Safety and e1 TheHealth Care Quality of

David W. Bates
The safety and quality of care are two of the central dimensions of health care. It is increasingly clear that both could be much better, and in recent years it has become easier to measure both safety and quality. In addition, the public is—with good justification—demanding measurement and accountability, and increasingly payment for services will be based on performance in these areas. Thus, physicians must learn about these two domains, how they can be improved, and the relative strengths and limitations of our current ability to measure them. Safety and quality are closely related but do not completely overlap. The Institute of Medicine has suggested in a seminal series of reports that safety is the first part of quality, and that health care first must guarantee that it will deliver safe care, although quality is also pivotal. In the end, it is likely that more net clinical benefit may be derived from improving quality than safety, though both are important, and safety is in many ways more tangible to the public. Accordingly, the first section of this chapter will address issues relating to the safety of care, while the second will cover quality of care. SAFETY IN HEALTH CARE Safety Theory Safety theory clearly points out that individuals make errors all the time. Think of driving home from the hospital; you intend to stop and pick up a quart of milk on your way home, but you find yourself entering your driveway, without realizing how you got there. We all use low-level, semi-automatic behavior for many of our activities in daily life; this kind of error is called a “slip.” Slips occur often during care delivery; e.g., when someone intends to write an order but forgets because they have to complete another action first. “Mistakes,” by contrast, are errors of a higher level; they occur in new or non-stereotypic situations in which conscious decisions are being made. An example would be in dosing a medication with which the physician is not familiar. The strategies used to prevent slips and mistakes are often different. Another theory relating to errors is human factors theory, which describes how activities are carried out and offers a variety of insights into how to make them safer and more reliable. Systems theory suggests that most accidents occur as the result of a series of small failures, which happen to line up in an individual instance such that an accident can occur (Fig. e1-1). It also suggests that most individuals in an industry such as health care are trying to do the right thing (e.g., deliver safe care), and most accidents can be seen as the result of defects in the systems. Correspondingly, systems should be designed both to make errors less likely and to identify those that do occur, as some inevitably will. Factors That Increase the Likelihood of Errors A number of factors ubiquitous in health care systems can increase the likelihood of errors, including fatigue, stress, interruptions, complexity, and transitions. The effects of fatigue in other industries are clear, but its effects in health care have until recently been more controversial. For example, the accident rate in truck drivers increases dramatically if they work over a certain number of hours in a week, and especially with prolonged shifts. A recent study of house officers in the intensive care unit demonstrated that they were about one-third more likely to make errors when they were on a 24-h shift than when they were on a schedule that allowed them to sleep 8 h the previous night. The American College of Graduate Medical Education (ACGME) has moved to address this issue by putting in place the 80-h work week. While this is a step forward, it does not address the most important cause of fatigue-related errors, i.e., extended-duty shifts. High levels of stress and workload can also increase error rates. Thus, in extremely high-pressure situations, such as cardiac arrests, errors are more likely to occur. Strategies

e1
Hazards Some holes due to active failures

CHAPTER e1
The Safety and Quality of Health Care

Other holes due to latent conditions (resident "pathogens") Losses Succesive layers of defenses, barriers and safeguards

FIGURE e1-1 “Swiss cheese” diagram. Reason has argued that most accidents occur when a series of “latent failures” in a system are present, and that they happen to line up in a given instance, resulting in an accident. Examples of latent failures in the case of a fall might be that the unit was unusually busy that day, and that the floor happened to be wet. (Adapted from J Reason: Human error: Models and management. BMJ 320:768–770, 2000; with permission.) such as using protocols in these settings can be helpful, as can simply recognizing that the situation is stressful. Interruptions also increase the likelihood of error and are frequent in health care delivery. It is common to forget to complete an action when one is interrupted partway through it by a page, for example. Approaches that may be helpful in this area include minimizing the use of interruptions and setting up tools that help define the urgency of the interruption. In addition, complexity represents a key issue that contributes to errors. Providers are confronted by streams of data, such as laboratory tests and vital signs, many of which provide little useful information, but some of which are important and require action or suggest a specific diagnosis. Tools that emphasize specific abnormalities or combinations of abnormalities may be helpful in this area. Transitions between providers and settings are also frequent in health care, even more so with the advent of the 80-h work week, and generally represent vulnerabilities. Tools that provide structure in exchanging information, e.g., when transferring care between providers, may be helpful. The Frequency of Adverse Events in Health Care Most of the large studies focusing on the frequency and consequences of adverse events have been performed in the inpatient setting; some data are available for nursing homes, and much less information is available in the outpatient setting. The Harvard Medical Practice Study was one of the largest studies to address this issue, and was performed with hospitalized patients in New York. The primary outcome was the adverse event, which is an injury caused by medical management, rather than the patient’s underlying disease. In this study, an event either resulted in death or disability at discharge, or prolonged the length of stay by at least 2 days. Key findings were that the adverse event rate was 3.7%, and 58% of adverse events were considered preventable. Although there was some concern that New York is not representative of the rest of the country, the study was replicated later in Colorado and Utah, where the rates were essentially similar. Since then, other studies have been performed in a variety of developed nations using analogous methodologies, and the rates in most countries appear to be ~10%. In the Medical Practice Study, adverse drug events (ADEs) were the most frequent type, accounting for 19% of adverse events, followed by wound infections (14%) and technical complications (13%). Almost half of the adverse events were associated with a surgical procedure. Among the nonoperative events, 37% were ADEs, 15% were diagnostic mishaps, 14% were therapeutic mishaps, 13% were procedurerelated, and 5% were falls. ADEs have been studied more than any other category. Studies focusing specifically on ADEs have found that they appear to be much

