendations from the task force on CGA of the International Society of Geriatric Oncology. Crit Rev Oncol Hem 2005;55:241–52. [13] Solomon D, Brown AS, Brummel-Smith K, et al. National Institutes of Health Consensus Development Conference statement: geriatric assessment methods for clinical decision-making. J Am Geriatr Soc 1988;36:342–7.

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[14] Stuck AE, Siu AL, Wieland GD, et al. Comprehensive geriatric assessment: a meta-analysis of controlled trials. Lancet 1993;342:1032–6. [15] Stuck AE, Egger M, Hammer A, et al. Home visits to prevent nursing home admission and functional declinein elderly people: systematic review and meta-regression analysis. JAMA 2002;287:1022–8. [16] Reuben DB, Frank JC, Hirsch SH, et al. A randomized clinical trial of outpatient comprehensive geriatric assessment coupled with an intervention to increase adherence to recommendations. J Am Geriatr Soc 1999;47(3):269–76. [17] Cohen HJ, Feussner JR, Weinberger M, et al. A controlled trial of inpatient and outpatient geriatric evaluation and management. N Engl J Med 2002;346:905–12. [18] Rich MW, Beckham VT, Wittenburg C, et al. A multidisciplinary intervention to prevent the readmission of elderly patients with congestive heart failure. N Engl J Med 1995;333: 1190–5. [19] Rao AV, Hsieh F, Feussner JR, et al. Geriatric evaluation and management units in the care of the frail elderly cancer patient. J Gerontol: Med Sci 2005;60A:798–803. [20] Ingram SS, Seo PH, Martell RE, et al. Comprehensive assessment of the elderly cancer patient: the feasibility of self-report methodology. J Clin Oncol 2002;20(3):770–5. [21] Hurria A, Gupta S, Zauderer M, et al. Developing a cancer-specific geriatric assessment: a feasibility study. Cancer 2005;104:1998–2005. [22] Extermann M, Meyer J, Mcginnis M, et al. A comprehensive geriatric intervention detects multiple problems in older breast cancer patients. Crit Rev Oncol Hematol 2004;49:69–75. [23] Yancik R, Wesley MN, Ries LA, et al. Comorbidity and age as predictors of risk for early mortality of male and female colon carcinoma patients: a population-based study. Cancer 1998;82(11):2123–34. [24] Yancik R, Wesley MN, Ries LA, et al. Effect of age and comorbidity in postmenopausal breast cancer patients aged 55 years and older. JAMA 2001;285(7):885–92. [25] Passick SD, Dugan W, McDonald MV, et al. Oncologists’ recognition of depression in their patients with cancer. J Clin Oncol 1998;16(4):1594–600. [26] Chodosh J, Petitti DB, Elliot M, et al. Physician recognition of cognitive impairment: evaluating the need for improvement. J Am Geriatr Soc 2004;52(7):1051–9. [27] Extermann M, Overcash J, Lyman GH, et al. Comorbidity and functional status are independent in older cancer patients. J Clin Oncol 1998;16(4):1582–7. [28] Repetto L, Fratino L, Audisio RA, et al. Comprehensive geriatric assessment adds information to Eastern Cooperative Oncology Group performance status in elderly cancer patients: an Italian Group for Geriatric Oncology Study. J Clin Oncol 2002;20(2): 494–502. [29] Fried LP, Tangen CM, Walston J, et al. Cardiovascular Health Study Collaborative Research Group. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci 2001;56(3):M146–56. [30] Ferrucci L, Guralnik JM, Cavazzini C, et al. The frailty syndrome: a critical issue in geriatric oncology. Crit Rev Oncol Hematol 2003;46:127–37. [31] Balducci L, Stanta G. Cancer in the frail patient: a coming epidemic. Hematol Oncol Clin North Am 2000;14:235–50. [32] Audisio RA, Osman N, Audisio MM, et al. How do we manage breast cancer in the elderly patients? A survey among members of the British Association of Surgical Oncologists. Crit Rev Oncol Hematol 2004;52:135–41. [33] Biganzoli L, Goldhirsch A, Straehle C, et al. Adjuvant chemotherapy in elderly patients with breast cancer: a survey of the British International Group. Annal Oncol 2004;15: 207–10. [34] Saliba D, Elliott M, Rubenstein LZ, et al. The Vulnerable Elders Survey: a tool for identifying vulnerable older people in the community. J Am Geriatr Soc 2001;49(12):1691–9. [35] Monson K, Litvak DA, Bold RJ. Surgery in the aged population: surgical oncology. Arch Surg 2003;138(10):1061–7.

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[36] Muss H, Woolf S, Berry D, et al. Cancer and leukemia group B. Adjuvant chemotherapy in older and younger women with lymph node-positive breast cancer. JAMA 2005;293(9): 1073–81. [37] Rose JH, O’Toole EE, Dawson NV, et al. Perspectives, preferences, care practices, and outcomes among older and middle-aged patients with late-stage cancer. J Clin Oncol 2004; 22(24):4907–17. [38] Rao A, Cohen HJ. Symptom management in the elderly cancer patient: fatigue, pain, and depression. J Natl Cancer Inst Monogr 2004;32:150–7. [39] Bukberg J, Penman D, Holland JC. Depression in hospitalized cancer patients. Psychosom Med 1984;46:199–212. [40] Hopwood P, Stephens RJ. Depression in patients with lung cancer: prevalence and risk factors derived from quality-of-life data. J Clin Oncol 2000;18(4):893–903. [41] Cassileth BR, Lusk EJ, Brown LL, et al. Factors associated with psychological distress in cancer patients. Med Pediatr Oncol 1986;14:251–4. [42] Roberts RE, Vernon SW. The Center for Epidemiologica Studies Depression Scale: its use in a community sample. Am J Psychiatry 1983;140:41–6. [43] Montorio I, Izal M. The Geriatric Depression Scale: a review of its development and utility. Int Psychogeriatr 1996;8:103–12. [44] Koenig HG, Cohen HJ, Blazer DG, et al. A brief depression scale for use in the medically ill. Int J Psychiatry Med 1992;22:183–95. [45] Demark-Wahnefried W, Morey MC, Clipp EC, et al. Leading the way in exercise and diet (Project LEAD): intervening to improve function among older breast and prostate cancer survivors. Control Clin Trials 2003;24:206–23. [46] Demark-Wahnefried W, Aziz NM, Rowland JH, et al. Riding the crest of the teachable moment: promoting long-term health after the diagnosis of cancer. J Clin Oncol 2005; 23(24):5814–30. [47] Ingram SS, Seo PH, Sloane R, et al. The association between oral health and general health and quality if life in older male cancer patients. J Am Geriatr Soc 2005;53:1504–9. [48] Hewitt M, Rowland JH, Yancik R. Cancer survivors in the United States: age, health, and disability. J Gerontol A Biol Sci Med Sci 2003;58(1):82–91. [49] Clipp EC, Hollis DR, Cohen HJ. Considerations of psychosocial illness phase in cancer survival. Psychooncology 2001;10(2):166–78. [50] Haley WE. The costs of family caregiving: implications for geriatric oncology. Crit Rev Oncol Hematol 2003;48(2):151–8. [51] Sutton LM, Demark-Wahnefried W, Clipp EC. Management of terminal cancer in elderly patients. Lancet Oncol 2003;4(3):149–57. [52] Lewis JH, Kilgore ML, Goldman DP, et al. Participation of patients 65 years of age or older in cancer clinical trials. J Clin Oncol 2003;21:1383–9. [53] Kemeny MM, Peterson BL, Kornblith AB, et al. Wheeler J. Levine E. Bartlett N. Fleming G. Cohen HJ. Barriers to clinical trial participation by older women with breast cancer. J Clin Oncol 2003;21(12):2268–75. [54] Kornblith AB, Kemeny M, Peterson BL, et al. Cancer and leukemia group B. Survey of oncologists’ perceptions of barriers to accrual of older patients with breast carcinoma to clinical trials. Cancer 2002;95(5):989–96. [55] Yancik R. Integration of aging and cancer research in geriatric medicine. J Gerontol A Biol Sci Med Sci 1997;52(6):M329–32. [56] Balducci L. Geriatric oncology. Crit Rev Oncol Hematol 2003;46:211–20. [57] Monfardini S. Geriatric oncology: a new subspecialty? J Clin Oncol 2004;22(22):4655. [58] Mathias S, Nayak US, Isaacs B. Balance in elderly patients: the ‘‘get-up and go’’ test. Arch Phys Med Rehabil 1986;67(6):387–9.

Med Clin N Am 90 (2006) 983–1004

Palliative Care and Pain Management Laura J. Morrison, MDa,*, R. Sean Morrison, MDb a

Department of Medicine, Section of Geriatrics, Baylor College of Medicine, 1709 Dryden, Suite 850, Houston, TX 77030, USA b Brookdale Department of Geriatrics, Box 1070, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA

Demographic shifts highlight the changing picture of the United States population. By 2030, one in five people will be age 65 and older. Moreover, those 85 and over are the fastest growing segment of the general population. At the same time, most deaths occur in those age 65 and older. As more people live longer, the opportunity to maintain independence, productivity, and health is real and inspiring. In the midst of these later years, however, most older adults will develop a potentially life-limiting illness, sometimes multiple coexisting ones. A typical course is one of chronic illness with gradual functional and cognitive decline and loss of independence caused by increasing morbidity over years, eventually leading to death. Progressive dependence on caregivers is commonly part of this passage. Family members often meet most caregiving needs [1] but suffer the financial and emotional burden of providing this care directly or indirectly [2]. According to a recent study, elderly spouses may be impacted by an increased risk of death associated with the hospitalization of their partner [3]. Multiple sources, including Institute of Medicine reports [4,5] and the SUPPORT [6] and HELP [7] studies, have documented pervasive gaps in care for persons with serious and advanced illness. Specific deficiencies have been demonstrated in symptom control; continuity of care; and unmet spiritual, psychologic, and communication needs for the dying and their loved ones [2,3,6]. The fragmentation of the United States health care system and the resulting strain on the parties involved plays a significant L.J.M. is the recipient of a Geriatric Academic Career Award (K01 HP00117) from the Division of State, Community, and Public Health, Bureau of Health Professions, Health Resources and Services Administration, Department of Health and Human Services. R.S.M. is the recipient of a Mid-Career Investigator Award in Patient-Oriented Research (K24AG022345) from the National Institute on Aging. * Corresponding author. E-mail address: [email protected] (L.J. Morrison). 0025-7125/06/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.mcna.2006.05.016 medical.theclinics.com

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role. One instructive gap is the mismatch surrounding location of death. Although most Americans indicate a desire to die at home, most currently die in the hospital setting [8]. Such disparities have surfaced partly from the sense that the fundamental goals of medicine, to cure or prolong life and to comfort or prevent suffering, are mutually exclusive rather than able to coexist. The field of palliative care has grown in response to this tension and the glaring deficiencies and suffering that has been detailed [9]. Prevention and relief of suffering is the chief goal of palliative care. In current practice, palliative care is the interdisciplinary specialty that focuses on improving quality of life for persons with advanced illness and their families [10]. It is aggressive care that is offered simultaneously with all other appropriate medical treatments. Palliative care practitioners are experts in the domains of communication; symptom management; coordination of care, including hospice and community resources; psychosocial and spiritual realms; grief and bereavement; and legal and ethical concerns. Typical teams may include a physician, nurse, social worker, chaplain, bereavement counselor, volunteer, pharmacist, and others. The story of Mrs. B is illustrative. She is a 79-year-old woman with newly diagnosed recurrent, metastatic breast cancer to bone and liver, osteoporosis, and underlying chronic obstructive pulmonary disease. Whereas her initial breast cancer achieved remission 10 years ago and had little, lasting effect on her daily function, her chronic obstructive pulmonary disease has progressed steadily over the last 20 years, leaving her dependent on oxygen intermittently for the last 5 years and on oral steroids for the last year. With a recent pathologic hip fracture, her pain and dyspnea have become difficult to control. She is much weaker and no longer ambulatory. Constipation, anorexia, and anxiety are active concerns. She remains mentally intact and agrees that her health has declined significantly in the last few weeks. Mrs. B could clearly benefit from assistance in multiple palliative care domains. Her loved ones could receive additional interventions directed to their needs. This case demonstrates how commonly palliative care domains are active issues for elderly patients, especially those approaching the end of life. Clinicians providing care to older adults need to develop palliative care expertise and recognize the critical role of geriatric palliative care in serving this population. This article examines the palliative care domains of communication, management of common symptoms in the geriatric patient, care coordination, psychosocial and spiritual realms, and grief and bereavement. Communication Doctor-patient communication is a cornerstone of palliative care [11]. To prevent and relieve suffering and optimize quality of life, skills to assess patient and family needs and negotiate goals of care are crucial. Not only does good communication increase the likelihood that patient needs will

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be clarified and addressed, it may also be therapeutic in itself by letting the patient tell their story. Studies have shown that improved physician-patient communication correlates with improved emotional well-being of patients [12] and increased patient satisfaction [13]. Unfortunately, the literature also demonstrates significant divergence between an idealized end-of-life communication model and the current reality. During clinical encounters, clinicians typically avoid discussion of goals of care, treatment preferences, and patient values, and neglect to address most patient concerns [14]. This is not surprising given that physicians have received little training directed at care of patients at the end of life during medical school [15]. The communication skill set for palliative care includes four major domains: (1) advance care planning; (2) communicating bad news; (3) negotiating goals of care (prognosis, code status, hospice); and (4) withholding or withdrawing medical treatment. Proficiency in conducting a family meeting is fundamental to all. One might conceptualize these discussions ideally as a four-stage temporal progression toward death: (1) death is hypothetical, (2) death is possible, (3) death is probable, and (4) death is inevitable. Of note, the knowledge and skill domains for these encounters overlap significantly but must be uniquely tailored to a specific clinical situation. Fortunately, communication guidelines for many of these challenging discussions have been established (Fig. 1) [16–19]. Although these strategies have not undergone empiric testing, they are considered to be useful tools in improving clinical practice and are disseminated widely and taught in postgraduate courses that address provider communication skills [17,20]. The literature is clear in supporting certain strategies to achieve good communication. Techniques that improve patient disclosure of issues of concern include establishing eye contact with patients, asking open-ended questions, attending to psychologic content, responding to patient affect, summarizing, and expressing empathy [14]. The patient-centered interview with open-ended questions is emphasized over the physician-centered interview based on closed-ended questions. Some open-ended questions that are suggested to initiate discussion around dying are ‘‘What are your hopes (your expectations, your fears) for the future?’’, ‘‘What has been most difficult about this illness for you?’’, and ‘‘How is treatment going for you (your family)?’’ [21]. At the center of good end-of-life communication is the negotiation of the patient’s goals of medical care. Because the same treatments that are potentially curative and life-prolonging may also cause significant burden, helping patients identify realistic goals is imperative. Not surprisingly, a patient’s goals may shift, waver, and even conflict over time as their disease and the information they understand changes. This may cause frustration for those involved in a patient’s care. It is very important to recognize that such frustration, a warning sign, may indicate a patient’s goals need to be established or revisited. Other warning signs include physician feelings of guilt, anger, or helplessness; physician sense of failure, burden, or

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Fig. 1. Protocols for communicating with patients about major topics in palliative care. (From Morrison RS, Meier DE. Palliative care. N Engl J Med 2004;350:2582–90; Copyright Ó 2004 Massachusetts Medical Society; All rights reserved.)

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disengagement; and prolonged or frequent patient hospitalizations [22]. Here again, open-ended, yet pointed questions can be useful in initiating such discussions: ‘‘What makes life most worth living for you?’’ ‘‘Given the severity of your illness, what is most important for you to achieve?’’ [23]. If goals of care can be clarified, other challenging topics like advance care planning, code status, withholding or withdrawing of medical therapies, and pertinent medical recommendations may become easier to address. For example, if a patient with end-stage renal disease is able to define their goals as (1) being comfortable, (2) avoiding any further medical interventions to prolong life, and (3) staying at home with their family for the time remaining, then recommendations for discontinuation of hemodialysis, Do Not Resuscitate status (alternatively termed ‘‘Allow Natural Death’’), and consideration of hospice are logical next steps.

Symptom management A key domain of palliative care is the focus on optimizing comfort and reducing physical suffering through management of bothersome symptoms. Palliative care clinicians recognize the existence of an extensive list of possible symptoms to address, including common ailments like pain and dyspnea and rare ones like hiccups and pseudobulbar affect. The underrecognition and undertreatment of such symptoms is well documented in the literature. In one study by Walke and colleagues [24], 86% of community dwellers age 60 or older with advanced chronic obstructive pulmonary disease, congestive heart failure, or cancer reported at least one symptom as moderate or severe. Limited activity (61%), fatigue (47%), and physical discomfort (38%) were the most commonly reported symptoms [24]. This review of symptoms focuses on some of the most common and prevalent symptoms in older adults: pain, dyspnea, constipation, and nausea. Table 1 summarizes the approach to management of these and other common palliative care symptoms. Delirium and depression are also addressed more in depth elsewhere in this issue. Pain management People frequently equate suffering with intolerable pain. Likewise, many clinicians use pain as the starting point for a symptom assessment. As significant gaps in pain management have surfaced, some institutions have responded with attempts at system level improvements, most notably the Joint Council on Accreditation of Health Care Organization’s introduction of pain as the fifth vital sign. Despite these efforts, the cancer and noncancer pain literature continues to document a significant burden of suffering for patients in multiple settings [4–6,25]. Certain patient populations are even more at risk, specifically elderly patients, those in nursing homes, and those with dementia. Fortunately, when pain is recognized, more than 80% of

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Assessment and treatment recommendations

Pain







Pain medications should be administered on a standing or scheduled basis. PRN or rescue doses should be available for breakthrough pain or pain not controlled by the standing regimen. All patients on opioids should be started on a bowel regimen. The World Health Organization Analgesic Ladder should be used as a guide for most pain syndromes.