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e2 more frequent than was suggested by the Medical Practice Study, although most other studies use more inclusive criteria. Detection approaches in the research setting include chart review and use of a computerized ADE monitor, which is a tool that explores the database and identifies signals that suggest an ADE may have occurred. Studies that use multiple approaches find more ADEs than any individual approach, suggesting that the true underlying rate in the population is higher than would be identified by any individual approach. About 6– 10% of patients admitted in U.S. hospitals suffer an ADE. Injuries caused by drugs are also frequent in the outpatient setting. One study found a rate of 21 ADEs per every 100 patients per year when patients were called to assess whether or not they had had a problem with one of their medications. The severity level was lower than in the inpatient setting, but approximately one-third of the ADEs were preventable. Another area that appears to be very risky is the period immediately after the patient is discharged from the hospital. One recent study of patients hospitalized on a medical service found an adverse event rate of 19%; about a third of these were preventable, and another third were ameliorable in that they could have been made less severe. ADEs were the single leading category. Prevention Strategies Most of the work on adverse event prevention strategies has targeted specific types of adverse events in the inpatient setting, with ADEs and nosocomial infections having received the most attention. For ADEs, several strategies have been found to reduce the medication error rate, although it has been harder to demonstrate that they reduce the ADE rate, and studies with adequate power to demonstrate a clinically meaningful reduction have not been published as yet. Computerized physician order entry (CPOE) linked with clinical decision support has been found to reduce the serious medication error rate—serious medication errors are those that harm someone or have the potential to do so. In one study, CPOE, even with limited decision support, decreased the serious medication error rate by 55%. CPOE can prevent medication errors by suggesting a default dose, ensuring that all orders are complete (e.g., include a dose, route, and frequency), and checking orders for allergies, drug-drug interactions, and drug-laboratory issues. In addition, clinical decision support can suggest the right dose for the patient, tailoring it to the patient’s level of renal function and age. In one study, without decision support patients with renal insufficiency received the appropriate dose only one-third of the time, while this fraction increased to approximately two-thirds with decision support, and patients with renal insufficiency were discharged from the hospital one-half day earlier. As of 2006, only about 15% of U.S. hospitals had implemented CPOE, but many more have plans to do so. Another technology that can improve medication safety is bar-coding linked with an electronic medication administration record. Barcoding can help ensure that the right patient gets the right medication at the right time. Electronic medication administration records can make it much easier to determine what medications a patient has received. Studies to assess the impact of bar-coding on medication safety are underway, and the early results are promising. Another technology that can be used to improve the safety of medication administration is “smart pumps.” These are pumps that can be instructed in which medication is being given, and at what dose; if the nurse tries to administer too high a dose, he or she will receive a warning. Non-technology-oriented interventions can also be highly effective. For example, having a pharmacist round with the team in the intensive care unit has been shown to decrease the ADE frequency substantially in that setting; this oversight is now a Joint Commission of Accreditation of Healthcare Organizations (JCAHO) requirement. The National Picture around Safety Several organizations, including the National Quality Forum (NQF) and the JCAHO, have made recommendations about how to improve safety. In particular, the NQF has released recommendations to the country’s hospitals about what

practices will most improve the safety of care, which all hospitals are expected to implement (Table e1-1). Many of these practices arise frequently in routine care. One example is “readback,” which is the practice of recording all verbal orders and immediately reading them back to the physician to verify the accuracy of what was heard. Another is to use only standard abbreviations and dose designations, since some abbreviations and dose designations are particularly prone to error; for example, 7U may be read as 70. Measurement of Safety Measuring the safety of care is quite difficult and expensive, since adverse events are fortunately rare. Most hospitals rely on spontaneous reporting to identify errors and adverse events, but this approach has a very low sensitivity, with only ~1 in 20 ADEs reported. There are promising research techniques that involve searching the electronic record for signals suggesting that an adverse event has occurred, which will likely be routine in the future but are not yet in wide use. Claims data have been used to identify the frequency of adverse events; this approach works much better for surgical care than for medical care and still requires additional validation. The net result is that except for a few specific types of events, such as falls and nosocomial infections, hospitals have little idea about the true frequency of safety issues. Nonetheless, all providers have the responsibility to report problems with safety as they are identified. All hospitals have spontaneous reporting systems, and if providers report events as they occur, these events can be used as lessons for subsequent improvement. Conclusions about Safety It is now abundantly clear that the safety of health care can be improved substantially; as more areas are studied closely, more problems are identified. Compared to the outpatient setting, much more is known about the epidemiology of safety in the inpatient setting, and a number of effective strategies for improving safety have been identified and are being used increasingly. Some effective strategies are also available in the outpatient setting. Transitions appear to be especially risky. The solutions to improving care will often involve leveraging information technology, but they will also involve many other domains, such as use of human factors techniques, team training, and building a culture of safety. QUALITY IN HEALTH CARE Quality of care has remained somewhat elusive, although the tools for measuring it have increasingly improved. Selecting health care and measuring its quality is a complex process. Quality Theory Donabedian has suggested that quality of care can be divided by type of measurement into structure, process, and outcome. Structure refers to whether or not a particular characteristic is present, e.g., whether a hospital has a catheterization laboratory or whether a clinic uses an electronic health record. Process refers to the way that care is delivered, and examples of process measures are whether a Pap smear was performed at the recommended interval or whether an aspirin was given to a patient with a suspected myocardial infarction. Outcomes refer to what actually happens, e.g., the mortality rate in myocardial infarction. It is important to note that good structure and process do not always result in good outcomes. For instance, a patient may present with a suspected myocardial infarction to an institution with a catheterization laboratory and receive recommended care, including aspirin, but still die because of their infarction. Quality theory also suggests that overall quality will be improved more in the aggregate by raising the level of performance of all providers rather than finding a few poor performers and punishing them. This view suggests that systems changes are especially likely to be helpful in improving quality, since large numbers of providers may be affected simultaneously. The theory of continuous quality improvement suggests that organizations should be evaluating the care they deliver on an on-going basis and continually making small changes to improve their individual processes. This approach can be very powerful if embraced over time.

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Introduction to Clinical Medicine