Mild pain (1–3/10 on a 10-point scale): Begin acetaminophen or a nonsteroidal anti-inflammatory agent (consider opioids in older adults). Moderate pain (4–7/10 on a 10-point scale): Begin an opioid combination product (acetaminophen þ codeine, acetaminophen þ oxycodone, acetaminophen þ hydrocodone) and dose based on opioid halflife (3–4 hours) not acetaminophen halflife (6–8 hours). Acetaminophen dose should not exceed 4 g in 24 h. Severe pain (8–10/10): Begin a strong standing opioid (hydromorphone, morphine sulfate, oxycodone) and titrate until pain relief is obtained or intolerable side effects develop. Long-acting opioids (sustained-release morphine or oxycodone, transdermal fentanyl) should be started after pain is well controlled and steady state is achieved. Methadone should only be used by clinicians experienced in its use. Rescue doses using immediate-release opioids should be 10% of the 24-hour total opioid dose and given every hour (oral) and every 30 min (parenteral) as needed. Adjuvant agents (corticosteroids, anticonvulsants, tricyclic antidepressants, bisphosphonates) should be used for specific pain syndromes when applicable (eg, neuropathic pain).

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Table 1 Approach to the management of pain and other common symptoms in palliative care

Anorexia or cachexia

Anxiety

Delirium

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Constipation


Assess whether symptom is caused by disease process or secondary to other symptoms (nausea, constipation).
Determine if patient is troubled by the symptom before initiating pharmacologic therapy.
Effective pharmacologic therapies include: Megestrol acetate, 400–800 mg daily Dexamethasone, 4–10 mg daily.
Common in patients with advanced illness.
Signs and/or symptoms include restlessness, agitation, insomnia, hyperventilation, tachycardia, and excessive worry.
Effective therapies include supportive counseling, or therapy, and benzodiazepines.
Benzodiazepines with long half-lives (diazepam, clonazepam) should generally be avoided in the elderly.
Regular and routine assessment of constipation is critical, particularly for patients on opioids.
All patients should be evaluated for fecal impaction before initiating therapy.
Patients underreport constipation, and life-threatening complications of fecal impaction and perforation can develop quickly if regular bowel movements are not maintained.
Most patients respond to a stool softener plus escalating doses of a stimulant.
If dose escalation of the stimulant proves ineffective, agents from alternate classes should be added.
Pharmacologic agents include: Stool softeners (ineffective alone and should be combined with other agents): docusate sodium, calcium docusate Stimulant laxatives: prune juice, senna, bisacodyl Osmotic laxative: lactulose, propylene glycol, milk of magnesia, magnesium citrate Large-volume tap water enemas, high-colonic enemas, or disimpaction may be needed in cases of severe constipation
Delirium is an acute onset of change in cognition characterized by disorientation, changes in level of consciousness, minute-to-minute fluctuations, and is usually reversible.
Treatment should be directed at identifying the underlying cause and managing symptoms.
Behavioral therapies include: Reducing excess stimulation, frequent reorientation, reassurance, ensuring presence of family caregivers
Pharmacologic therapies include: Haloperidol, risperidone, olanzapine Chlorpromazine can be used for agitated or terminal delirium Benzodiazepines have been found to exacerbate delirium and should be avoided (continued on next page)

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Table 1 (continued ) Assessment and treatment recommendations

Depression


Depression is not normal in the setting of serious illness and should be regularly assessed.
The question ‘‘Are you depressed?’’ is a sensitive and specific question for patients with advanced illness.
Reliable symptoms include feelings of helplessness, hopelessness, anhedonia, loss of self-esteem, worthlessness, persistent dysphoria, and suicidal ideation.
Somatic symptoms are not reliable indicators of depression in this population.
Supportive psychotherapy, cognitive approaches, behavioral techniques, and pharmacologic therapies have all been shown to be effective for treatment of depression in patients with advanced disease.
Patients should be asked specifically about suicidal ideation, which often represents a measure of extreme distress in patients with advanced illness.
Choice of pharmacologic therapy is often dictated by the patient’s estimated life expectancy: Psychostimulants (eg, methylphenidate, dextroamphetamine) provide rapid treatment of symptoms (within days) with minimal side effects. Selective serotonin reuptake inhibitors are highly effective but may require 3–4 weeks to take effect. Tricyclic antidepressants are relatively contraindicated because of their side effect profile.
Evaluate and treat reversible causes if possible.
Pharmacologic management includes: Oxygen provides relief of dyspnea in circumstances of hypoxia but has also been shown to provide symptomatic relief in situations where hypoxia is not present. A cool breeze across the face (either from oxygen or a fan) has been shown to decrease breathlessness through stimulation of the V2 branch of the trigeminal cranial nerve. Opioids significantly reduce breathlessness in randomized controlled trials without measurable reductions in respiratory rate or oxygen saturation. Effective doses are often lower than those used to treat pain and tolerance has not been demonstrated to be a clinical problem. Anxiolytics: Anxiety and breathlessness are tightly intertwined. Anxiety may worsen breathlessness and breathlessness may heighten anxiety. Low-dose benzodiazepines, reassurance, relaxation, distraction, and massage therapy may decrease anxiety and improve breathlessness.

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Symptom

Nausea

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Nausea is mediated through several mechanisms and successful treatment is dependent on identifying the specific cause.
Chemoreceptor trigger zone stimulation: Causes include: drugs (opioids, digoxin, estrogen, chemotherapy agents); biochemical disorders (hypercalcemia, uremia); toxins (tumor-produced peptides, infection, radiotherapy, abnormal metabolites) Effective pharmacologic agents include: Butyrophones/phenothiazines: (e.g., haloperidol, prochlorperazine); Prokinetic agents: (e.g., metoclopramide); Serotonergic antagonists: (e.g., odansetron); Atypical neuroleptics (olanzapine)
Gastric stimulation: Causes include: gastric irritation (drugs, alcohol, iron, mucolytics, expectorants, blood); tumors (external compression, intestinal obstruction, constipation, liver capsule stretch, upper bowel, genitourinary, and biliary stasis, peritoneal inflammation, cardiac pain); gastric distension (opioid induced stasis). Effective pharmacologic agents include: Antihistamines (e.g., diphenhydramine); Serotonergic antagonists (e.g., odansetron); Prokinetic agents (e.g., metoclopramide); Cytoprotective agents (e.g., ranitidine, omeprazole).
Delayed gastric emptying/squashed stomach: Effective pharmacologic agents include: metoclopramide and cisapride (if not contraindicated)
Non- surgical bowel obstruction: Effective pharmacologic agents include: octreotide is effective both for nausea and for abdominal pain resulting from bowel obstruction
Intracranial processes: Causes include: increased central nervous system pressure, anticipatory nausea Effective pharmacologic agents include: corticosteroids, benzodiazepines
Vestibular vertigo: Causes include: local tumors, opioids, motion sickness Effective pharmacologic agents include: Acetylcholine antagonists (transdermal scopolamine, meclizine)

Adapted with permission, 2006. Morrison RS, Meier DE. Palliative care. N Engl J Med 2004;350:2582–90. Copyright Ó 2004 Massachusetts Medical Society. All rights reserved.

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patients with pain can be brought under control with a basic approach. At most, 20% of cases or less require the attention of a clinician with advanced expertise in pain management. Pain control starts with routine screening and assessment for pain. Pain is a subjective sensation that cannot be objectively validated; clinicians must rely principally on patient self-report. Studies have shown that the use of assessment scales is helpful. Multiple tools have been created for this purpose, including the familiar 0 to 10 verbal scale, written instruments, and other scales for special populations like children and nonverbal patients. The guiding principle with assessment scales is fitting the scale to the individual and using the tool consistently for serial assessment. For example, some elderly patients find the three-component scale of mild-moderate-severe easier to use than a 0 to 5 or 0 to 10 scale. By using the same scale serially, the clinician can judge pain control over time, determine retrospective bests and worsts, set reasonable goals, and foster patient trust. The World Health Organization Analgesic Ladder [26] provides a general framework for choosing an approach to pain management in the setting of chronic illness. The starting point for mild pain is acetaminophen, nonsteroidal anti-inflammatory medications, and less commonly aspirin. For moderate pain, weak opioids and combination products like hydrocodone-acetaminophen, oxycodone-aspirin, and tramadol are recommended. Of note, medications in both of these categories have ceiling doses based on maximum daily doses of acetaminophen, nonsteroidal anti-inflammatory medications, and aspirin to prevent possible end-organ damage. For severe pain, strong opioids like morphine, hydromorphone, fentanyl, and oxycodone are recommended. Opioid medications have no ceiling dose. Dosing is guided by past exposure to opioid medications and systematic dose escalation based on pain. For mild, moderate, and severe pain categories, consideration of nonpharmacologic treatments like massage, aromatherapy, and music therapy, adjuvant medications like anticonvulsants, antidepressants, and steroids, and interventional procedures, if indicated, is recommended. Propoxyphene and meperidine should be avoided, especially in the elderly population, because pain control is inferior to other agents, and metabolites may build up to cause neurotoxicity and lower the seizure threshold. For the patient with pain in advanced illness, a regimen of scheduled or standing dose pain medication is indicated. For moderate pain or rapid dose escalation in uncontrolled pain, short-acting opioids are recommended. For moderate to severe pain, short-acting opioids can be converted to long-acting opioids once pain is well controlled. Rescue or as-needed doses should always be ordered or available to address breakthrough pain, pain not controlled by the scheduled medication. Rescue dosing is based on a shortacting opioid dose of 10% of the 24-hour total opioid dose prescribed every 30 minutes intravenously or every hour orally. Additionally, a bowel regimen should be instituted with the initiation of any level of opioid therapy.

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Opioid medications are part of basic pain management, and clinicians need to be knowledgeable about prescribing practices, comfortable with dose titration, and familiar with issues of tolerance, dependence, addiction, and pseudoaddiction to use them effectively. Tolerance is a pharmacologic property that describes the need for a higher dose of medication to achieve the same effect over time. It also occurs with nonopioid medications. This is best understood in the context of opioid side effects. Sedation and nausea are common opioid side effects but ones to which tolerance develops over hours to a few days. By contrast, constipation is an opioid side effect to which very few people develop tolerance. For this reason, with few exceptions, all patients started on opioids should receive a laxative. Interestingly, people seem to develop little tolerance to the analgesic properties of opioids; thus, when pain worsens significantly or suddenly, other reasons should be considered first. Disease progression is often the underlying cause. Patient education regarding tolerance and potential side effects is crucial when initiating any opioid medication, particularly in the elderly where side effects may have more physiologic impact. Dependence is also a pharmacologic property common to opioid and nonopioid medications. Dependence occurs when abrupt cessation of a medication causes a patient to experience unpleasant or dangerous effects like nausea, fever, hypertension, or tachycardia. In the case of opioids, such a withdrawal syndrome is not usually life-threatening. Opioid dependence can develop over days to weeks of consistent exposure. Again, patient education is important to help people avoid barriers to obtaining their opioid medication, like finding a pharmacy that carries the medication, and maintain adherence to the regimen. Withdrawal can be avoided by a gradual taper of medication over days, usually recommended at 50% dose decrease per day or slower. Fears of addiction by both clinician and patient can be a major barrier to opioid use, particularly in the elderly [27], and can contribute to poor pain control. Education is a key factor for both parties. Addiction is the continued use of a substance despite persistent negative consequences or harm usually for nonanalgesic effects. Clinicians are highly sensitized to issues of addiction through oversight by regulatory agencies at the state and federal level. Conversely, physicians are obligated to treat pain and relieve suffering for those with serious chronic illness; this professional duty has been repeatedly espoused by national physician organizations and is the standard of care. Importantly, when physicians address pain in patients without a history of substance abuse with appropriate assessment, escalation of dosing, and follow-up over time, opioid addiction is very rare. In the setting of the seriously ill patient with pain and addictive-type behaviors, the phenomenon of pseudoaddiction should be considered. Pseudoaddiction occurs when a patient exhibits behaviors typical of addiction (watching the clock, requests for dose escalations, persistent pain complaints) in response to uncontrolled pain [28]. It is an iatrogenic phenomenon in that undertreatment of real pain creates the behavior. The true test

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in this situation is to systematically treat the pain and monitor to see if the behaviors in question disappear with better control. Dyspnea Dyspnea is another very common symptom for patients with chronic progressive illnesses, especially those with advanced lung disease. Similar to pain, dyspnea is often unrecognized and underreported, and identification and assessment depends on patient perception and self-report. Assessment scales can also be used for dyspnea when addressing subjective intensity. Here again, serial assessment using the same scale for a given patient is most useful. In other cases, measures of functional capacity may be more useful, (eg, New York Heart Association Classification for congestive heart failure). Dyspnea is a subjective discomfort around breathing. It can vary with activity and be described in different ways, commonly as shortness of breath, trouble catching one’s breath, chest tightness, and sensation of smothering or suffocation. Dyspnea has clear emotional and psychologic components and may exacerbate and be exacerbated by such fear, anxiety, and depression. Because prevalence is high and commonly increases toward the end of life, patients with advanced lung disease and cardiac disease should be screened and assessed for dyspnea. The SUPPORT trial [6] found that 32% and 56% of patients with severe chronic obstructive pulmonary disease and stage III-IV non–small cell lung cancer, respectively, had severe dyspnea [29]. Surrogates for patients with congestive heart failure in the last 6 months of life reported that 63% were severely short of breath in the 3 days before death [30]. Uncontrolled dyspnea impairs quality of life for patients and causes significant distress for caregivers. As death approaches, patients and caregivers are commonly concerned about the patient suffocating or gasping for air, perceiving this a suffering. Clinicians may be asked to provide specific interventions to prevent this from happening. As with other symptoms, it is best to manage dyspnea by treating the underlying cause if possible (eg, thoracentesis for pleural effusion or diuresis for pulmonary edema). The elderly population presents unique challenges because other common medical issues like hypothyroidism, anemia, and deconditioning may blur the exact etiology of dyspnea. Symptom-directed management is indicated during the diagnostic work-up and optimal disease-specific treatment (eg, pulmonary rehabilitation for chronic obstructive pulmonary disease). Oxygen, opioids, and anxiolytics are the main components of dyspnea management. Oxygen should be used therapeutically when patients exhibit hypoxemia with appropriate titration. In patients without hypoxia, oxygen can also be used for symptomatic relief. A decreased sense of breathlessness, or air hunger, is credited to airflow stimulation of receptors in the face and nasal passages. Airflow from directed fans and from open windows across

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the face is thought to act similarly in supplementing this effect and can be quite helpful for some patients. Of note, for patients benefiting from oxygen therapy who do not meet Medicare reimbursement criteria for home oxygen therapy, the Medicare Hospice Benefit covers such costs on enrollment. Opioid medications are very effective for some patients with dyspnea and work by decreasing the central perception of air hunger. However, the literature shows inconsistent findings for efficacy of opioid use. Current recommendations support a trial of opioids for dyspnea in terminally ill cancer patients with difficult-to-manage dyspnea and in patients with advanced lung disease who also have pain [31,32]. The burden of opioid-related side effects may outweigh the benefit of therapy for ambulatory patients, and the evidence for opioid use in patients with dyspnea from nonmalignant advanced lung disease is less clear [32]. Morphine is commonly used for dyspnea, although the literature supports similar efficacy with other opioid medications. Dosing depends on the symptom burden and the patient’s history of opioid exposure. Asneeded oral dosing is reasonable initially but scheduled medication is more appropriate for chronic dyspnea. Breakthrough dosing, short-acting opioids, and long-acting opioids should be prescribed for dyspnea in a similar fashion to the approach previously described for pain management. For uncontrolled dyspnea in an opioid-naive older adult, morphine sulfate, 2–5 mg intravenously or subcutaneously every 10 to 15 minutes until improvement, is a reasonable starting point. In any case, it is important to use the lowest possible effective dose of opioid medication and titrate the bowel regimen accordingly. Concerns about opioids and respiratory depression are common among clinicians and the public and contribute to poor symptom control. People fear that respiratory depression can hasten death. Although opioids can cause sedation and respiratory depression, careful and systematic titration of these medications should keep patients safe. Moreover, a progression from somnolence and confusion to sedation always precedes respiratory depression and serves as a warning sign that a decreased dose and closer monitoring is indicated [33]. The use of opioid medications is ethical and standard of care for patients with symptom distress as long as the primary intent is relief of suffering. In fact, there is no legal or ethical justification for withholding such treatment from a dying patient in distress [34]. Anxiolytic medications should also be considered in the management of dyspnea, particularly short-acting benzodiazepines like lorazepam and alprazolam. The few studies that address efficacy of benzodiazepines in treating dyspnea have shown mixed results. Given the potential side effects of sedation and confusion, especially in geriatric patients, these medications should also be used with caution. In the case of refractory dyspnea or in patients with significant components of anxiety, however, titration of initial low-dose short-acting benzodiazepines may be appropriate.