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TABLE e1-1 SAFE PRACTICES FOR BETTER HEALTH CARE a
1. Create a health care culture of safety. 2. For designated high-risk, elective surgical procedures or other specified care, patients should be clearly informed of the likely reduced risk of an adverse outcome at treatment facilities that have demonstrated superior outcomes and should be referred to such facilities in accordance with the patient’s stated preference. 3. Specify an explicit protocol to be used to ensure an adequate level of nursing based on the institution’s usual patient mix and the experience and training of its nursing staff. 4. All patients in general intensive care units (both adult and pediatric) should be managed by physicians having specific training and certification in critical care medicine (“critical care certified”). 5. Pharmacists should actively participate in the medication-use process, including, at a minimum, being available for consultation with prescribers on medication ordering, interpretation and review of medication orders, preparation of medications, dispensing of medications, and administration and monitoring of medications. 6. Verbal orders should be recorded whenever possible and immediately read back to the prescriber—i.e., a health care provider receiving a verbal order should read or repeat back the information that the prescriber conveys in order to verify the accuracy of what was heard. 7. Use only standardized abbreviations and dose designations. 8. Patient care summaries or other similar records should not be prepared from memory. 9. Ensure that care information, especially changes in orders and new diagnostic information, is transmitted in a timely and clearly understandable form to all of the patient’s current health care providers who need that information to provide care. 10. Ask each patient or legal surrogate to recount what he or she has been told during the informed consent discussion. 11. Ensure that written documentation of the patient’s preference for life-sustaining treatments is prominently displayed in his or her chart. 12. Implement a computerized prescriber order entry system. 13. Implement a standardized protocol to prevent the mislabeling of radiographs. 14. Implement standardized protocols to prevent the occurrence of wrong-site procedures or wrongpatient procedures. 15. Evaluate each patient undergoing elective surgery for risk of an acute ischemic cardiac event during surgery, and provide prophylactic treatment of high-risk patients with beta blockers. 16. Evaluate each patient upon admission, and regularly thereafter, for the risk of developing pressure ulcers. This evaluation should be repeated at regular intervals during care. Clinically appropriate preventive methods should be implemented consequent to the evaluation. 17. Evaluate each patient upon admission, and regularly thereafter, for the risk of developing deep vein thrombosis (DVT)/venous thromboembolism (VTE). Utilize clinically appropriate methods to prevent DVT/VTE. 18. Utilize dedicated anti-thrombotic (anti-coagulation) services that facilitate coordinated care management. 19. Upon admission, and regularly thereafter, evaluate each patient for the risk of aspiration. 20. Adhere to effective methods of preventing central venous catheter–associated bloodstream infections. 21. Evaluate each preoperative patient in light of his or her planned surgical procedure for the risk of surgical site infection, and implement appropriate antibiotic prophylaxis and other preventive measures based on that evaluation. 22. Utilize validated protocols to evaluate patients who are at risk for contrast media-induced renal failure, and utilize a clinically appropriate method for reducing risk of renal injury based on the patient’s kidney function evaluation. 23. Evaluate each patient upon admission, and regularly thereafter, for risk of malnutrition. Employ clinically appropriate strategies to prevent malnutrition. 24. Whenever a pneumatic tourniquet is used, evaluate the patient for the risk of an ischemic and/or thrombotic complication, and utilize appropriate prophylactic measures. 25. Decontaminate hands with either a hygienic hand rub or by washing with a disinfectant soap prior to and after direct contact with the patient or objects immediately around the patient. 26. Vaccinate health care workers against influenza to protect both them and patients from influenza. 27. Keep workspaces where medications are prepared clean, orderly, well lit, and free of clutter, distraction, and noise. 28. Standardize the methods for labeling, packaging, and storing medications. 29. Identify all “high alert” drugs (e.g., intravenous adrenergic agonists and antagonists, chemotherapy agents, anticoagulants and anti-thrombotics, concentrated parenteral electrolytes, general anesthetics, neuromuscular blockers, insulin and oral hypoglycemics, narcotics and opiates). 30. Dispense medications in unit-dose or, when appropriate, unit-of-use form, whenever possible.

processes, making this tool especially impor- e3 tant for improvement.

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The Safety and Quality of Health Care

Factors Relating to Quality Many factors can decrease the level of quality, including stress to providers, high or low levels of production pressure, and poor systems, to name but a few examples. Stress can adversely affect quality because it can lead providers to omit important steps, as can a high level of production pressure. Low levels of production pressure can also sometimes result in worse quality, as providers may be bored or have little experience with a specific problem. Poor systems can have a tremendous impact on quality, and even extremely dedicated providers typically cannot achieve high levels of performance if they are operating within a poor system. Data about the Current State of Quality A recent RAND study has provided the most complete picture of quality of care delivered in the United States to date. The results were sobering. The authors found that across a wide range of quality parameters, patients in the United States received only 55% of recommended care overall; there was little variation by subtype, with scores of 54% for preventive care, 54% for acute care, and 56% for care of chronic conditions, leading the authors to conclude that the chances of getting highquality care in the United States broadly were little better than those of winning a coin flip.