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Constipation Constipation is common in advanced illness and the prevalence increases with age. In addition, the consequences of constipation can be substantial ranging from mild annoyance to nausea and abdominal pain to fecal impaction and even death from colon perforation. For this reason, screening and assessment of bowel function should be a routine part of all geriatric patient encounters. Multiple objective criteria for constipation exist; however, given the wide variation in individual bowel habits, deviation from an individual’s normal bowel function may be the best indication of constipation [35]. Treatment of constipation should be systematic. Opioids are common culprits, although many other medication types may also contribute (eg, anticholinergic agents, calcium, and iron). The minimum effective dose of all such medications should be used to lessen the pharmacologic contribution to constipation. All patients on opioids need to receive a prophylactic bowel regimen of stool softener (eg, docusate sodium) and stimulant laxative (eg, dulcolax, senna), unless diarrhea is an issue, titrated to an effective dose. Osmotic laxatives (eg, sorbitol, lactulose) and enemas can also be added if needed. In those presenting with constipation, the threshold for performing a digital rectal examination or abdominal radiograph to check for fecal impaction or obstruction, respectively, should be low. A rectal examination should be performed if no stool has passed in 3 to 4 days. An abdominal radiograph is indicated if constipation persists with an empty rectal vault on examination or abdominal symptoms and signs like abdominal distention, discomfort, and nausea. In the case of fecal impaction, manual disimpaction or enemas should precede the start of oral laxatives. Depending on radiographic findings, bowel rest and decompression may be required. Finally, given that opioid tolerance does not develop for constipation, a patient’s laxative regimen should be titrated up or down with the opioid dosing. The goal of treatment is to achieve minimal straining and comfortable defecation [35]. Nausea Of patients with a terminal illness, 60% experience nausea and 30% vomiting [36]. Before treating, it is important to clarify the likely causes, realizing these symptoms are commonly caused by multiple factors, including a disease process itself or various therapies. If a probable cause with a physiologic mechanism can be identified, however, chances are higher for choosing an effective antiemetic regimen of one or more medications. Emesis is mediated by neurotransmitter signals and other stimuli that are communicated from the chemoreceptor trigger zone, the vestibular apparatus, the cerebral cortex, and the gut to the brain’s vomiting center. These pathways show different levels of dopamine, serotonin, acetylcholine, histamine, and muscarine activity. The chemoreceptor trigger zone, in the

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area postrema of the fourth ventricle of the brain, is a central pathway that senses chemical stimuli to nausea and vomiting, like opioids, uremia, and hypercalcemia. This central nausea is often responsive to dopamine antagonists like haloperidol, prochlorperazine, chlorpromazine, and metoclopramide. Serotonin antagonists, such as odansetron and granisetron, may also be effective in this setting and are often superior agents for nausea from gut irritation like that caused by chemotherapy and radiotherapy. Metoclopramide is also a prokinetic agent and may be useful for impaired gut motility like that caused by gastroparesis. Muscarinic blockers (eg, scopolamine) and anticholinergics (eg, meclizine) may counteract vestibular nausea. Antihistamines, such as promethazine and hydroxyzine, can be used as adjuvants to other antiemetics because of potential activity at multiple physiologic sites. Importantly, many of the antiemetics previously listed, especially antihistamines and anticholinergics, should be used with caution in older adults because of possible side effects like sedation and delirium. Other medications may also be useful in relieving nausea and vomiting. Corticosteroids have potent intrinsic antiemetic activity and should be routinely considered. They may also counteract nausea and vomiting by decreasing intracranial pressure and decreasing local gut inflammation specifically. Directed treatment of exacerbating factors like anxiety, constipation, and reflux disease may also be helpful. Coordination of care Another important domain of palliative care is the coordination of chronic disease care. Given the current disarray and discontinuity of the health care system and the diverse needs of patients with advanced illness and their families, clinicians need to be knowledgeable about and able to coordinate their local options for social and medical services. Comprehensive care models may be an excellent choice for many patients, including the elderly, but they exist in different forms and may be difficult to access because of geographic variability. Palliative care Comprehensive palliative care programs are becoming increasingly prevalent across the United States. Currently, however, access to palliative care varies by clinical setting and region of the country. Interdisciplinary palliative care teams are present in many hospitals, nursing homes, clinics, and homecare programs sometimes providing primary care but more commonly assisting primary physicians with care. Fortunately, attention to palliative care at the national level has fueled rapid growth in palliative care through foundation support and multiple educational, research, and clinical initiatives. The Center to Advance Palliative Care [37], a central resource and support for those trying to improve existing or start up new palliative

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care programs, is a product of these efforts. The growth has been measurable [38,39]. From 2000 to 2003, the number of United States hospitals with palliative care programs increased from 15% to 25% [38]. Hospice The overlap between palliative care and hospice is important to delineate. It is helpful to remember that the larger body of palliative care as it is today takes its roots from the original hospice movement that began in the United States in the 1970s. Hospice is a key subset of palliative care. In this sense, all those receiving hospice are receiving palliative care, but not all those receiving palliative care are receiving hospice. A number of facets make hospice distinct. First, the structure of hospice in the United States is defined by the Medicare Hospice Benefit, a system of capitated care initiated by Congress in 1982. Only patients with Medicare A may access this benefit. Four levels of care and per diem reimbursement are defined: (1) inpatient care, (2) continuous care, (3) home care, and (4) respite. Medicaid and many commercial insurers have similarly structured benefits. Second, patients must meet specific eligibility criteria for enrollment. A referring physician must certify a 6-months or less prognosis if the disease follows its natural course. An attending physician must be responsible for the patient’s hospice care, either the referring physician or the hospice medical director. The patient or proxy must then elect the benefit indicating the preference for palliative goals of care. This is generally at the exclusion of potentially life-prolonging or disease-modifying interventions, although some hospices have evolved a broader definition of ‘‘palliative’’ to include therapies like blood transfusions and tube feeding. Patients are recertified for hospice at regular intervals and can always revoke the benefit if goals of care change. Finally, more than 90% of hospice care occurs in the home setting, usually a private residence or nursing home. If acute symptom issues arise, patients may be transferred to an inpatient setting for management. Familiarity with what services are provided by hospice is critical for clinicians taking care of older persons. Hospice affords access to an interdisciplinary team, including at minimum a physician, nurse, home health aide, social worker, chaplain, volunteer, and bereavement counselor, that formulates a biweekly plan of care. All indicated medications, tests, other treatments, and durable medical equipment are then provided at no cost as long as they are related to the terminal diagnosis and palliative in nature. Bereavement support for family and other loved ones is provided for 13 months after a patient’s death. As part of the increased focus on end-of-life care, hospice programs, like palliative care programs, have expanded significantly in the United States. From 2000 to 2004, the number of hospice programs nationally grew from 3100 to 3650 and the milestone of 1 million patients cared for annually was achieved [40]. Significant efforts have also been undertaken to standardize

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and improve performance of hospices [41]. Looking closer at hospice quality and performance, a 2004 study suggested that Medicare beneficiaries with certain terminal illnesses, including congestive heart failure, chronic obstructive pulmonary disease, and some cancers, who elect the Medicare Hospice Benefit had lower costs and longer mean survival time than controls who did not elect the Benefit [42]. These findings clearly challenge the common misconception that hospice is only about dying and may help some patients and physicians make the transition to hospice more easily. Program of All-Inclusive Care of the Elderly The Program of All-Inclusive Care of the Elderly (PACE) is a comprehensive care program [43]. This program is a capitated Medicare and Medicaid benefit that provides comprehensive, interdisciplinary medical and social care for frail elders. It grew out of a demonstration project in the mid1980s to official status in 1997, now with 35 sites across the United States. Most care occurs in the adult day care setting, but inpatient, home, and nursing home settings are used as patient needs change. Palliative care is part of this full spectrum of care, because these patients are not eligible for the Medicare Hospice Benefit while enrolled in PACE. Multiple outcome measures have shown this program to be quite successful, including lowered rates of hospitalization and death in hospital for these patients [44], and the number of sites is expanding. Psychosocial and spiritual realms Addressing the psychosocial and spiritual needs of patients and families is a core component of palliative care. Patients may experience suffering that is not physical. The important concept of total pain was put forth by hospice pioneer Cicely Saunders [45] when she described that pain and suffering may comprise spiritual, social, emotional, psychological, and physical elements. Nonphysical suffering can take a toll. For some patients, concerns like guilt, hopelessness, fear, and loss may lead to significant distress, even contributing to worsened physical symptoms (ie, pain and anxiety). Loved ones may manifest similar distress. Spouses experiencing emotional and psychological distress have shown increased morbidity and mortality, especially those who are in the caregiver role [46]. Spiritual and religious beliefs can also play a prominent role in treatment decisions for patients and families, especially with regard to initiation and continuation of life-prolonging therapies. Physicians may find their treatment recommendations at odds with patient and family decisions based on religious reasons. Although difficult, respectful listening and continued caring are usually the best approach. Evidence suggests that most patients would welcome a physician-initiated discussion about their spiritual or religious beliefs if they became gravely ill;

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furthermore, most would view this inquiry as increasing their trust in the doctor [47]. When patients are critically ill or dying, the first step for the clinician is to identify spiritual concerns and potential distress. Experts agree that the next steps are to listen empathetically and provide support while not trying to fix existing distress or conflict [48]. Initiating such discussions can be challenging. One suggested entrance to patient spiritual concerns is ‘‘Are you at peace?’’ [49]. Other opening questions, such as ‘‘What has given you strength in the past during difficult times?’’ and ‘‘Do you consider yourself spiritual or religious?’’ may also be helpful. FICA is a mnemonic that suggests an ordered approach to spiritual history taking with multiple questions suggested for each category: Faith or beliefs (eg, What is your faith or belief?); Importance and influence (eg, What role do your beliefs play in regaining your health?); Community (eg, Are you part of a spiritual or religious community?); and Address (eg, How would you like your provider to address these issues in your health care?) [50,51]. Depending on the setting and availability, chaplains and social workers can often provide physicians with very helpful resources and expertise in exploring these realms.

Grief and bereavement Palliative care also attends to issues of grief and bereavement support. Loss through death is a common experience; thus, health care providers have many opportunities to provide bereavement care. Although many physicians lack confidence in this area [52], clinicians caring for older patients, in particular, should be skilled in identifying those bereaved persons at high risk for complicated grief and those who need treatment. Clinicians are exposed to a spectrum of bereavement in their patients before death and in patients’ loved ones before and after the death. Normal grief predominates but complicated grief may occur in 10% to 20% of bereaved persons [53]. Complicated grief lasts at least 6 months after a death. Defining features include a preoccupation with often distressing thoughts of the loved one and their death, bitterness and a sense of disbelief about the death, avoidance behavior, and persistent pangs of emotional pain and yearning for the deceased [52]. The bereaved person is unable to resume a normal routine because of substantial functional impairment. With an estimated five bereaved persons per death, this suggests that more than 1 million people in the United States are expected to develop complicated grief annually [53]. Accessing grief and bereavement support may be very difficult for some because of regional, socioeconomic, and cultural variation. In many cases, hospice enrollment may be a way to fill this gap with the 13 months of postdeath bereavement support. Whether through the hospice pathway or another resource, psychiatric referral is indicated for patients with complicated grief. Although formal strategies for treating complicated grief are used, few studies have tested their outcomes. This trend, however, may

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be changing; a recent study suggests that a targeted complicated grief treatment program can achieve a higher and more rapid response rate compared with interpersonal psychotherapy [53]. Summary Palliative care aims to improve quality of life and relieve suffering for patients with advanced illness and those close to them by specifically addressing communication, symptom management, coordination of care, psychosocial and spiritual realms, grief and bereavement support, and legal and ethical concerns. It has an interdisciplinary focus and may co-exist with curative and lifeprolonging treatment. Palliative care is a key component of appropriate, routine medical care, especially for clinicians caring for older adults. In revisiting Mrs. B, the many needs of a typical elderly patient are apparent, as are the gaps in the current level of care. A discussion of prognosis and goals of care is a potential starting point. This includes obtaining input from an oncologist with regard to treatment options for Mrs. B’s metastatic breast cancer and her pathologic hip fracture. Soliciting her treatment goals in the context of her chronic obstructive pulmonary disease and significant recent decline is the next challenge. Pain, dyspnea, constipation, anorexia, and anxiety could then be addressed with pointed assessment and symptom-specific management. Code status discussion, communication with her support network, and care coordination for her increased care needs would follow. Hospice should be introduced as a potential option. Advance care planning might also be initiated. Psychological and spiritual support needs could also be explored in time. Clearly, there is much to be done for Mrs. B and her loved ones in clarifying and coordinating whatever path comes to be. Older patients and their families face prolonged courses of chronic disease and gradual decline. Physicians caring for these patients need to be expert in the domains of palliative care so these patients and their families can receive the best quality of care while they are still living full lives and later as they approach the end of life. References [1] Emanuel EJ, Fairclough DL, Slutsman J, et al. Assistance from family members, friends, paid care givers, and volunteers in the care of terminally ill patients. N Engl J Med 1999; 341:956–63. [2] Emanuel EJ, Fairclough DL, Slutsman J, et al. Understanding economic and other burdens of terminal illness: the experience of patients and their caregivers. Ann Intern Med 2000;132: 451–9. [3] Christakis NA, Allison PD. Mortality after the hospitalization of a spouse. N Engl J Med 2006;354:719–30. [4] Field MJ, Cassel CK, editors. Approaching death: improving care at the end of life. Washington: National Academy Press; 1997.

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[5] Foley KM, Gelband H, editors. Improving palliative care for cancer. Washington: National Academy Press; 2001. [6] The SUPPORT Principal Investigators. A controlled trial to improve care for seriously ill hospitalized patients: the Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments (SUPPORT). JAMA 1995;274:1591–8 [erratum: JAMA 1996; 275:1232]. [7] Wu AW, Yasui Y, Alzola C, et al. Predicting functional status outcomes in hospitalized patients aged 80 years and older. J Am Geriatr Soc 2000;48(Suppl 5):S6–15. [8] The Gallup Organization. Knowledge and attitudes related to hospice care. Survey conducted for the National Hospice Organization. Princeton (NJ): The Gallup Organization; 1996. [9] Morrison RS, Meier DE. Palliative care. N Engl J Med 2004;350:2582–90. [10] National Consensus Project for Quality Palliative Care. Clinical practice guidelines for quality palliative care, 2004. Available at: http://www.nationalconsensusproject.org. Accessed March 26, 2006. [11] Steinhauser KE, Christakis NA, Clipp EC, et al. Factors considered important at the end of life by patients, family, physicians, and other care providers. JAMA 2000;284:2476–82. [12] Roter DL, Hall JA, Kern DE, et al. Improving physicians’ interviewing skills and reducing patients’ emotional distress: a randomized clinical trial. Arch Intern Med 1995;155:1877–84. [13] Tierney WM, Dexter PR, Gramelspacher GP, et al. The effect of discussions about advance directives on patients’ satisfaction with primary care. J Gen Intern Med 2001;16:32–40. [14] Tulsky JA. Doctor-patient communication. In: Morrison RS, Meier DE, editors. Geriatric palliative care. New York: Oxford University Press; 2003. p. 314–31. [15] Sullivan AM, Lakoma MD, Block SD. The status of medical education in end-of-life care: a national report. J Gen Intern Med 2003;18:685–95. [16] Buckman R. How to break bad news: a guide for health care professionals. Baltimore: Johns Hopkins University Press; 1992. [17] The EPEC Project. Education in palliative and end-of-life care. Available at: http://www. epec.net. Accessed March 26, 2006. [18] Ambuel B, Weissman DE. Conducting a family conference. Fast fact and concept #16. 2nd edition. August 2005. End-of-Life Physician Education Resource Center (EPERC). Available at: http://www.eperc.mcw.edu. Accessed March 26, 2006. [19] Von Gunten CF. Discussing hospice. Fast fact and concept #38. 2nd edition. August 2005. End-of-Life Physician Education Resource Center (EPERC). Available at: http://www. eperc.mcw.edu. Accessed March 26, 2006. [20] Harvard Medical School Center for Palliative Care. Practical aspects of palliative medicine: integrating palliative care into clinical practice. Available at: http://www.hms.harvard.edu/ cdi/pallcare. Accessed March 26, 2006. [21] Lo B, Quill T, Tulsky J. Discussing palliative care with patients. Ann Intern Med 1999;130: 744–9. [22] Meier DE, Back AL, Morrison RS. The inner life of physicians and care of the seriously ill. JAMA 2001;286:3007–14. [23] Quill TE. Perspectives on care at the close of life: initiating end-of-life discussions with seriously ill patients: addressing the ‘‘elephant in the room.’’ JAMA 2000;284:2502–7. [24] Walke LM, Gallo WT, Tinetti ME, et al. The burden of symptoms among community-dwelling older persons with advanced chronic disease. Arch Intern Med 2004;164:2321–4. [25] Bernabei R, Gambassi G, Lapane K, et al. Management of pain in elderly patients with cancer. JAMA 1998;279:1877–82 [erratum: JAMA 1999;281:136]. [26] World Health Organization Pain Ladder. Available at: http://www.who.int/cancer/ palliative/painladder/en/. Accessed March 26, 2006. [27] Portenoy RK. Opioid therapy for chronic non-malignant pain: current status. In: Fields HL, Libeskind JC, editors. Pharmacological approaches to the treatment of chronic pain: new

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Andropause: A Quality-of-Life Issue in Older Males Matthew T. Haren, PhDa,b, Moon Jong Kim, MDc, Syed H. Tariq, MDa,b, Gary A. Wittert, MB, BChd, John E. Morley, MD, BCha,b,* a

Division of Geriatric Medicine, Saint Louis University School of Medicine, 1402 South Grand Boulevard, M238, St. Louis, MO 63104, USA b Veterans Affairs Medical Center, GRECC, #1 Jefferson Barracks Dr., St. Louis, MO 63125, USA c Department of Family Medicine, Pochon CHA University, 351 Yatup-dong, Bundang-gu, Sungnam-si, Kyonggi-do, 463-712, Seoul, South Korea d Department of Medicine, University of Adelaide, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000

Introduction Andropause or androgen deficiency in aging men is a condition in which low levels of testosterone in an older man are associated with a decrease in sexual satisfaction or a decline in a feeling of general well-being [1–3]. Cross-sectional and longitudinal studies have demonstrated that testosterone levels decline at a rate of approximately 1% per year after the age of 30 years [4–9]. Because of the increase of sex hormone-binding globulin (SHBG) levels with aging there is an even greater decline in the free or bioavailable testosterone levels with aging. In this article we discuss the pathophysiology of testosterone decline with aging; the problems in the determination of biochemically meaningful testosterone deficiency; testosterone’s relationship to sexual activity, sarcopenia, physical function, and cognitive function; the development of diagnostic questionnaires; and the methods of treatment of male hypogonadism. It should be recognized that this is a complex and controversial syndrome with limited numbers of studies. Thus, all conclusions should be considered tentative until the completion of larger studies [10].

* Corresponding author. Division of Geriatric Medicine, Saint Louis University School of Medicine, 1402 South Grand Boulevard, M238, St. Louis, MO 63104. E-mail address: [email protected] (J.E. Morley). 0025-7125/06/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.mcna.2006.06.001 medical.theclinics.com

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The pathophysiology of late-onset hypogonadism In young people the most common form of hypogonadism is testicular failure characterized by a decrease in testosterone and an increase in luteinizing hormone (LH). In older people testosterone levels decrease but rarely to the levels seen in primary hypogonadism in young men. This decrease is associated with only a small increase in LH, except late in life [4,11]. The prevalence of hypogonadism has been estimated to be between 2% to 5% at 40 years of age and 30% to 70% by 70 years of age [12]. It is estimated that at least 5 million men in the United States have hypogonadism, with less than 10% receiving hormone replacement. The causes of late-life hypogonadism are multifactorial [13–15]. Defects have been shown to occur at the level of gonadotrophin-releasing hormone (GnRH) pulse generator in the hypothalamus, the pituitary, and the testes. With aging there is a decrease in Leydig cells and the testicular response to stimulation with human chorionic gonadotropin. The negative feedback of testosterone at the pituitary level increases with aging. There is a decreased pulse generation of GnRH, with the pulses being generated more chaotically. It is the combination of these factors that leads to the age-related decline in testosterone level. In addition, with aging the normal circadian rhythm of testosterone secretion is lost [16]. Testosterone circulates in a free form and bound to albumin and SHBG. In general, it is believed that the testosterone that is free and bound to albumin is available to tissues (bioavailable) whereas that bound to SHBG is not capable of entering tissues. The exception to this is reproductive tissues, where megalin is a receptor for SHBG that may then allow testosterone to penetrate cells. With aging an increase in SHBG decreases the amount of bioavailable testosterone. After entering cells, either testosterone itself or dihydrotestosterone binds to a receptor in the cytoplasm. This receptor then dimerizes and is carried along filamin into the nucleus. This testosterone-receptor complex then binds to androgen response elements (AREs) on DNA with its action being modulated by several coactivators and corepressors. Binding to the DNA results in generation of messenger RNA and proteins. The function of the testosterone receptor is regulated by the number of CAG repeats. When there are a large number of CAG repeats the receptor functions less well than when there are fewer CAG repeats. Finally, testosterone also has several nongenomic, membrane-mediated effects. The effects of aging on these complex intracellular actions of testosterone have not been studied. Fig. 1 summarizes these agerelated changes in the male hypothalamic-pituitary-testicular axis. Biochemical determination of testosterone Although the measurement of testosterone is relatively simple, the development of a large number of kits for platform assays has made it into

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Fig. 1. Age-related changes in hypothalamic-pituitary-testes axes. DHT, dihydrotestosterone; FSH, follicle-stimulating hormone; LH, luteinizing hormone; MRNA, messenger RNA; SHBG, sex hormone-binding globulin.

a jungle. There is a large variability in the values for each of these assays [17,18]. This variability makes it essential that normal values, and not the manufacturers’ values, are determined for each laboratory. This procedure entails obtaining three pooled values in the morning on at least two occasions from at least 40 healthy men between 20 and 40 years of age. Most laboratories use a value between 250 to 350 ng/dl as the lower limit of normal. Many authorities believe that especially with the older person free or bioavailable (albumin-bound þ free) testosterone should be obtained [19,20]. Most laboratories offer an analog free-testosterone assay, which generally is believed to be of no value. Salivary testosterone provides a reasonable approximation of free testosterone levels.

Testosterone and sexuality It generally is believed that testosterone is a prime driver of libido. People with a low libido generally have lower testosterone levels than those with a normal libido, but there is a marked overlap in testosterone levels in people with normal and abnormal libido [21]. Hajjar and colleagues [22] showed that testosterone replacement leads to a marked increase in libido, but this effect also can be seen with placebo [23]. A meta-analysis has confirmed that

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testosterone increases enthusiasm for sex and sexual activity [24]. The placebo effect seen on sexuality is equivalent to that seen in people with depression, with the testosterone effect being of the same magnitude as that seen with antidepressant treatment. Testosterone levels are particularly low in people with diabetes mellitus [25], and low libido and erectile dysfunction commonly are associated with diabetes [26]. Erectile dysfunction and lower urinary tract symptoms Epidemiology The prevalence of erectile dysfunction (ED) is difficult to estimate because of the assumed underreporting of the problem. Various age-dependent estimates have been made from population-based studies [27–29]. Pinnock and colleagues [27] reported that erections inadequate for intercourse affected 3% of men in their 40s and increased to 64% of men in their 70s in an Australian community sample. In another Australian sample of consecutive male attendees to general medical practices, Chew and coworkers [28] reported the prevalence of complete ED to be 2% of men in their 40s and 50% of men in their 70s. Data on the incidence of ED from the Massachusetts Male Aging Study report an increase from 12.4 cases per 1000 man-years for men in their 40s to 29.8 per 1000 man-years for men in their 50s and 46.4 per 1000 man-years for men in their 60s [30]. The prevalence of lower urinary tract symptoms (LUTS), such as urgency, frequency, nocturia, incontinence, and reduced urine flow, increase with age [31,32], from approximately 26% in men 18 to 64 years old to 48% in those more than 65 years old. These symptoms often significantly affect quality of life and sexual functioning. Benign prostatic hyperplasia (BPH) also increases with age, being present in as many as 50% of men aged 50 and in nearly 90% of autopsies in men aged more than 80 [33]. LUTS and ED are strongly associated with aging and numerous small epidemiologic studies have postulated an association between the two conditions but have failed to show a direct relation after the effect of aging has been accounted for. In a large, multi-center study (United Kingdom [Birmingham], The Netherlands [Boxmeer], France [Auxere], and Korea [Seoul]) men who had an International Prostate Symptom Scale (IPSS) score of 8 to 35 were more likely to have ED, based on a score of 0 to 4 on the Sexual Function Inventory of O’Leary and colleagues [34], after adjusting for age and country (odds ratio [OR] 1.39, 95% CI 1.10–1.74) [35]. Men who had diabetes (OR 1.57, 95% CI 1.09–2.25) and high blood pressure (OR 1.38, 95% CI 1.09–1.75) also were more likely to have an ED score of 0 to 4. Associations between serum testosterone levels and ED have not been clear in epidemiologic studies. Serum free-testosterone concentrations correlate with impaired relaxation of cavernous endothelial and corporeal

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smooth muscle in response to vasoactive challenge, independent of age [36]. Factors that may be associated with both ED and low T levels include determinants of health (age, education, occupation, ethnicity), behavioral and lifestyle (quality of life, alcohol intake, smoking, diet, and physical activity), clinical (diabetes, heart disease, hypertension, and drug therapies), and psychologic factors, including depression and anxiety [29,37]. There is a strong positive relationship between ED and cardiovascular risk factors [29] and depression (the probability of ED is w90% in men who have severe depression but only 25% in men who have mild depression) [37]. The causal relationship is unclear and possibly occurs through mechanisms involving reduced testosterone levels [38]. A longitudinal study of the evolution of ED, associated factors, and comorbidities will provide this much-needed data. Haidinger and colleagues [32] reported that age was the single most influential predictor of LUTS, as measured by the IPSS, in 1557 Viennese men aged 40 to 96 years. It usually is assumed that BPH is responsible for LUTS, particularly when the urine flow is reduced. Numerous crosssectional studies have shown either no or inconsistent relationships between LUTS, BPH, and urine flow [39,40]. Moreover, urine flow may be low in young men without symptoms. Concomitant detrusor instability [41] or other factors may predict LUTS in men who have BPH. The longitudinal rate of change in maximal urine flow rate may correlate more strongly with symptom scores than the flow rate at any given time in cross-sectional studies. Prostate volume was not significantly related to circulating testosterone levels, but increased with increasing age and body mass index and decreased with increasing levels of SHBG in African American men [42]. Neither elevated testosterone nor dihydrotestosterone predisposes men to BPH [38]. Prostate-specific antigen (PSA) is a glycoprotein produced by prostatic epithelium. Serum levels of PSA correlate positively with age. PSA screening for prostate cancer remains controversial because of problems associated with sensitivity and specificity of cutoff values in predicting prostate cancer. Recent reports suggest that a lower threshold level of PSA for recommending prostate biopsy may improve the clinical value of the PSA test for prostate cancer. Meigs and coworkers [43] reported that elevated free PSA levels predicted BPH, independent of total PSA levels, in 1019 men without prostate cancer at 9-year followup. Biochemistry In animal studies, androgen deprivation alters the functional responses and structure of erectile tissue [44]. Penile tissue possesses high concentrations of locally synthesized androgens and thus androgen-dependent functions need not reflect circulating androgen levels [45]. It is well documented in rats that testosterone is required for adequate function of nitric oxide synthase, which produces nitric oxide necessary for relaxation of cavernosal endothelial and corporeal smooth muscle resulting in erection

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[46]. There are also possible non-nitric oxide–dependent effects of testosterone on penile erection that involve stimulation of cyclic GMP synthesis [47]. In animals, testosterone has been shown to inhibit detrusor muscle contraction [48] and therefore low testosterone levels may promote unstable function of the detrusor muscle and LUTS, particularly in men who have concomitant BPH. The prostate is androgen dependent, in particular to dihydrotestosterone that is produced within the gland by way of 5a-reduction from testosterone. The relative contribution of changes in androgens to LUTS is unclear. Intervention In the absence of significant hypogonadism, testosterone treatment does not have an effect on erectile function but it does improve the response to sildenafil [49]. Aversa and colleagues [35] showed that in men who had erectile dysfunction, low free testosterone levels, independent of age, correlated with impaired relaxation of cavernous endothelial and corporeal smooth muscle cells. Moreover, a follow-up study in men who had arteriogenic erectile dysfunction, testosterone levels in the lower quartile of the normal range, and who were nonresponsive to sildenafil treatment after six attempts, demonstrated that 1 month of transdermal testosterone supplementation improved erectile response to sildenafil [50]. Several other studies have suggested enhanced strength or maintenance of erections following testosterone or dihydrotestosterone replacement in older men [23,51–55]. Furthermore, a meta-analysis of the usefulness of androgen replacement for erectile dysfunction showed that testosterone-treated patients improve significantly more than placebo-treated patients and that patients with primary testicular failure respond better to treatment than those with secondary testicular failure. Moreover, transdermal therapy is more effective than oral or intramuscular therapy [56]. Of great clinical importance is the independent association between LUTS and ED. Both conditions can have profound but variable levels of bothersomeness in aging men and it has been estimated that more than 60% of Australian men bothered by LUTS do not seek medical help [31]. These coexisting conditions raise interesting management issues and it is recommended that older men presenting with one condition also be investigated for the other. Skeletal muscle mass and strength Epidemiology Muscle mass decreases and fat mass increases with increasing age. In the New Mexico Ageing Process Study the best predictor of loss of muscle mass and strength (sarcopenia) was free testosterone. Other predictors included age, caloric intake, physical activity, and insulinlike growth factor- (IGF) 1 [57,58]. Sarcopenia leads to frailty, an important precursor of subsequent functional deterioration and death. Frailty has been defined objectively by the criteria of weight loss, exhaustion, weakness (grip strength), slow

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walking speed, and low physical activity [57,59]. Several hormones are believed to play a role in the pathophysiology of frailty. People who have diabetes mellitus are at high risk for developing premature frailty. Weight loss, which can be because of sarcopenia, anorexia, cachexia, or dehydration, is a hallmark of frailty. In men, obesity, particularly when the fat is distributed within the abdomen (visceral), is associated with low plasma testosterone [60–62]. Conversely, decreased testosterone levels in men are associated with increased accumulation of visceral fat [63,64] and are reversible on testosterone administration [65,66]. Van den Beld and coworkers [67] reported inverse cross-sectional associations between total, free, and bioavailable testosterone and total fat mass in 403 community-dwelling men aged 73 to 94 years. Moreover, both total and bioavailable testosterone were positively associated with handgrip strength. Denti and colleagues [68] showed an age-independent, inverse association between SHBG and whole body fat percentage estimated from four skinfold measurements using the Durnin-Wormsely and Siri equations in 206 healthy volunteers aged 18 to 95 years. In a longitudinal study it was shown that people who have lost muscle mass but remain obese (sarcopenic obesity) have an extremely high rate of future disability and death [69]. It has been shown that sarcopenia is strongly related to the loss of hormones, such as testosterone and IGF-1, and to mild increases in cytokines, such as TNF-a and IL-6 [57,70,71]. Other causes of sarcopenia include diminished neuronal input to muscle, decreased food intake (particularly protein and creatine), and peripheral vascular disease [72]. Low levels of gonadal steroids and changes in the activity of the IGF axis therefore may be markers of the metabolic syndrome associated with increasing age, visceral obesity, impaired glucose tolerance and insulin signaling, and cardiovascular disease, resulting in accelerated frailty and death. Biochemistry Changes in the IGF/insulin signaling pathway with aging are likely to play a central role in regulation of skeletal muscle mass. Skeletal muscle is responsible for the production of 25% of circulating IGF-1. There are two muscle isoforms, one similar to liver IGF-1 and the other (IGF-IEc: mechanogrowth factor [MGF]) having local actions on muscle [73]. Exercise (stretch) leads to upregulation of the mRNA for both muscle isoforms and reduced muscle IGF-1 signaling leads to muscle atrophy. Hormones (growth hormone, testosterone, insulin, and vitamin D) and exercise regulate muscle IGF-1 [74]. It is the decline in the muscle isoforms of IGF-1 (liverlike and MGF) [73] that are likely to contribute most to age-related sarcopenia. Moreover, age-related decline in testosterone and growth hormone may lead to increased myostatin expression and dissociation in IGF-1 autocrine effects on protein synthesis in skeletal muscle [70]. Recent research has focused on the testosterone and IGF-1 stimulation of myogenic satellite cell activity in aged skeletal muscle. Satellite cells are

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responsible for muscle regeneration and repair after injury or atrophy. Older muscle exhibits a reduced number and proliferative capacity of satellite cells, but this is amenable to change with the nature of the systemic environment [75]. In rats, IGF-1 enhances muscle growth partially by increasing satellite cell proliferation [76] and electroporation of IGF-1 stimulates muscle fiber hypertrophy [77]. IGF-IEc also stimulates protein synthesis in muscle [78]. A localized IGF-IEc transgene prevented age-related muscle atrophy and allowed older animals to develop a proliferative response to muscle injury similar to that seen in younger animals [79]. The mechanisms by which testosterone, growth hormone, IGF-1, and other growth factors interact with receptor activity, myostatin gene expression, and satellite cell function in aged skeletal muscle to influence muscle protein synthesis warrant further vigorous research. Intervention Testosterone replacement in young hypogonadal men [80,81] and supraphysiologic treatment in eugonadal young men [82] have been shown to increase muscle mass and strength. In older men who have low bioavailable testosterone [83] or low-normal total testosterone levels [84,85], intramuscular testosterone increases muscle mass and strength. Numerous studies of oral and transdermal testosterone in older men who have low-normal total testosterone levels, however, show significant increases in lean mass without improvements in muscle strength [86–88]. In the study by Wittert and colleagues [88] it was shown that change in lean mass correlated with change in quadriceps strength from baseline to month 12 in the testosterone but not in the placebo group. Urban and coworkers reported that intramuscular testosterone increases muscle IGF-1 mRNA and Snyder and colleagues [86] reported an increase in serum IGF-1 in men receiving testosterone by transdermal patch. Oral testosterone undecanoate had no effect on serum IGF-1 levels [88]. Bhasin and coworkers [89] have shown that the muscle response to testosterone in young men is related to dose. The use of muscle function testing in the elderly is confounded by wide variability in most measures. Motivation, tolerance to pain, and potential learning effects may be some of the major factors limiting the ability of these tests to identify differences between the treatment groups in interventional studies. Accordingly, large study groups may be required to determine small treatment benefits [90]. Testosterone and bone Men fracture their hips approximately 10 years later than women do [91]. Men have a higher mortality rate than women when they fracture their hips. Minimal trauma hip fracture is associated with low testosterone levels [92,93]. The relationship of testosterone to bone is less clear in men. Several studies have shown that testosterone treatment can increase bone mineral density [94,95]. This effect of testosterone is not blocked by the

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5-alpha-reductase inhibitor. It would seem that aromatization of testosterone to estrogen is the major cause of the positive effects of testosterone on bone. This effect has been demonstrated clearly in people with congenital aromatase deficiency [96]. Testosterone also seems to have direct effects on the osteoblast. Testosterone and cognition Low bioavailable testosterone levels are correlated with poor cognition, especially visuospatial cognition [97–99]. Some studies have demonstrated that testosterone replacement may improve visuospatial cognition [100]. This has not been a universal finding, however [101]. The SAMP8 mouse has poor cognition, which is attributable to overproduction of amyloid-beta protein associated with increased oxidative damage [102–107]. The SAMP8 mouse has low testosterone levels. Testosterone replacement in this mouse model of Alzheimer disease improves learning and memory [108]. Testosterone treatment decreased amyloid precursor protein. Low testosterone levels are associated with an increased likelihood of developing Alzheimer disease [109,110]. Patients with Alzheimer disease have low testosterone levels in brain tissue compared with controls [111]. Testosterone replacement has been shown to produce small improvements in cognition in people who have Alzheimer disease [100,112]. Testosterone and health-related quality of life Health-related quality of life (HRQOL) is a complex and abstract concept that includes physical, psychologic, social, and other domains of functioning specific to a given health condition. It focuses on the ways in which a disease modifies the happiness and satisfaction of an individual. It represents the patient’s viewpoint of the effects of treatment. It generally has several domains, including symptoms, function, emotional stability, social functioning, and general satisfaction with life. In the case of hypogonadism, decreased energy levels and impaired sexual performance appear to be the most important quality-of-life areas. Lowering testosterone levels in patients who have prostate cancer results in deterioration in the HRQOL [113]. The effects of testosterone replacement on HRQOL in older hypogonadal men have been less dramatic (Table 1) [86,114–119,125]. Overall testosterone has had an effect on the physical performance scale of the SF-36 (a quality-of-life questionnaire). Of the eight trials that have examined quality of life involving 390 patients, only four studies (193 patients) showed positive effects. In a small study of men who had prostate cancer, there was a significant increase in the hormone domain of the extended prostate inventory composite HRQOL [117]. There is a need to develop better HRQOL scales for hypogonadal men.