Strategies for Improving Quality and Performance A number of specific strategies can be used to improve quality at the individual level, including rationing, education, feedback, incentives, and penalties. Rationing has been effective in some specific areas, such as convincing physicians to prescribe within a formulary, but it generally has been resisted. Education is effective in the short run and is necessary for changing opinions, but its effect decays fairly rapidly with time. Feedback on performance can be given either at the group or individual level. Feedback is most effective if it is individualized and if it is given in close temporal proximity to the original events. Incentives can be effective, and many believe that this will be a key to improving quality, especially if pay-for-performance with sufficient incentives is broadly implemented (see below). Penalties produce provider resentment and are rarely used in health care. a These 30 practices are the recommendations from the National Quality Forum (NQF) for improving the safety of Another set of strategies for improving quality involves changing the systems of care. An exhealth care; the NQF believes these should be universally utilized in applicable care settings to reduce the risk of patient harm. The practices all have strong supporting evidence and are likely to have a significant benefit. ample would be introducing reminders about which specific actions need to be taken at a visit for a specific patient, which is a strategy that has A number of specific tools have been developed to help improve been demonstrated to improve performance in certain situations, e.g., in process performance. One of the most important of these tools is delivery of preventive services. Another approach that has been effective the Plan-Do-Check-Act cycle (Fig. e1-2). This approach can be is the development of “bundles” or groups of quality measures that can used to perform what is called rapid cycle improvement for a pro- be implemented together with a high degree of fidelity. A number of hoscess, e.g., the time for a patient with pneumonia to receive antibi- pitals have now implemented a bundle for ventilator-associated pneumootics after diagnosis. Often, specific statistical tools, such as control nia in the intensive care unit, which includes five measures, including, for charts, are used in conjunction to determine whether or not example, ensuring that the head of the bed is elevated. The hospitals have progress is being made. Most medical care comprises one or many found that they were able to substantially improve performance.
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e4

Adopt or abandon strategies based on results

A

ct

Pl

an

Identify potential improvement strategies

Ch
Measure effectiveness of strategies

Do

ec k

Try out strategies

FIGURE e1-2 Plan-do-check-act (or PDCA) cycle. The PDCA cycle approach can be used to improve a specific process rapidly. First, planning is performed, and several potential improvement strategies are identified. Next, these strategies are trialed in small “tests of change.” “Checking” is measuring whether or not they appeared to make a difference, and “act” refers to acting on the results. Perhaps the most pressing need is to improve the quality of care for chronic diseases. The Chronic Care Model has been developed by Wagner and colleagues (Fig. e1-3); it suggests that a combination of strategies will be necessary, including self-management support, changes in delivery system design, decision support, and information systems, and that these must be delivered by a practice team composed of several providers, not just a physician. Recent evidence about the relative efficacy of strategies in reducing hemoglobin A1c (HbA1c) in outpatient diabetes care (Fig. e1-4) supports this general premise. It is especially notable that the outcome was HbA1c, as it has generally been much more difficult to improve outcome measures than process measures (such as whether a HbA1c was performed). In this meta-analysis, a variety of strategies were effective, but the most effective ones were the use of team changes and use of a case manager. When cost-effectiveness is considered in addition, it appears likely that an amalgam of strategies will be needed. However, the more expensive strategies, such as use of case managers, will likely be implemented widely only if pay-for-performance takes hold.

National State of Quality Measurement In the inpatient setting, quality measurement is now being performed by a very large proportion of hospitals for several conditions, including myocardial infarction, congestive heart failure, pneumonia, and surgical infection prevention; 20 measures are included in all. This is the result of the Hospital Quality Initiative, which represents a collaboration among many entities, including the Hospital Quality Alliance, the JCAHO, the NQF, and the Agency for Healthcare Research and Quality, among others. The data are housed at the Center for Medicare and Medicaid Services, which publicly releases performance on the measures on a website called Hospital Compare. These data are voluntarily reported and are available for a very high proportion of the nation’s hospitals; they were first released in April 2006. Early analyses demonstrate that there is substantial regional variation in quality and that there are important differences among hospitals. Analyses by the Joint Commission for very similar indicators demonstrate that performance on measures by hospitals did improve over time, and that, as might be hoped, lower performers improved more than higher performers. Analogous national data for ambulatory care are not yet available, but a group called the Ambulatory care Quality Alliance (AQA) has been formed and is developing an analogous set of measures. Public Reporting Overall, public reporting of quality data is becoming increasingly common. There are now commercial websites that have quality-related data for most regions of the country that can be accessed for a fee. Similarly, national data for hospitals are available. The evidence to date is that patients have not used such data very much, but that such data have had an important effect on provider and organization behavior. Instead, patients have relied on provider reputation to make choices. Part of the reason for this choice basis is that until very recently little information was available, and it was not necessarily represented in ways that were easy for patients to access. Many believe that as more information about quality becomes available, it will become increasingly central to patient choices about where to access care. Pay-for-Performance Currently, providers in the United States get paid exactly the same amount for a specific service regardless of what quality care is delivered. The theory of pay-for-performance suggests that if providers are paid more for higher-quality care, they will invest in strategies that enable them to deliver that care. The current key issues in the pay-for-performance debate relate to (1) how effective it is, (2) what levels of incentives are needed, and (3) what perverse consequences are produced. The evidence about effectiveness is fairly limited to date, although a number of studies are ongoing. With respect to levels, most performance incentives around quality have accounted for merely 1–2% of total payment in this country to date, but in the United Kingdom, 40% of general practitioners’ salaries have recently been placed at risk based on performance across a wide array of parameters. This has been associated with large improvements in reported quality performance, although it is still unclear as to what extent this represents better performance versus better reporting. The potential for perverse consequences exists with any incentive scheme. One problem is that if incentives are tied to outcomes, this introduces the incentive to transfer the sickest patients to other providers and systems. Another concern is that providers will pay too much attention to quality measures with incentives, and ignore the rest of the quality picture. The validity of these concerns remains to be determined. CONCLUSIONS The safety and quality of care in the United States could be improved substantially. A number of interventions are available today that have been demonstrated to improve the safety of care and should be used more widely; others are undergoing evaluation or will be evaluated. Quality could also be dramatically better, and the science of quality improvement is increasingly mature. Implementation of pay-forperformance should make it much easier for organizations to justify investments in improving these parameters, including health informa-