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Table 1 Testosterone and quality of life Study

n

Age (years)

Effect (scale)

[86] [114] [118] [115] [116] [101] [117]

108 22 46 29 39 60 10

72 65þ 62 52 d 60–78 59–69

[119]

76

64

Physical (SF-36) None (SF-36) Physical (SF-36) None (Endicott) Improved (PNUH QoL) None (Visual analog) Improved (Hormone Domain of Extended Prostate Inventory Composite [HRQOL] None (MLHF)

Abbreviations: SF-36, short form-36; PNUH Qol, Puson National University Hospital Quality of Life; MLHF, Minnesota Living with Heart Failure Questionnaire.

Diagnosis of hypogonadism in older men The diagnosis of hypogonadism in older men requires the presence of a constellation of signs and symptoms and a demonstrated low total testosterone or preferably free or bioavailable testosterone level [120,121]. Several questionnaires have been developed to help screen for andropause and to provide an objective measure of treatment response [122–127]. Two of these have excellent specificity: the Saint Louis University ADAM questionnaire and the Aging Male Survey. Unfortunately, neither questionnaire has very good sensitivity [128]. Nevertheless, they can be considered a reasonable approach to symptom identification. Because of the multiple causes of symptoms similar to the male hypogonadism in older men, it is unlikely that any questionnaire will perform much better. A simplified algorithmic approach to diagnosing late-life hypogonadism is presented in Box 1. This approach is compatible with recent consensus recommendations [121,129,130].

Testosterone treatments Several different methods of testosterone treatments have been developed [131]. Testosterone can be given as injections every 1 to 3 weeks. The major problem with this approach is that the levels of testosterone vary from supraphysiologic to low over each treatment period. This approach has been used successfully, however, for more than 70 years. A long-acting testosterone undecanoate injection has been developed in Asia and Europe and should be available in the United States within the next year [132]. This treatment is similar to testosterone pellet implant therapy, which can be implanted every 4 to 6 months.

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Box 1. St. Louis University Androgen Deficiency in Aging Male (ADAM) questionnaire A positive screen for hypogonadism includes a ‘‘Yes’’ response to numbers 1 and 7, or any other 3 questions. Do you have a decrease in libido (sex drive)? Do you have a lack of energy? Do you have a decrease in strength and/or endurance? Have you lost height? Have you noticed a decreased enjoyment of life? Are you sad and/or grumpy? Are your erections less strong? Have you noticed a recent deterioration in your ability to play sports? Are you falling asleep after dinner? Has there been a recent deterioration in your work performance?

Testosterone patches have a high rate of skin irritation because of alcohol being part of the vehicle. Hydroalcoholic gels containing 1% testosterone have become popular in the United States. They have a lower rate of skin irritation and a better patient acceptance. Doses vary from 50 to 100 mg of gel daily. Three-year safety data for this form of treatment have been reported [133]. This study showed continued positive results of treatment on muscle, bone, fat, and libido in men aged 19 to 67 years. Two forms of testosterone gel, AndroGel and Testim, are available in the United States. A buccal delivery form of testosterone (Striant) has had little success in the United States [134]. Oral testosterone undecanoate is absorbed mainly through the lymphatic system, thus avoiding the effects of high-dose testosterone on the liver during the first pass. It has been used widely throughout the world and 10-year safety data have been reported [135]. It is not available in the United States. Because of the high concentrations of 5-alpha-reductase in gut epithelium, its administration is associated with high serum levels of dihydrotestosterone. A nasal delivery form of testosterone (baccaltestosterone) has been developed. It has adequate bioavailability and does not increase dihydrotestosterone. In rabbit studies it did not damage the nasal mucosa. At present it is undergoing the FDA approval process in the United States. There is little evidence to recommend the use of dehydroepiandrosterone as an androgen replacement [136–138]. Nandrolone, an injectable androgen, has been used successfully to improve strength in men and women [139]. Several oral selective androgen receptor molecules have been developed in hopes that they will be useful for the treatment of sarcopenia. Some

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authorities have suggested that dihydrotestosterone may be an alternative approach to testosterone replacement, but in view of potential effects on the prostate this is unlikely [140]. Human chorionic gonadotropin, which stimulates testicular secretion of testosterone, also has been used to treat andropause [141]. Testosterone and the cardiovascular system Low testosterone levels are correlated with increased atherosclerosis and an increased carotid-intima media thickness [142,143]. Testosterone decreases angina and decreases ST depression [118,144]. It has minimal effects on cholesterol. Testosterone improves walking speed in people with congestive heart failure [119]. Overall, these small studies suggest a beneficial effect of testosterone on heart disease. Side effects The major side effect of testosterone is an excessive increase in hematocrit. When the hematocrit increases to more than 55, testosterone therapy should be withheld. Testosterone also can be associated with worsening sleep apnea [145]. Testosterone therapy can be associated with the development of gynecomastia related to the aromatization of testosterone to estrogen. Parenteral testosterone administration has minimal deleterious effects on the liver. Testosterone therapy increases PSA levels slightly. Testosterone may increase prostate size, worsening BPH. The effects of testosterone on the development or the acceleration of prostate cancer are uncertain [51]. There is a need for a large study to determine these effects. At present the prudent physician should follow PSA levels and conduct a rectal examination every 6 to 12 months. Summary Testosterone deficiency occurs commonly in men as they grow older. This deficiency often is associated with a decline in sexual activity and a loss of muscle mass. Testosterone replacement can reverse many of these effects. At present, no ideal form of testosterone replacement is available. Like the phosphodiesterase-5 inhibitors, testosterone replacement in older men is a quality of life issue. References [1] Morley JE, Haren MT, Kim MJ, et al. Testosterone, aging and quality of life. J Endocrin Invest 2005;28(3 Suppl):76–80. [2] Morales A. Andropause (or symptomatic late-onset hypogonadism): facts, fiction and controversies. Aging Male 2004;7:297–303.

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[3] Jockenhovel F. Testosterone therapydwhat, when and to whom? Aging Male 2004;7: 319–24. [4] Morley JE, Kaiser FE, Perry HM 3rd, et al. Longitudinal changes in testosterone, luteinizing hormone, and follicle-stimulating hormone in healthy older men. Metab Clin Exper 1997;46:410–3. [5] Harman SM, Metter EJ, Tobin JD, et al. Baltimore Longitudinal Study of Aging. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. J Clin Endocrinol Metab 2001;86:724–31. [6] Korenman SG, Morley JE, Mooradian AD, et al. Secondary hypogonadism in older men: its relation to impotence. J Clin Endocrinol Metab 1990;71:963–9. [7] Matsumoto AM. Andropause: clinical implications of the decline in serum testosterone levels with aging in men. J Gerontol Med Sci 2002;57A:M76–99. [8] Kaiser FE, Viosca SP, Morley JE, et al. Impotence and aging: clinical and hormonal factors. J Am Geriatr Soc 1988;36:511–9. [9] Li JY, Li XY, Li M, et al. Decline of serum levels of free testosterone in aging healthy Chinese men. Aging Male 2005;8:203–6. [10] Morley JE. The need for a men’s health initiative. J Gerontol Med Sci 2003;58A:614–7. [11] Tariq SH, Haren MT, Kim MJ, et al. Andropause: is the emperor wearing any clothes? Rev Endocr Metab Disord 2005;6:77–84. [12] Morley JE, Perry HM 3rd. Andropause: an old concept in new clothing. Clin Geriatr Med 2003;19:507–28. [13] Morley JE. Androgens and aging. Maturitas 2001;38:61–71. [14] Keenan DM, Takahashi PY, Liu PY, et al. An ensemble model of the male gonadal axis: illustrative application in aging men. Endocrinology 2006;147:2817–28. [15] Liu PY, Iranmanesh A, Nehra AX, et al. Mechanisms for hypoandrogenemia in health aging men. Endorcinol Metab Clin North Am 2005;34:935–55. [16] Kaiser FE, Morley JE. Gonadotropins, testosterone, and the aging male. Neurobiol Aging 1994;15:559–63. [17] Goncharov N, Katsya G, Dobracheva A, et al. Serum testosterone measurement in men: evaluation of modern immunoassay technologies. Aging Male 2005;8:194–202. [18] Vermeulen A. Reflections concerning biochemical parameters of androgenicity. Aging Male 2004;7:280–9. [19] Morley JE, Patrick P, Perry HM 3rd. Evaluation of assays available to measure free testosterone. Metabolism: Clin Exper 2002;51:554–9. [20] Tremblay RR, Gagne JM. Can we get away from serum total testosterone in the diagnosis of andropause? Aging Male 2005;8:147–50. [21] Kelleher S, Conway AJ, Handelsman DJ. Blood testosterone threshold for androgen deficiency symptoms. J Clin Endocrinol Metab 2004;89:3813–7. [22] Hajjar RR, Kaiser FE, Morley JE. Outcomes of long-term testosterone replacement in older hypogonadal males: a retrospective analysis. J Clin Endocrinol Metab 1997;82:3793–6. [23] Haren M, Chapman I, Coates P, et al. Effect of 12 month oral testosterone on testosterone deficiency symptoms in symptomatic elderly males with low-normal gonadal status. Age Ageing 2005;34:125–30. [24] Isidori AM, Giannetta E, Gianfrilli D, et al. Effects of testosterone on sexual function in men: results of a meta-analysis. Clin Endocrinol (Oxf) 2005;63:601–2. [25] Morley JE, Melmed S. Gonadal dysfunction in systemic disorders. Metabolism 1979;28: 1051–73. [26] Nakanishi S, Yamane K, Kamei N, et al. Erectile dysfunction is strongly linked with decreased libido in diabetic men. Aging Male 2004;7:113–9. [27] Pinnock CB, Stapleton AM, Marshall VR. Erectile dysfunction in the community: a prevalence study. Med J Aust 1999;171(7):353–7. [28] Chew KK, Earle CM, Stuckey BG, et al. Erectile dysfunction in general medicine practice: prevalence and clinical correlates. Int J Impot Res 2000;12(1):41–5.

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Med Clin N Am 90 (2006) 1025–1036

Aging and Sexuality Terrie B. Ginsberg, DO University of Medicine and Dentistry of New Jersey, School of Osteopathic Medicine, New Jersey Institute for Successful Aging, 42 East Laurel Road, Suite 1800, Stratford, NJ 08084-1504, USA

Introduction The textbook definition of sexuality is the sum of a person’s sexual behaviors and tendencies and the strength of such tendencies [1]. A more comprehensive definition may be ‘‘a complex interplay of needs for intimacy, affection, connection, self-pleasure, self-image, and the individual’s context related to gender, ethnicity and community’’ [2]. The combination of the ability to enjoy a satisfying sexual relationship and the ability to express one’s sexual desires need not diminish with age [3]. Factors that affect the ability to interact with one’s sexual partner or engage in any sexual activity fall under physical, psychologic, and cultural domains.

Sexual changes that occur with aging The four stages of the sexual response cycledexcitement, plateau, orgasm, and resolutiondare affected by aging [4]. Excitement combines olfactory, visual, auditory, memory, and different types of physical stimuli. The plateau phase is characterized by maintenance and intensification of arousal. The orgasmic stage involves rhythmic muscular contractions followed by relaxation, which is the same as resolution. Both men and women change physiologically as they age and it impacts their sexuality. Physiologic changes affecting female and male sexual function are summarized in Box 1. With female aging there is an association of elongation of the excitement and plateau stages. This change is associated with increased time to attain sufficient vaginal lubrication for coitus. Orgasmic contractions may decrease in number and intensity and there is Dr. Ginsberg is supported in part by a career development grant from the Health Resources and Services Administration for Geriatric Medicine education. E-mail address: [email protected] 0025-7125/06/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.mcna.2006.06.003 medical.theclinics.com

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Box 1. Physiologic changes in sexual function with aging in women and men Normal aging changes Women
Decreased vaginal lubrication
Atrophy of the bladder
Thinning of the vaginal mucosa
Decreased estrogen levels
Reduced elasticity and muscle tone
Decreased vaginal length and width
Loss of vulvar tissue
Decrease in the size of the clitoris [5] Men
Testosterone levels gradually decline [7]
Decline in excitement, plateau, orgasm, and resolution
More time is required for penile stimulation to obtain and maintain a sufficient erection
Prolongation of the plateau phase
Orgasm becomes weaker with shorter intervals
Reduction of semen volume [8]
In the resolution stage, penile detumescence occurs rapidly.
Prolongation in the refractory period in the interval between erections [9].
Longer periods of stimulation to achieve an erection and climax. a decrease in length of the resolution stage. There are physiologic benefits to postmenopausal women who have regular sexual relationships, use watersoluble lubricants, topical creams, and engage in Kegel exercises (pelvic muscle exercises). The benefits and risks of these adjunctive measures should be evaluated by the prescribing physician. Of course, the state of health is a factor pertaining to sexual response and enjoyment. Dynamic changes in the female sexual physiology occur at the time of menopause. Menopause signifies the permanent cessation of menstruation and the end of reproductive potential. Estrogen loss at the time of menopause is a dominant factor and can affect sexual function. Depletion of estrogen can lead to hot flashes, loss of sleep, irritability, mood swings, diminished acidic secretions in the vagina, and predisposition to vaginal infections [6]. Aging also has a definite impact on male sexuality. For men, as testosterone levels gradually decline the impact on male sexual physiology increases [7]. There is marked decline in excitement, plateau, orgasm, and resolution with male aging. As male aging occurs more time is required for penile

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stimulation to obtain and maintain sufficient erection to engage in coitus. There is prolongation of the plateau phase with a lessening of the urge to experience a transition from orgasm to ejaculation. In general, as men age, the orgasm becomes weaker and occurs during shorter intervals with a reduction in the number of contractions over time of the ischial and bulbocavernosi muscles. There is a reduction of semen volume in the aging man compared with his younger counterpart [8]. In the resolution stage, penile detumescence occurs rapidly. There is a prolongation in the refractory period in the interval between erections [9]. Older men require a longer period of stimulation to achieve an erection and a longer period of time to achieve climax. Although there are some distinctive differences in psychologic issues between men and woman during the aging process, many of these issues are similar. Stressors that may affect sexuality include career, finances, life stressors, physical or mental fatigue, overindulgence in food and alcohol, lack of a partner, and sexual performance issues [3]. In addition to psychologic issues, women’s loss of desire may be associated with religious and cultural beliefs after the perimenopausal period (ie, coitus is acceptable for procreation only). Additional psychologic issues in the aging patient affecting sexuality include sexual experience throughout life, level of satisfaction pertaining to life, self esteem, body image, and attitudes toward sex. Health issues and living arrangements may impact psychologic issues. Historically, loss of a spouse has provided the surviving spouse with psychologic issues regarding future sexual liaisons or relationship (widow’s or widower’s syndrome) [10]. In some women, loss of reproductive capacity psychologically diminishes interest in sexual activities. Conversely, some menopausal women become more relaxed and eager to engage in sexual activities when the fear of pregnancy has ceased [11]. When couples view sexuality in a positive way their sexual encounters become more enjoyable. Although sex appeal is associated with physical attraction, it is also a barometer of one’s self worth and provides a source and comfort level for one’s need to be loved [11]. Although depression in the male patient may play a part in sexual dysfunction, depression is one of the most significant psychogenic factors in women, pertaining to a loss of interest and a decrease in the ability to engage in a sexual relationship [5]. It is important to consider the physiologic and psychologic changes that occur in the aging population when evaluating sexual issues in that population. Sexual myths of aging Contrary to many of our cultural and societal views of the aging individual, our aging population continues to enjoy their sexuality. Stereotypically, an older individual is slow moving, slow thinking, requires total assistance, and never thinks, indulges in, or explores his or her sexuality. The myths

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surrounding sexuality in the elderly truly have no basis in reality. Common myths surrounding sexuality in the elderly include: erectile dysfunction is normal for aging, older people do not have sexual desires, elderly people do not have the capability of making love, elderly people are too frail and prone to injury to attempt coitus, the elderly are unattractive and sexually undesirable, and the elderly who engage in sexual activities are perverse. Unfortunately, these myths are perpetuated by an ongoing ignorance pertaining to these myths by professionals and intellectuals who exhibit a narrow-minded and short-sighted perspective of the elderly [12]. Pfeiffer summarized eloquently his overview of perpetuating sexuality in the elderly and neutralized the sexual myths associated with the elderly when he wrote, ‘‘.successful aging persons are those who have made a decision to stay in training in major areas in their lives. In particular, they have decided to stay in training physically, socially, emotionally and intellectually. We have every reason to believe that staying in training sexually will help to improve the quality of life in the later years’’ [12]. Until recently the media has portrayed the elderly in a negative way pertaining to sexuality. Stereotypes such as ‘‘that dirty old man’’ and ‘‘that horny old woman’’ are examples of the negativity created by the media in reference to sexuality in the elderly. At times there have been media misrepresentations that may serve to discourage our elderly population in their efforts to fulfill their sexual desires [3]. Society must be open-minded and tolerant of its aging population pertaining to sexuality. Erectile dysfunction Erectile dysfunction can be defined as ‘‘the consistent inability to achieve or maintain an erection suitable for intercourse’’ (penetration) [13]. It is associated with advancing aging, decline in quality of life, and interpersonal issues that profoundly impacts one’s mental and physical well-being. The cause of erectile dysfunction is primarily organic; however, psychogenic causes cannot be ruled out as part of a differential diagnosis. Included among the organic causes are endocrine dysfunction, such as diabetes mellitus; vascular disease, including atherosclerosis and associated hypertension; penile trauma; priapism; and neurologic disturbances (cerebrovascular accidents). Other causes may include hypogonadism, hyperprolactinemia, spinal cord injury, multiple sclerosis, chronic obstructive pulmonary disease, chronic renal failure, and Parkinson disease. Among psychogenic causes, consider anxiety, depression, and stress. Risk factors associated with erectile dysfunction include obesity, smoking, lower urinary tract symptoms, and sedentary lifestyle [14]. Medications, such as antihypertensives, antidepressants, antipsychotics, and anticholinergic medications, may predispose an individual to erectile dysfunction. Abusive drugs, such as alcohol, heroin, cocaine, and tobacco, have been associated with male sexual dysfunction.