PART 1
Introduction to Clinical Medicine
Community
Resources and policies Selfmanagement Support

Health System
Organization of health care Delivery system design Decision support Clinical information systems

Informed, activated patient

Productive interactions

Prepared, proactive practice team

Improved Outcomes FIGURE e1-3 The chronic care model. The chronic care model, which focuses on improving care for chronic diseases, suggests that delivery of high-quality care demands a range of strategies that must closely involve and engage the patient, and, in addition, that team care is essential. (From Wagner et al: Eff Clin Pract 1:2, 1998.)

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Quality Improvement Strategy Team changes Case management Patient reminders Patient education Electronic patient registry Clinician education

No. of Trials 26 26 14 38 8 20 15 20 9 18 3 66 –1.0

Favors intervention

Favors control

Facilitated relay of clinical information Self-management Audit and feedback Clinician reminders Continuous quality improvement All interventions

much more robust; it would be particularly useful e5 if organizations had measures that they could use in routine operations to assess safety at reasonable cost. While the quality measures available are more robust than those for safety, they still cover a relatively small proportion of the entire domain of quality, and more need to be developed. The public and payers are now demanding better information about safety and quality, as well as better performance in these areas. The clear implication is that these domains will need to be addressed directly by providers.

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The Safety and Quality of Health Care

FURTHER READINGS
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BATES DW et al: Effect of computerized physician order entry and a team intervention on prevenDifference in postintervention HbA1c, % tion of serious medication errors. JAMA 280:1311, 1998 FIGURE e1-4 The efficacy of various strategies for improving diabetes care in outpatients. Shojania et al. performed a meta-analysis of evaluating the efficacy of strategies BRENNAN TA et al: Incidence of adverse events and negligence in hospitalized patients: Results for reducing hemoglobin A1c (HbA1c) in diabetic outpatients; they found that team from the Harvard Medical Practice Study I. N changes and case management had the largest impact on HbA1c, although there was a Engl J Med 324:370, 1991 trend toward improvement for many strategies. Interventions in which nurse or pharmacist case managers can make medication adjustments without awaiting physician autho- MCGLYNN EA et al: The quality of health care delivered to adults in the United States. N Engl J rization resulted in the largest reductions. (From Shojania et al: JAMA 296:427, 2006.) Med 348:2635, 2003 SHOJANIA KG et al: Effects of quality improvement tion technology; however, many will also require changing the strucstrategies for type 2 diabetes on glycemic control: A meta-regresture of care, e.g., moving to a more team-oriented approach, and sion analysis. JAMA 296:427, 2006 ensuring that the patients are more involved in their own care. The WAGNER EH et al: Improving chronic illness care: Translating evidence into action. Health Aff (Millwood) 20:64, 2001 measures of safety are still relatively immature and could be made