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As mentioned, vascular disease is a common cause of erectile dysfunction [9]. There are two primary mechanisms by which vascular disease causes erectile dysfunction: arterial insufficiency and venous leakage. Atherosclerotic arterial occlusive disease leads to obstruction, which decreases the perfusion pressure and arterial flow to the lacunar spaces that are necessary to achieve a rigid erection [9]. Sufficient pressure within the corpora cavernosa is not obtained because of excessive outflow through the subtunical venules. This disruption of venous outflow or venous leakage prevents achieving a rigid penile erection [9]. Diabetes mellitus, associated with atherosclerosis and vascular changes, causes changes in neurotransmitters (ie, nitric oxide, vasoactive intestinal peptide) possibly resulting in a negative impact on erectile ability [6]. In addition, complications of smooth muscle and endothelial dysfunction are common sequelae of diabetes mellitus. These changes also play a part in the pathophysiology of erectile dysfunction [6]. Hormonal influences predisposing men to develop erectile dysfunction include elevated prolactin levels associated with uremia, psychotropic drugs, hypothyroidism, and pituitary tumors [15]. Although organic ideology for erectile dysfunction should be ruled out, psychogenic causes should not be neglected if testing for organic causes is not fruitful. Specific types of psychogenic erectile dysfunction include performance anxiety and fear of sexually transmitted diseases. Widower’s syndrome is a defense mechanism whereby the widower develops erectile dysfunction secondary to guilt feelings relating to his dead spouse, which prevents erection [9]. The diagnosis of erectile dysfunction requires differentiation between organic and psychogenic cause considering presentation of symptoms. Were the symptoms developing over time or of sudden onset? Sudden onset of such symptoms is associated with psychogenic erectile dysfunction. Gradual onset would be more pathognomonic of an organic cause. The basic examination to evaluate for erectile dysfunction should include genital examination, observing for penile plaques and femoral bruits, evaluating secondary sexual characteristics, and blood pressure assessment [15]. A history should include medical, social, and sexual information. Laboratory studies commonly used in diagnosing erectile dysfunction include blood glucose, cholesterol, and testosterone levels. Although prolactin level testing is controversial many primary care physicians include it in their diagnostic regimen. Although not considered as a first-line diagnostic modality, color Doppler ultrasonography or penile cavernosography should be relegated to those patients being studied for reconstructive penile vascular surgery [15]. Treatment options can be divided into mechanical, surgical, and pharmacologic. Nonpharmacologic treatment of erectile dysfunction includes vacuum erection devices, penile implants, intracavernosal injection, and intraurethral administration. A surgical option is penile arterial bypass surgery. Limitations of these modalities include necessity of dexterity, appropriate

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vision, fear of injection, lack of spontaneity, risk for priapism, fibrosis, and penile pain [9]. The phosphodiesterase-5 (PDE-5) inhibitors, including sildenafil, vardenafil, and tadalafil, are pharmacologic treatments. Sildenafil and vardenafil provide a four-hour activity window. Tadalafil provides a thirty-six hour window. ‘‘PDE-5 is an enzyme found in trabecular smooth muscle. It catalyzes the degradation of Cyclic Guanosine Monophosphate (CGMP) which results in an elevated cytosolic calcium concentration and smooth muscle contraction. PDE-5 inhibitors, therefore block this biochemical pathway to promote erection’’ [16]. These oral agents are contraindicated in men who take nitrates because of the possibility of an abrupt drop in blood pressure. Lifestyle changes, psychosocial issues, sexual technique, and iatrogenic causes of erectile dysfunction should be taken into consideration when formulating a treatment plan [9]. Menopause The essential concept of menopause has become a controversial issue. The following are the most common accepted criteria. Menopause is the permanent cessation of the menses [17]. ‘‘It is the culmination of some fifty years of reproductive agingda process that unfolds as a continuum from birth through ovarian senescence to the menopausal transition and the post menopause’’ [3]. It occurs physiologically between ages 40 and 55 with a mean age of 51.3. If menopause occurs before the age of 40 it is considered pathologic and is considered to be premature ovarian failure. The most common cause is autoimmune oophoritis [18]. Menopause can be brought on abruptly by bilateral oophorectomy. The pathophysiology of menopause has not been identified clearly. It is universally accepted, however, that estrogen deficiency is considered the primary diagnostic criterion. The changes brought about by menopause, for the most part, are adverse and increase the risk for cardiovascular, musculoskeletal, and psychogenic sequelae. The common symptoms include hot flashes, urogenital symptoms, sexual dysfunction, impaired cognition, and sleep and mood disorders [18]. In women with follicle stimulating hormone (FSH) levels greater than 40, the diagnosis of menopause is considered appropriate. Because of the transition from premenopause to perimenopause to menopause, measurement of FSH may not be the most accurate way to assess menopausal status [4]. Menopause provides a paradoxic perspective. Some women feel relaxed and free because of being liberated from the fear of pregnancy. Other women experience a psychologic diminishing of their femininity and sexuality. Vaginal changes secondary to menopause can lead to dyspareunia and have a negative impact on sexuality. Decreased estrogen levels predispose the menopausal woman to more frequent vaginal infections and atrophic vaginitis with associated vaginal itching, burning, and discharge [19].

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Hormone replacement therapy in the form of estrogen replacement was once considered almost mandatory and not only a safeguard against the progression of osteoporosis but a significant protection against cardiovascular disease in women. Updated studies have revealed that estrogen replacement may result in increased cardiac events and cerebrovascular disease in the female population and predispose women to increased risk for breast and uterine cancer. Presently, physicians are focusing on treating the sequelae of menopause, such as osteoporosis, urogenital problems, postmenopausal depression, and sexual dysfunction. To adequately achieve a smooth transition from premenopausal, perimenopausal, and menopausal stages of life physicians must develop a protocol early in life, preferably during the woman’s adolescence, and follow her through menopause, providing whatever care is necessary to diminish the incidence of chronic disease and psychogenic dysfunction [18].

Sexually transmitted diseases in the aging population As people live longer, a greater percentage of the geriatric population will be diagnosed with sexually transmitted diseases (STDs). According to the Centers for Disease Control and Prevention, the number of acquired immunodeficiency syndrome (AIDS) cases in the aging population has risen from 739 in 1999 to 886 in 2003 [20]. Review of epidemiologic data reveals a paucity of information relating to human immunodeficiency virus (HIV/AIDS) in the geriatric population. Lack of data in this area reflects this issue being bypassed during history taking [21]. Although the number of HIV/AIDS cases from blood transfusions has dropped because of improved screening, the number of HIV/AIDS cases caused by other sources, such as sexual intercourse, IV drug use, and multiple sexual partners, has actually increased the number of documented cases [22,23]. Risk factors for contracting HIV/AIDS in the aging population are similar to those in the general population and include sexual contact, blood transfusion, STDs, substance abuse, multiple sexual partners, and IV drug use. All of these factors underscore the importance of educating physicians and the growing aging population about safe sexual behavior. Although HIV/AIDS has a significant impact on the immune system, aging also has a significant impact on that system. An associated decline in the humoral and cell-mediated immune response can occur during the aging process. In the geriatric population, as a result of these immune system changes, the aging individual is more susceptible to opportunistic infections (ie, mycobacterium tuberculosis, herpes zoster, and cytomegalovirus). Postmenopausal women are at a higher risk for contracting HIV infections because of decreased lubrication and vaginal wall thinning [24]. In the aged there is an associated increase in viral load following seroconversion, more rampant and aggressive progression of the disease state, and a greater

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intolerance to HIV agents. With aging there are chronic comorbidities, decreased renal function, and compromise of hepatic metabolism leading to a more rapid decline in health and to earlier demise in the presence of AIDS [21,22,24]. More commonly, patients in this group die of AIDS with the HIV component of their disease never being diagnosed. The diversity of presentations for HIV-positive individuals in the aging population presents a formidable challenge in the diagnostic process. Because HIV infection has been considered the ‘‘great imitator’’ of other conditions, this disease entity should be included automatically in many differential diagnoses [21]. A prime example is the undiagnosed HIV-positive patient who has neurologic deficits, who presents with cognitive impairment and is misdiagnosed with Alzheimer dementia [21]. Drug treatment of HIV-positive patients is similar in the general patient population and the geriatric population. Because of multiple comorbidities commonly seen in the aging population and the common use of multiple pharmacotherapies in that group, there is a greater propensity for drug interactions and adverse events than in the younger population. In the aging population, antiretroviral therapy should be initiated with low doses, monitored carefully, and dosages increased according to efficacy, tolerability, and response. In extremely weak geriatric patients and in patients who are considered terminal, consideration should be given to benefit, risk, and quality of end of life issues when considering antiretroviral therapy [21]. Older adults have the combined problems of compromised health and compromised cognitive ability to cope with the emotional stress when dealing with their HIV/AIDS virus. Appropriate counseling and emotional support therefore are mandated in this patient population [3]. As physicians we should consider it a mandatory professional obligation to remind men and women of the aging population that aging is not a barrier to, nor does it nullify, the opportunity of developing a sexually transmitted disease [4]. In the aging population it is not uncommon to diagnosis gonococcal urethritis, vaginitis, trichomoniasis, and Chlamydia [3,7]. Herpes and human papillomavirus also should be included as possible differential diagnoses in that population. In aging patients who have memory impairment, syphilis should be ruled out in an effort to evaluate the patient for neurosyphilis. Although rapid plasma reagin and treponemal antibody studies are benchmark studies for syphilis, cerebrospinal fluid studies may be considered the gold standard [21]. In the nursing home environment, STDs should be considered for various reasons. The patient could have developed the STD years earlier, before the necessity of institutionalization, or the disease could have been transmitted consensually or nonconsensually. Sexual assault of a cognitively impaired individual in this type of environment should also be considered [21]. Also, patients in this environment who have been diagnosed with pediculosis pubis and scabies, which are commonly contracted as a result of sexual activities, should be evaluated for STDs [21]. When developing a differential

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diagnosis of STD in the elderly, cervicitis, bacterial vaginosis, genital ulcer disease, and chancroid should not be ignored. Comorbidities affecting sexuality Although comorbid disease states are not unique to the aging population, they do create major problems and have a major impact on sexual function. Disease processes of any kind can affect sexual function negatively. Disease states in general cause fatigue, pain, cognitive impairment, muscle weakness, and psychologic disturbances in the form of anxiety or depression [2]. Surgery also can affect anatomic function and self image, which may translate into problems with sexual attraction or self esteem [4]. Efforts should be made on the part of the physician and allied health care providers to address the special needs of patients affected by chronic disease, surgical sequelae, and emotional sequelae [7]. For example, after a myocardial infarction (MI) patients should be provided with proper instructions for the purpose of restoring them to optimal function, both general and sexual [25]. These instructions should include proper graduated exercise such as bringing ‘‘your heart rate to 120 beats per minute without occasioning chest pain or shortness of breath, the equivalent of climbing two flights of stairs rapidly’’ [25]. Counseling should be provided to make both sexual partners cognizant and comfortable with the sexual activities after an MI. Poststroke patients must deal with reduced libido, less frequent intercourse, and diminished orgasm. Fear of a second stroke may result in a decreased willingness to participate in sexual activities. Poststroke weakness, commonly unilateral, which affects the ability to engage in intercourse, can be addressed by alternative positioning [25]. Emptying of the bowel and bladder is also important in stroke patients before sexual intercourse [25]. Concern also exists that the medication used in poststroke patients to maintain normal blood pressure may result in sexual dysfunction. As mentioned, diabetes is a common cause of impotence in men [3]. It is also a cause of decreased vaginal secretion in the female patient and possible decrease in libido. Other sequelae of diabetes, such as blindness, amputation, renal insufficiency, peripheral neuropathy, and chronic neuropathic pain, negatively impact sexual activity. Chronic arthritis is a major cause of diminished sexual interest and activity in the aging patient [4]. Pain, joint swelling, and severe restriction of joint motion are definite deterrents. As in poststroke patients, patients with chronic arthritis may benefit by adjusting positions to accommodate a more comfortable and pleasant sexual liaison [26]. Application of heat before and after sexual intercourse may alleviate the pain and discomfort of arthritis [26]. The rheumatoid patient who experiences morning stiffness may be able to experience quality sexual activity later in the day. Breast cancer and postsurgical implications can take its toll on the patient’s ability and desire to engage in a sexual relationship [2]. Side effects

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of surgery, including postsurgical pain, scarring, and lymphedema, can interfere with the patient’s ability and desire to engage in sexual activities [2]. In addition to the physical and emotional complications directly affecting the patient, the sexual partner may find it difficult to cope with their partner’s sexual difficulties and not feel a sexual attraction under those circumstances. Counseling both partners is important in this situation. Hysterectomy is a common procedure in the United States [25]. Most women posthysterectomy, including those with a total hysterectomy, were found not to have decreased desire or enjoyment during sexual intercourse [27]. Some even had a greater desire and enjoyment because of freedom of concern about pregnancy. Also, because of cessation of prehysterectomy symptoms, such as lower abdominal pain and bleeding, sexual activity desire and enjoyment were also improved [27]. One of the most common cancers diagnosed in the male aging population is prostate cancer. With this diagnosis come the concerns related to impotency, failure of ejaculation, and diminished libido [28]. Prostatectomy as a primary treatment may not negatively impact erectile function, however, if a nervesparing procedure is performed by an experienced urological surgeon. Damage to nerves as a result of this type of surgery may cause erectile dysfunction. In addition, prostate surgery may alert the patient to consider his own mortality and possibly consider the surgery as an assault on his male sexuality [28]. Radiation therapy can also have an impact on sexual function. Urinary incontinence, with its multiplicity of associated stressors, can impact sexual behavior negatively in the elderly [28]. Bed wetting, necessity to void at inopportune moments, fear of incontinence side effects, and potential for genitourinary tract infections all place a damper on sexual desire and activity. Appropriate treatment, including medication, behavioral modification, and Kegel exercises may improve the concerns about incontinence and improve sexual enjoyment. Included in chronic psychologic issues associated with sexual dysfunction in the elderly are depression and anxiety. It sometimes is difficult to ascertain whether the psychologic problems preceded the sexual dysfunction or were a result of the sexual dysfunction. Regardless of the time frame, the issues must be addressed. Psychotherapy or pharmacotherapy may provide significant improvement in depression or anxiety. Some antidepressants cause sexual side effects, however, such as impotence and decreased sexual desire [26]. It is important to carefully evaluate the specific drugs prescribed.

Religious and cultural aspects of sexuality Religion has a marked influence on the psychologic development of our sexuality. In the aging population, it is not uncommon for religious concepts and philosophies, taught in childhood and propagated through the years, to have significant impact on sexual behavior. Some cultures, on a religious

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basis, paint a picture of sin and darkness related to sexual expression. Other cultures allow for extreme sexual freedom. In their youth, many individuals may disregard religious concepts, which may be in conflict with their own physical and emotional desires and sexual needs [29]. In some instances, deep-seated religious teachings may detract from an expressive sexual relationship because of the presence of guilty feelings. Regardless of the origin, the treating physician must attempt to understand an individual’s religious feelings and attempt to integrate the treatment of sexual dysfunction with sensitivity to those religious precepts [29]. The aging population, specifically those over 60 years old, has experienced enormous changes in the cultural view of sexual behavior [30]. The change of sexual inhibition in women and the paucity of information provided to men regarding sexual behavior have been subject to an explosive redirection [30]. Contraceptive devices have played a major role in allowing women to expect more and experience a greater sexual pleasure [30]. In turn, this has allowed the aging man to also be more expressive and enjoy the sexual relationship [30]. Summary Sexuality, although only one aspect of one’s being, plays an integral role during the aging process. This role has physical and psychologic ramifications. A healthy sexual attitude combined with addressing physical health needs provides a greater potential for enjoying a more fulfilled lifestyle as one ages. With aging come significant potential medical problems and associated psychologic disturbances. These issues present a challenge to those in the medical profession who treat this age group. It is important to those physicians accepting this responsibility to become extremely familiar with all the nuances affecting those in the golden years of their lives. This enormous responsibility requires knowledge, caring, compassion, understanding, and sensitivity. With luck, we will all reach those golden years and receive the freedom to experience and express sexuality that is most certainly deserved. References [1] Spraycar M. Stedman’s medical dictionary. 26th edition. Baltimore: Williams & Wilkins; 1995. [2] Kaiser F. Sexual function and the older woman. Clin Geriatr Med 2003;19(3):463–72. [3] Lenahan P, Ellwood A. Sexual health and aging. Clinics in Family Practice 2004;6(4): 917–39. [4] Kaiser F. Sexuality practice of geriatrics. 3rd edition. Philadelphia: WB Saunders; 1998. p. 48–56. [5] Pariser S, Niedermier J. Sex and the mature woman. J Womens Health 1998;7(7):849–59. [6] Sherman S. Defining the menopausal transition. Am J Med 2005;118(12, Suppl 2):3–7. [7] Hobson KG. The effects of aging on sexuality. Health Soc Work 1984;9(1):25–35.