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e2 Economic Considerations in the Practice of Medicine
David Meltzer
The enormous and continuing growth of health care spending in the United States and many other countries over recent decades has focused attention on the causes, consequences, and possible responses to rising expenditures on health care. A variety of strategies to control costs have been developed that have made it increasingly important that physicians and other health care professionals understand a wide range of economic considerations in the practice of medicine. HEALTH CARE COSTS Between 1960 and 2005, health care spending in the United States increased from about $27 billion to $2.1 trillion. This growth in spending was about 2–3% higher per year than growth in the overall economy, causing health care spending to rise from 6% of gross domestic product to >16%. This increase in spending has produced enormous challenges for everyone who pays for health care. For government, these challenges include rising federal, state, and local government health care budgets, which have required increases in taxes. For firms and their workers, the biggest challenge is the high cost of insuring workers, which causes employers to drop (or reduce) health insurance coverage, to move jobs overseas, or to reduce wages. The rising cost of insurance coverage that is passed on to workers also increases rates of uninsurance, because some workers choose to forego insurance even when it is available or take jobs that do not offer insurance coverage. The increasing cost of medical care also raises the cost of any attempts through public policy to provide insurance coverage to the >45 million Americans who now lack health insurance. Increased outof-pocket costs for patients are also a common outgrowth of rising health care expenditures. Overall, about 15–20% of health care costs are now paid out of pocket by consumers. Because some persons consume no health care, the fraction of health care costs paid out of pocket by persons who actually use health care is even higher, ~35% of their total health care costs. The combination of rising costs and high rates of uninsurance, along with the knowledge that many other developed countries spend only about half as much on health care yet are able to provide universal coverage and have health outcomes that are as good as or better than those in the United States, has understandably created widespread concern that the U.S. health care system is neither as efficient nor as effective as it could be. This, in turn, has produced many efforts to understand the causes of increased costs and to improve the delivery and financing of health care in the United States. Causes of Rising Costs Many causes of the rise in health care costs have been suggested. An aging population is commonly cited but has actually contributed rather little to recent increases in per capita spending. One reason for this is that, unlike the large cohort of baby boomers who will reach old age in the coming years, the cohort of persons born during the Depression Era of the 1930s who have reached retirement age in recent years is relatively small, because birth rates were low during that depression. Another reason that aging has not contributed so greatly to increasing expenditures is that improving health during old age has tended to delay the onset of serious illness and high health care expenditures. Another commonly suggested cause of rising expenditures has been medical malpractice and resulting defensive medicine, but evidence suggests that this is not a large contributor to health care costs in the United States. Administrative costs have also have been suggested to play an important role and are probably at least 10–15% of total costs for private insurance. Despite the significant and rising number of persons who lack insurance in the United States, one possible cause of rising health care costs since 1960 for which there is strong evidence is the increasing in-

surance coverage of health care and resulting increases in demand for e7 health care. Some scholars date the growth in health insurance coverage to the beginning of World War II when an Internal Revenue Service ruling established that employer-provided health insurance would be exempt from personal income tax. Today, employer-sponsored health insurance provides insurance coverage for ~60% of Americans. The growth of Blue Cross and Blue Shield insurance plans dates from this period of the establishment of employer-sponsored health insurance, and these plans formed a model for private health insurance in the United States. This was followed in the 1960s by the creation of Medicare and then Medicaid and a series of subsequent expansion of these programs. Nevertheless, based on data from the effects of health insurance coverage on the demand for health care, experts have estimated that these increases in insurance coverage account for only about one-quarter of the increase in health care spending since 1960. Instead, most health economists now believe that the primary cause of increasing spending on health care is the development of new technologies that, on average, offer improvements in health that are of substantial value to patients. An illustrative example of this is the cost of treating an acute myocardial infarction, which grew at ~5% annually in real terms over the mid-1980s and -1990s. This occurred at the same time that the cost of the individual major treatments for acute myocardial infarction—medical management, fibrinolysis, percutaneous coronary intervention, and coronary bypass surgery—either fell or increased minimally. The change in the overall cost occurred because the more expensive treatment options (e.g., revascularization) were increasingly used over the less expensive ones (e.g., medical management). Most economists have concluded that similar increases in the use of new technologies explain most of the increase in health care spending over this period. Estimates of the value of these increases in spending in terms of health indicate that on average they have yielded benefits far in excess of their costs, suggesting that these changes are the result of expanding opportunities to produce increases in health that are valued well above the cost of producing them. However, a broad body of evidence also indicates that many new technologies are not worth their costs, and it has been suggested that the broad expansion of insurance coverage has increased the incentives to develop costly medical technologies, even when they are not worth their cost. These conclusions suggest that efforts to control the cost of health care must consider both immediate and longer-term effects and be acutely aware of the value of health that is produced. THE DEMAND FOR AND SUPPLY OF HEALTH CARE Demand and supply are the fundamental tools that economists use to analyze health care markets and the spending within them. The demand for health care derives ultimately from the desire of individuals to be healthy. Health economists think of health as a capital good (“health capital”) in the sense that it tends to be durable, so that health today contributes positively to health tomorrow. A logical consequence of this is that rational decisions about health involve thinking about benefits and costs both in the present and in the future. Although individuals cannot buy health, they can buy health care that they hope will improve their health. Because health care costs can be high and variable, health insurance is desirable to protect against the risk of catastrophic costs that could otherwise lead to bankruptcy and/or to limit access to health care. Insurance can produce incentives to consume more medical care than individuals would purchase if they faced the true cost of care, but such inefficiencies need to be balanced against the financial and health risks of lacking insurance. Contractual limits on what insurance will cover are a strategy to address this tendency for excessive consumption but are often sources of controversy and patient dissatisfaction. One reason for this is that health care spending tends to be highly concentrated, with ~5% of the population accounting for 50% of total spending. This concentration of spending makes it difficult to use cost-sharing to control health care without having these costs fall heavily on a small fraction of individuals. Because simple across-the-board cost-sharing can produce unacceptable financial risk, health care insurance is better constructed by