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[8] Jung A, Schill WB. Male sexuality with advancing age. Eur J Obstet Gynecol Reprod Biol 2004;113:123–5. [9] Mulligan T, Reddy S, Gulur P, et al. Disorders of male sexual function. Clin Geriatr Med 2003;19:473–81. [10] Masters W, Johnson V. Sex and the aging process. J Am Geriatr Soc 1981;29:385–90. [11] Drench M, Losee R. Sexuality and sexual capacities of elderly people. Rehabil Nurs 1996; 21(3):118–23. [12] Rienzo B. The impact of aging on human sexuality. J Sch Health 1985;55(2):66–8. [13] Kamel H, Kaiser FE, Morley JE. Erectile dysfunction. In: Hazard WR, Blass JP, editors. Principles of geriatric medicine and gerontology. 4th edition. New York: McGraw-Hill; 1999. p. 1585–94. [14] Rosen RC, Wing R, Schneider S, et al. Epidemiology of erectile dysfunction: the role of medical co-morbidities and lifestyle factors. Urol Clin North Am 2005;32:403–17. [15] Baldo O, Eardley I. Diagnosis and investigation of men with erectile dysfunction. J Mens Health Gender 2005;2(1):79–86. [16] Fazio L, Brock G. Erectile dysfunction: management update. Can Med Assoc J 2004;170(9): 1429–37. [17] Spraycar M. Stedman’s. 26th edition. Baltimore: Williams & Wilkins; 1995. p. 1089. [18] Wilson MM. Menopause. Clin Geriatr Med 2003;19(3):483–506. [19] Noblett Kl, Ostergard DR. Gynecologic disorders. In: Hazard WR, Blass JP, editors. Principles of geriatric medicine and gerontology. 4th edition. New York: McGraw-Hill; 1999. p. 797–807. [20] US Department of Health and Human Services Centers for Disease Control and Prevention, National center for health statistics. Chartbook on trends in the health of Americans, 2005. http://www.cdc.gov/hiv/ststa/hasrlink.htm. Accessed February 2006. [21] Wilson MM. Sexually transmitted diseases. Clin Geriatr Med 2003;19:637–55. [22] United Nations. HIV/AIDS. Global action on aging, World Assembly on Ageing II, March 2002. [23] AIDS among persons aged O50 years. Centers for Disease Control and Prevention, United States, 1998. http://www.thebody.com/cdc/mmwr472.html. Accessed February 2006. [24] Senior K. Growing old with HIV. Lancet 2005;5:739. [25] Morley JE, Kaiser FE. Female sexuality. Med Clin North Am 2003;87:1077–90. [26] Butler RN, Lewis MI. Sexuality and Aging. In: Hazard WR, Blass JP, editors. Principles of geriatric medicine and gerontology. 4th edition. New York: McGraw-Hill; 1999. p. 171–8. [27] Goetsch M. The effect of total hysterectomy on specific sexual sensations. Am J Obstet Gynecol 2005;192:1922–7. [28] Morley JE, Tariq SH. Sexuality and disease. Clin Geriatr Med 2003;19:563–73. [29] Hogan R. Influences of culture on sexuality. Nurs Clin North Am 1982;17(3):365–76. [30] Dunn M, Cutler N. Sexual issues in older adults. AIDS Patient Care STDS 2000;14(2):67–9.

Med Clin N Am 90 (2006) 1037–1048

Index Note: Page numbers of article titles are in boldface type.

A Abrasion, in pressure ulcer, 934

Androgen Deficiency in Aging Male (ADAM) Questionnaire, 1015

Absence seizures, 949–950

Andropause. See Testosterone, deficiency of.

Acarbose, for diabetes mellitus prevention, 915 Acetaminophen, for palliative care, 988 Acetylcholine in detrusor muscle control, 827 in memory, 770–771

Anemia frailty in, 842–843 macrocytic, in folate deficiency, 901–902 pernicious, 900–901 Angina pectoris, 850–852, 854

Activities of daily living, inability to perform, fall risk in, 810–811

Angiotensin receptor blockers, for heart failure, 871–872, 875

ADAM (Androgen Deficiency in Aging Male) Questionnaire, 1015

Angiotensin-converting enzyme inhibitors for heart failure, 871, 875 for sarcopenia, 839–840

Adaptive response, in older adults, 969 Advance care planning, in palliative care, 985–987 Age and aging cancer and biology of, 970–971 principles of, 967–970 versus fall risk, 812 versus weight, 888 Aldosterone antagonists, for heart failure, 873–874 Alginate dressings, for pressure ulcers, 939 Alzheimer’s disease, 776–777 amyloid deposition in, 771 in diabetes mellitus, 915 in testosterone deficiency, 1013 mild cognitive impairment in, 772–774 American Medical Director Association guidelines, for urinary incontinence management, 829–830 Amyloid-b protein in Alzheimer’s disease, 776 in memory, 771 Amyotrophy, diabetic, 913

Anorexia frailty in, 842 in heart failure, 865 in palliative care, 989 of aging, 887, 890–892 treatment of, 894–895 Antidepressants, for depression, 793–797 Antiepileptic drugs, 958–965 Antimuscarinic drugs, for urinary incontinence, 831 Antineoplastic agents, 969–970, 975–976 Antipsychotics, atypical, for depression, 794, 796–797 Anxiety after falling, 809 in palliative care, 989, 995 sexuality and, 1034 Aortic valve regurgitation of, 854–855 stenosis of, 853–854 Aphasia, in frontotemporal dementia, 779 Apolipoprotein E defects, in Alzheimer’s disease, 776

0025-7125/06/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/S0025-7125(06)00100-3 medical.theclinics.com

1038 Appetite age-related changes in, 887, 891–892 stimulation of, 894–895 Aripiprazole, for depression, 796–797 Arthritis fall risk in, 810–811 sexuality and, 1033 Atherosclerosis, erectile dysfunction in, 1029 Atonic seizures, 950 Atrial fibrillation, 857–858

INDEX

Body composition, versus age, 888 Body mass, loss of, frailty in, 838–842 Body mass index, in obesity, 895 Body weight. See Weight. Bone loss in testosterone deficiency, 1012–1013 in vitamin D deficiency, 898 in weight loss diets, 896 Bovine spongiform encephalopathy, 779

Atypical absence seizures, 950

Braden Scale, for pressure sore risk assessment, 933

Aura, in seizure, 952

Breast cancer, sexuality and, 1033–1034

Autoimmunity, in diabetes mellitus, 912

Breathlessness. See Dyspnea.

Autolytic debridement, of pressure ulcers, 938

Brief dynamic therapy, for depression, 799

Automatisms, 947 B Bacteria, control of, in pressure ulcers, 939 Bad news, communicating, in palliative care, 985–986 Balance disorders, fall risk in, 810–811 Balance training, for fall prevention, 816 Behavioral therapy, for urinary incontinence, 830 Benign prostatic hyperplasia, testosterone levels and, 1008–1010 Bereavement support, in palliative care, 1000–1001 Beta-blockers, for heart failure, 872, 875 Biofeedback therapy, for urinary incontinence, 830–831 Biologic debridement, of pressure ulcers, 938–939 Bipolar affective disorder, 792 Bisoprolol, for heart failure, 872 Bladder age-related changes in, 825 incontinence of. See Urinary incontinence. overactive, 826–827, 830–832 pacemaker for, in urinary incontinence, 832 Blister, in pressure ulcer, 934

Bruise-like appearance, of pressure ulcer, 934–935 B-type natriuretic peptide, in heart failure, 866 Bumetanide, for heart failure, 873 Bupropion, for depression, 795 C Cachexia frailty in, 842 in diabetes mellitus, 913 in palliative care, 989 physiology of, 892 Calcification, annular, of mitral valve, 856 Calcium, deficiency of, 899 Calcium channel blockers, for heart failure, 875 Cancer, 967–982 biology of aging and, 970–971 geriatric assessment for, 971–975 principles of aging and, 967–970 sexuality and, 1033–1034 treatment of, 975–979 cancer-specific, 975–977 end-of-life, 979 geriatric clinical trials for, 979 supportive care in, 978–979 symptom-specific, 977–978 Carbamazepine for depression, 796 for epilepsy, 962 Cardiac resynchronization therapy, for heart failure, 876

1039

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Cardiomyopathy, 856

Complex partial seizures, 949, 952–953

Cardiovascular disease. See also Heart disease; Heart failure. in diabetes mellitus, 913–914 in testosterone deficiency, 1016

Comprehensive geriatric assessment, in cancer, 971–975

Cardioverter defibrillators, implantable, 876–877

Confusion acute, 780 after seizure, 953 fall risk in, 810 in heart failure, 865

Carvedilol, for heart failure, 872 Center to Advance Palliative Care, 997–998 Cerebrovascular disease dementia in, 777–778 depression in, 790–791 epilepsy in, 951–952 urinary incontinence in, 826 Chemotherapy, 969–970, 975–976 Chest pain, in coronary artery disease, 850–852 Chest radiography, in heart failure, 865 Cholecystokinin, in memory, 771 Ciliary neurotrophic factor, in muscle function, 841 Citalopram, for depression, 795 Clinical trials, for cancer, 979 Clonic seizure, 950 Clozapine, for depression, 796–797 Cognitive analytical therapy, for depression, 799 Cognitive behavioral therapy, for depression, 798 Cognitive impairment, 769–787. See also Dementia. cancer treatment decisions and, 977 epidemiology of, 769 fall risk in, 810, 812 identification of, 772 in delirium, 780 in depression, 791 in prion disease, 779 in testosterone deficiency, 1013 mild, 772–774 neurotransmitters in, 770–771 urinary incontinence in, 830 versus normal cognitive aging, 769–770 Collagen injections, for urinary incontinence, 832 Communication, in palliative care, 984–987

Computed tomography, in dementia, 775

Congestive heart failure. See Heart failure. Constipation, in palliative care, 989, 996 Coronary artery disease, 849–852, 867 Crater, in pressure ulcer, 934 Creutzfeldt-Jakob disease, 779 Cultural aspects, of sexuality, 1034–1035 Cystometry, in urinary incontinence, 830 Cytokines excess of, anorexia due to, 891–892 muscle strength and, 841 D Darifenacin, for urinary incontinence, 832 Death. See also End-of-life care; Mortality. progression toward, 985 Debridement, of pressure ulcers, 938–939 Deep brain stimulation, for depression, 800, 802–803 Defibrillators, cardioverter, implantable, 876–877 Delirium, 780 in heart failure, 865 in palliative care, 989 Dementia Alzheimer’s, 776–777 definition of, 774–775 diagnosis of, 772, 775, 780 epidemiology of, 769 fall risk in, 812 frontotemporal, 779 in diabetes mellitus, 915 reversible causes of, 775 vascular, 777–778 versus delirium, 780 with Lewy bodies, 778 Dementia syndrome of depression, 791 Dentition, poor, undernutrition in, 892

1040 Depression, 789–805 clinical features of, 790–792 epidemiology of, 789 fall risk in, 810–812 frailty in, 843 in cancer, 978 in diabetes mellitus, 914 in epilepsy, 957 in urinary incontinence, 828 minor, 791 sexuality and, 1034 treatment of, 792–803 in cancer, 978 in palliative care, 990 neuromodulation in, 799–803 pharmacologic, 792–797 psychotherapy in, 797–799 undernutrition in, 892 Desipramine, for depression, 795 Detrusor muscle dysfunction pathophysiology of, 826–827 treatment of, 831–832 Dexamethasone, for appetite stimulation, 989 Diabetes mellitus, 909–923 clinical features of, 913 complications of, 913–915 diagnosis of, 915–916 erectile dysfunction in, 1029, 1033 frailty in, 841–842 monitoring of, 915–916 pathogenesis of, 909–912 postprandial hyperglycemia in, 916–917 prevalence of, 909 prevention of, 915 screening for, 915–916 treatment of goals of, 916 options for, 917–920 Diastolic hypertension, 852 Digoxin, for heart failure, 873, 875 Dilated cardiomyopathy, 856 Disability, in obesity, 896–897 Diuretics, for heart failure, 873 Dizziness, fall risk in, 810 Documentation, of pressure ulcers, 935–937

INDEX

Duloxetine, for depression, 795 Dynamic therapy, brief, for depression, 799 Dyspnea in coronary artery disease, 850 in heart failure, 865 in palliative care, 990, 994–995 E Echocardiography in heart failure, 866 in hypertensive heart disease, 852–853 Edema, in heart failure, 865 Electrocardiography in coronary artery disease, 850–851 in hypertensive heart disease, 852–853 Electroconvulsive therapy, for depression, 799–801 Electroencephalography, in epilepsy, 956–957 End-of-life care communication in, 984–987 in cancer, 979 in heart failure, 878–879 Environment, assessment and modification of, for fall prevention, 816–817 Enzymatic debridement, of pressure ulcers, 938 Epilepsy, 945–966 causes of, 951–952 clinical presentation of, 952–954 diagnosis of, 955–957 differential diagnosis of, 953–954 elderly patient definitions in, 947, 951 epidemiology of, 951 prognosis for, 957–958 refractory (status epilepticus), 954–955 seizures in classification of, 947–950 definitions of, 946–947 surgical treatment of, 964 treatment of future, 963–965 medical, 958–963 Epileptic twilight state, 954

Donepezil, for Alzheimer’s disease, 777

Erectile dysfunction, 1008–1010, 1028–1030, 1034

Dressings, for pressure ulcers, 939

Erythema, of pressure ulcers, 934

Dronabinol, for appetite stimulation, 894

Eschar, in pressure ulcer, 934

Drop attack, fall risk in, 810

Escitalopram, for depression, 795

1041

INDEX

Estrogen deficiency, in menopause, 1030–1031

Focused multidimensional fall risk assessment, 815

Exercise for Alzheimer’s disease, 777 for diabetes mellitus, 918 for fall prevention, 815–816 for heart failure, 877–878 for urinary incontinence, 830–831 for weight loss, 897 intolerance of, in heart failure, 865

Folate deficiency, 901–902

F Falls, 807–824 antiepileptic drugs and, 961 causes of, 807, 809–814 epidemiology of, 808–809 fear of, 809 history of, 811 injurious versus noninjurious, 813 mortality in, 808 prevention of, 814–820 effectiveness of, 818–819 environmental modification in, 816–817 exercise in, 815–816 institutional interventions in, 817–818 multidimensional risk assessment in, 814–815, 818–819 multifactorial interventions in, 817 recurrent, 814 risk factors for, 809–814 urinary incontinence and, 828 Familial Alzheimer’s disease, 776 Family (systems) therapy, for depression, 798 Fat distribution of, 888 in muscle tissue, frailty and, 839, 842 versus age, 888

Fractures, hip in falls, 813, 819 in testosterone deficiency, 1012–1013 Frailty, 837–847 cascade of, 837–838 definition of, 837 development of, 837–838 diseases causing, 842–843 fall risk and, 812 in cancer, 974 in testosterone deficiency, 1010–1012 sarcopenia in, 838–842, 1010–1012 weight loss in, 842 Friction, in pressure ulcer development, 931 Frontotemporal dementia, 779 F-Tag 314 pressure ulcer risk factor guidelines, 932 Functional impairment fall risk in, 810–811 in obesity, 896 Functional incontinence, 826–827 Furosemide, for heart failure, 873 G Gabapentin, for epilepsy, 960–962 Gait disorders, fall risk in, 810–811 Generalized seizures, 949–950 Genital abnormalities, urinary incontinence in, 826 Geriatric assessment, in cancer, 971–975

Fatigue, in cancer, 977

Ghrelin for frailty, 840–841 in memory, 771

Fibrillation, atrial, 857–858

Gliclazide, for diabetes mellitus, 919

Fibroblasts, in healing, 927

Glimepiride, for diabetes mellitus, 919

FICA mnemonic, for spiritual history, 1000

Glipizide, for diabetes mellitus, 919

Film dressings, for pressure ulcers, 939 Fluoxetine for depression, 795 for diabetes mellitus, 920 Fluvoxamine, for depression, 795 Foam dressings, for pressure ulcers, 939

a-Glucosidase inhibitors, for diabetes mellitus, 918 Glutamine-NMDA receptor, in memory, 770–771 Glyburide, for diabetes mellitus, 918–919 Gonadotropin-releasing hormone, defects of, testosterone deficiency in, 1006

1042 Gosnell Scale, for pressure sore risk assessment, 933 Grand mal (tonic clonic) seizures, 950, 952, 954 Granulation tissue, in healing, 927 Grief support, in palliative care, 1000–1001 Growth hormone, in muscle hypertrophy, 840

INDEX

Hip fracture of in falls, 813, 819 in testosterone deficiency, 1012–1013 osteoarthritis of, in obesity, 895–896 Hippocampus, in memory processing, 770 Home safety checklists, for fall prevention, 816–817 Homeostasis, in older adults, 968 Hormonal therapy, for cancer, 975

H Habit training, for urinary incontinence, 830 Healing, phases of, 926–927 Health-related quality of life, testosterone deficiency and, 1013 Heart disease, 849–862 atrial fibrillation in, 857–858 cardiomyopathy, 856 coronary artery, 849–852 heart failure. See Heart failure. hypertensive, 852–853 pacemaker for, 858 rheumatic, 855 valvular, 853–856 Heart failure, 856–857, 863–885 clinical features of, 865 comorbid conditions with, 869 diagnosis of, 865–867 diastolic pathophysiology of, 864–865 treatment of, 874–875 economic impact of, 863 epidemiology of, 863 etiology of, 867–869 in aortic stenosis, 854 in middle adults versus older adults, 864–865 pathophysiology of, 863–865 precipitating factors in, 867–869 systolic, treatment of, 871–874 treatment of, 869–879 devices in, 875–877 diastolic, 874–875 end-stage, 878–879 exercise in, 877–878 future directions in, 879–880 multidisciplinary, 877 pharmacologic, 871–875 precipitating factor correction in, 869–871 systolic, 871–874 Hemostasis, in healing, 926

Hospice care, 998–999 Human immunodeficiency virus infection, 1031–1032 Hydralazine, for heart failure, 872 Hydrocolloid dressings, for pressure ulcers, 939 Hydrogel dressings, for pressure ulcers, 939 Hyperglycemia postprandial, in diabetes mellitus, 916–917 symptoms of, 913 Hypertension heart disease in, 852–853 heart failure in, 867 in diabetes mellitus, 917 Hypertrophic cardiomyopathy, 856 Hypoglycemia, in diabetes mellitus treatment, 914 Hypogonadism, in males. See Testosterone, deficiency of. Hypotension, postural, fall risk in, 810 Hysterectomy, sexuality after, 1034

I Ictal stupor, 954 Immobility, pressure ulcers in, 927, 929 Implantable cardioverter defibrillators, 876–877 Incontinence, urinary. See Urinary incontinence. Infections in diabetes mellitus, 913 of pressure ulcers, 939 Inflammation, in healing, 926–927 Insulin

1043

INDEX

for diabetes mellitus, 919 resistance to, 910–912

Mechanical debridement, of pressure ulcers, 938

Insulin-like growth factor, age-related changes in, testosterone levels and, 1011–1012

Medicare Hospice Benefit, 998–999

Interpersonal therapy, for depression, 798

Megestrol acetate, for appetite stimulation, 894, 989

Isosorbide dinitrate, for heart failure, 872 J Jakob-Creutzfeldt disease, 779 K Knee, osteoarthritis of, in obesity, 895–896

Medications, falls due to, 812

Memory neurotransmitters and, 770–771 normal aging-related changes in, 769–770 problems with. See also Dementia. diagnosis of, 772 Menopause, 1026–1027, 1030–1031 Mental status examinations, 772 Metformin, for diabetes mellitus, 918–919

L Lamotrigine, for epilepsy, 960–962

Metoprolol, for heart failure, 872

Left ventricular hypertrophy, in hypertension, 852–853

Mirtazapine, for depression, 795

Leg weakness, fall risk in, 810–813 Levetiracetam, for epilepsy, 960–961 Lewy bodies, dementia with, 778 Libido, deficiency of, 1007–1008 Lithium, for depression, 794, 796 M Macrocytic anemia, in folate deficiency, 901–902 Mad cow disease, 779 Maggots, for pressure ulcer debridement, 938–939 Magnetic resonance imaging, in epilepsy, 955–956 Magnetic stimulation, for depression, 800, 802 Major depressive disorders. See Depression. Malnutrition calcium deficiency in, 899 folate deficiency in, 901–902 obesity in, 895–897 pressure ulcers in, 930 protein-energy, 888–895 vitamin B12deficiency in, 900–901 vitamin D deficiency in, 898–899 Mattresses, for pressure ulcers, 938 Maturation phase, of healing, 927

Miglitol, for diabetes mellitus, 918

Mitral valve annular calcification of, 856 regurgitation of, 855–856 stenosis of, 855 Mixed incontinence, 826 Moisture, in pressure ulcer development, 931–932 Monoamine oxidase inhibitors, for depression, 793 Mood disorders, 789–805. See also Depression. clinical features of, 790–792 epidemiology of, 789 treatment of, 792–803 neuromodulation in, 799–803 pharmacologic, 792–797 psychotherapy in, 797–799 Mood stabilizers, for depression, 794, 796 Morphine, for dyspnea, 995 Mortality in diabetes mellitus, 913 in falls, 808 in obesity, 895 in protein-energy malnutrition, 889 in weight loss, 896–897 Multidimensional fall risk assessment, 814–815, 818–819 Multi-infarct dementia, 777–778 Murmurs, in valvular heart disease, 853–856

1044

INDEX

for muscle function, 841 obesity and, 895–897 supplements for, 894 vitamin B12 deficiency in, 900–901 vitamin D deficiency in, 898–899 weight changes and, 888

Muscarinic receptors, inhibitors of, for urinary incontinence, 831–832 Muscle(s) atrophy of, 840 hypertrophy of, 840 mass of loss of, frailty in, 838–842 testosterone levels and, 1010–1012 rejuvenation of, 840 versus fat, 888 Myocardial infarction, 850–852, 1033 Myoclonic seizures, 950 Myopathy, in vitamin D deficiency, 898

O Obesity consequences of, 895–896 frailty in, 839 prevalence of, 895 sarcopenia in, 839 testosterone deficiency in, 1011 treatment of, 896–897

Myostatin, in muscle rejuvenation inhibition, 841

Odor, of pressure ulcer, 936

Myosteatosis, 839, 842

Opioids endogenous, in memory, 770–771 for palliative care, 988, 992–995

N Nandrolone, for frailty, 842 Nateglinide, for diabetes mellitus, 919 National Pressure Ulcer Advisory Panel, staging system of, 934–937 Natriuretic peptide, B-type, in heart failure, 866

Olanzapine, for depression, 796–797

Orexin A, in memory, 770–771 Orthopnea, in heart failure, 865 Osteoarthritis, in obesity, 895–896 Osteomalacia, in vitamin D deficiency, 898

Nausea, in palliative care, 991, 996–997

Osteoporosis, in testosterone deficiency, 1012–1013

Nebivolol, for heart failure, 875

Overactive bladder, 826–827, 830–832

Necrosis, in pressure ulcer, 934

Overflow incontinence, 826–827

Negotiation, in palliative care, 985

Overnutrition, 895–897. See also Obesity.

Neurofibrillary tangles, in Alzheimer’s disease, 776

Oxcarbazepine for depression, 796 for epilepsy, 962

Neuromodulation for depression, 799–803 for urinary incontinence, 832

Oxybutynin, for urinary incontinence, 831–832

Neuropeptide Y, in memory, 770–771

Oxygen therapy, for dyspnea, 994–995

Neurosyphilis, 775, 1032 Neurotransmitters, in memory, 770–771 Norton Scale and Norton Plus Pressure Ulcer Scale, 932 Nortriptyline, for depression, 795 Nutrition, 887–907 appetite changes and, 887, 891–892 body composition changes and, 888 calcium deficiency in, 899 folate deficiency in, 901–902 food intake changes and, 887 for diabetes mellitus, 918

P PACE (Program of All-Inclusive Care of the Elderly), 999 Pacemaker bladder, for urinary incontinence, 832 cardiac, 858, 875–876 Pain assessment of, 992 chest, in coronary artery disease, 850–852 frailty in, 842 in pressure ulcers, 937

1045

INDEX

management of in cancer, 978 in palliative care, 987–988, 992–994 Palliative care, 983–1004 bereavement support in, 1000–1001 constipation treatment in, 989, 996 coordination of, 997–999 deficiencies in, 983–984 doctor-patient communication in, 984–987 dyspnea management in, 990, 994–995 example of, 984 goals of, 984 grief support in, 1000–1001 hospice in, 998–999 in cancer, 979 nausea treatment in, 991, 996–997 pain management in, 987–988, 992–994 Program of All-Inclusive Care of the Elderly (PACE), 999 psychosocial needs in, 999–1000 spiritual needs in, 999–1000 symptom management in, 987–997 Paroxetine, for depression, 795 Partial seizures, 948–949, 952 Pelvic examination, in urinary incontinence, 829 Pernicious anemia, 900–901

Pressure ulcers, 926–944 assessment of, 934–937 definition of, 926 documentation of, 935–937 economic impact of, 925 glossary for, 940 healing phases and, 926–927 risk factors for, 925–932 assessment of, 932–934 extrinsic, 928–929, 931–932 intrinsic, 927–930 size of, 935 stages of, 934–935 treatment of, 937–939 unstageable, 934 Prion disease, 779 Program of All-Inclusive Care of the Elderly (PACE), 999 Proliferative phase, of healing, 927 Prompted voiding, for urinary incontinence, 830 Prostate cancer of, sexuality and, 1034 hyperplasia of, testosterone levels and, 1008–1010 Prostatectomy for urinary incontinence, 832 sexuality after, 1034

Pharmacokinetics, of antineoplastic therapy, 969–970

Protein-energy undernutrition, 888–895 adverse effects of, 889 appetite changes and, 887, 891–892 causes of, 890–892 diagnosis of, 892–894 low body weight in, 889 pressure ulcers in, 930 prevalence of, 888 treatment of, 894–895 weight loss in, 889–890

Phenobarbital, for epilepsy, 961–962

Pseudodementia, 791

Phenytoin, for epilepsy, 958–959, 961–962

Psychoeducation, for depression, 799

Phosphodiesterase inhibitors, for erectile dysfunction, 1030

Psychologic issues in erectile dysfunction, 1029 in sexuality, 1027

Pessaries, vaginal, for urinary incontinence, 832 Petit mal (absence) seizures, 949–950 Pharmacodynamics, of antineoplastic therapy, 969–970

Polydipsia, in diabetes mellitus, 913 Polyuria, in diabetes mellitus, 913 Positioning, for pressure relief, in pressure ulcers, 937–938 Postural hypotension, fall risk in, 810 Postvoid residual volume, in urinary incontinence, 829 Pregabalin, for epilepsy, 960, 963

Psychosocial support in cancer, 978–979 in palliative care, 999–1000 Psychotherapy, for depression, 797–799 Purinergic transmission, in detrusor muscle control, 827 PUSH tool, for pressure ulcer assessment, 937

1046

INDEX

Q Quadriplegia, pressure ulcers in, 929

partial, 948–949, 952 petit mal (absence), 949–950 refractory, 946 secondarily generalized, 949 simple partial, 948, 952 symptomatic, 946 tonic, 950 tonic clonic, 950, 952, 954

Quality of life, testosterone deficiency and, 1013 Quetiapine, for depression, 796–797 Q-wave myocardial infarction, 850–851 R Radiation therapy, for cancer, 975 Ramipril, for heart failure, 875 Red-yellow-black system, for pressure ulcer description, 935–936 Regurgitation aortic, 854–855 mitral, 855–856

Selective serotonin reuptake inhibitors, for depression, 794–795 Selegiline, for depression, 793 Semantic dementia, 779 Sertraline, for depression, 795 Sex hormone-binding globulin, excess of, testosterone deficiency in, 1006

Rheumatic mitral stenosis, 855

Sexuality, 1025–1036 changes in, 1025–1027 comorbidities affecting, 1033–1034 cultural aspects of, 1034–1035 definition of, 1025 erectile dysfunction and, 1028–1030 menopause and, 1026–1027, 1030–1031 myths of, 1027–1028 religious aspects of, 1034–1035 sexual response cycle in, 1025–1027 sexually transmitted diseases and, 1031–1033 testosterone and, 1007–1010 urinary incontinence and, 828

Rickets, in vitamin D deficiency, 898

Sharp debridement, of pressure ulcers, 938

Risperidone, for depression, 796–797

Shear, in pressure ulcer development, 931

Religious aspects, of sexuality, 1034–1035 Repaglinide, for diabetes mellitus, 919 Repetitive transcranial magnetic stimulation, for depression, 800, 802 Resident Assessment Instrument, for pressure ulcer staging, 934 Restraints, for fall prevention, 818 Resynchronization therapy, for heart failure, 876

S Safety checklists, for fall prevention, 816–817 St. Louis University Mental Status Examination, 772

Sildenafil, for erectile dysfunction, 1010, 1030 Simple partial seizures, 948, 952 Simplified Appetite Questionnaire, 894 Skin aging of, pressure ulcer risk in, 930 pressure ulcers of. See Pressure ulcers.

Sarcopenia frailty in, 838–842 testosterone levels and, 1010–1012

Smell, impairment of, anorexia in, 891

Scar tissue, in pressure ulcer healing, 935

Solifenacin, for urinary incontinence, 832

Seizures. See also Epilepsy. absence, 949–950 atonic, 950 classification of, 947–950 clonic, 950 complex partial, 949, 952–953 definitions of, 946–947 generalized, 949–950 grand mal (tonic clonic), 950, 952, 954 myoclonic, 950

Somnolence, in heart failure, 865 Spinal cord injury, pressure ulcers in, 927, 929 Spiritual needs, in palliative care, 999–1000 Spironolactone, for heart failure, 873–874 Status epilepticus, 954–955 Stenosis

1047

INDEX

aortic, 853–854 mitral, 855 Strength, loss of, frailty in, 839 Strength training for fall prevention, 816 for heart failure, 878 Stress incontinence, 826–827 Stroke dementia in, 777–778 depression after, 790–791 epilepsy after, 951–952 in atrial fibrillation, 858 sexuality after, 1033 urinary incontinence in, 826 Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments, 879

erectile dysfunction in, 1008–1010 health-related quality of life and, 1013 hormone measurement in, 1006–1007 in receptor defects, 1006 pathophysiology of, 1006 sexuality and, 1007–1010, 1026–1027 skeletal muscle decrease in, 1010–1012 treatment of, 1014–1016 diabetes mellitus and, 910 for Alzheimer’s disease, 777 for appetite stimulation, 894 in muscle hypertrophy, 840–841 supplementation of, side effects of, 1016

Suburethral sling insertion, 832–833

Thiazolindinediones, for diabetes mellitus, 919

Sulfonylureas, for diabetes mellitus, 919

Tiagabine, for epilepsy, 963

Supportive care, for cancer, 978–979

Toileting protocols, for urinary incontinence, 830

Surgery for cancer, 975 for epilepsy, 964 sexuality and, 1033–1034 Syncope fall risk in, 810 in aortic stenosis, 854 a-Synuclein, in dementia with Lewy bodies, 778 Syphilis, 775, 1032 Systems (family) therapy, for depression, 798 Systolic hypertension, 852

Tolterodine, for urinary incontinence, 831–832 Tonic, seizures, 950 Tonic clonic seizures, 950, 952, 954 Topiramate for depression, 796 for epilepsy, 960–962 Transcranial magnetic stimulation, repetitive, for depression, 800, 802 Trazodone, for depression, 795 Tricyclic antidepressants, for depression, 793, 795 Trospium, for urinary incontinence, 832

T Tacrine, for Alzheimer’s disease, 777

Tumor necrosis factor, excess of, anorexia due to, 891–892

Tadalafil, for erectile dysfunction, 1030 Tai chi, for fall prevention, 816 Taste, impairment of, anorexia in, 891 Teeth, problems with, undernutrition in, 892 Testosterone deficiency of, 1005–1023 bone loss in, 1012–1013 cardiovascular effects of, 1016 cognitive dysfunction in, 1013 diagnosis of, 1014

U Ulcers, pressure. See Pressure ulcers. Undermining, of pressure ulcers, 936–937 Undernutrition. See Protein-energy undernutrition. Urinary incontinence, 825–836 causes of, 828–829 clinical assessment of, 828–829 complications of, 828 economic impact of, 825, 828

1048 Urinary (continued ) functional, 826–827 mechanistic classification of, 826–827 mixed, 826 overflow, 826–827 pathophysiology of, 825–826 prevalence of, 825 referral in, 829 sexuality and, 1034 stress, 826–827 treatment of, 829–833 Urinary tract symptoms, in testosterone deficiency, 1008–1010

INDEX

Video monitoring, in epilepsy, 956–957 Vigabatrin, for epilepsy, 961 Visual impairment, fall risk in, 810–811 Vitamin B12deficiency, 900–901 Vitamin D deficiency, 841, 898–899 Voiding diary, in incontinence, 829 Vomiting, in palliative care, 991, 996–997 Vulnerable Elders Survey, in cancer, 975

Urodynamic studies, in urinary incontinence, 829

W Waterlow Scale, for pressure sore risk assessment, 933

V Vaginal pessaries, for urinary incontinence, 832

Weakness, leg, fall risk in, 810–813

Vagus nerve stimulation for depression, 800–802 for epilepsy, 964 Valproate for depression, 796 for epilepsy, 962 Valvular heart disease, 853–856 Vardenafil, for erectile dysfunction, 1030 Vascular dementia, 777–778 Vascular depression hypothesis, 790

Weight loss of after age 60, 889–890 bone loss with, 896 frailty in, 842 versus age, 888 versus mortality curve, 889 Withholding or withdrawing treatment, in palliative care, 985–986 World Health Organization, Analgesic Ladder of, 992 Wound care, of pressure ulcers. See Pressure ulcers.

Venlafaxine, for depression, 795 Ventricular hypertrophy, in hypertension, 852–853

Z Ziprasidone, for depression, 796–797

Vertigo, fall risk in, 810

Zonisamide, for epilepsy, 962