CHAPTER e2

Economic Considerations in the Practice of Medicine

Copyright © 2008 by McGraw-Hill Company. All rights reserved.

the medical device industry. unlike Medicare. Patients in these programs generally give up flexibility in the providers they can see without paying for visits themselves but benefit from lower copayments for covered services or coverage for certain benefits that traditional Medicare may not cover. Medicare also interfaces with the Medicaid program to address the needs of lower income older persons. Hospital management in NFP hospitals is supervised by a board of directors that typically includes community. Like Medicare.. which can return profits to shareholders and is not required to provide benefits to its community in the same way as NFP hospitals are required to. Another major concern is the rising costs of developing new drugs.medicare. in so doing.. in part. leaving sicker persons alone in the high-cost plan. management tools such as process mapping.” in which physicians provide more care than is desirable because of the financial returns they receive from providing that care. All rights reserved. the large role of government as a payer in health care makes physician reimbursement a political issue in which lobbying and other strategies for specialty influence play a role. are among the most important aspects of the modern health care system and supply many of the products most responsible for improvements in public health. Medicaid is managed by the Centers for Medicare and Medicaid services (CMS). Medicare beneficiaries who can afford them can purchase supplemental Medicare (Medigap) policies that can sometimes fill these gaps in coverage. Medicare and Medicaid Medicare provides health insurance for almost all Americans age 65 and older. This program has a complicated benefit structure. There are also significant variations in the coverage provided by different plans. This contrasts with a for-profit (FP) hospital. However. These include lifetime caps on benefits and copayment rates that are sometimes lower for low-use patients than for higher-use patients. safety. Insurance coverage within Medicare has some idiosyncrasies that. ophthalmologists and optometrists or nurse practitioners and physician assistants) are not clear. and devices such as joint replacements and artificial lenses that allow the removal of cataracts. Medicare also has a special program that provides health insurance coverage for persons with end-stage renal disease. FP hospitals are managed by a corporate structure. These tradeoffs are increasingly being put in the hands of consumers as they choose among health plans. An example of adverse selection would be if a low-cost plan were chosen only by healthy individuals.gov to help patients and their families to make informed decisions. but this is increasingly less common in the United States as physicians more often work as part of large groups or for health plans. and continuous quality improvement approaches (e. immunizations. specialty areas. and there is a great deal of variation across states as to who is eligible and what benefits are provided. managers in both NFP and FP hospitals use similar tools to analyze and improve the cost and quality of care they provide. or another expert in health care costs is among the most valuable things a physician can do to help protect the family from unnecessary economic hardship. longer training periods are associated with higher earnings.S. hospitals. . Concerns about the rising cost of pharmaceuticals. one might expect the returns on investment to equalize across specialties as high earnings encourage more entrants into a field and lowers average earnings. human factors analysis. NFP hospitals are exempt from many taxes. Increasingly. Medicaid is a federal-state partnership with funding that is shared. and so there can be intense competition between. Medicaid currently provides coverage to about 14% of the U. physicians usually owned their own practices. Legal constraints exist to prevent physicians from gaining economically from referring patients for the services of other providers. population. This has the advantage of allowing consumer choice but can also result in adverse selection in which people choose insurance plans based on their personal needs but..e8 designing a package of benefits that provides variable subsidies for access to different medical technologies that can improve health while leaving an acceptable level of financial risk and an affordable annual premium. Typically. plan-do-study-act cycles) are becoming essential tools of a modern physician leader. which might then become unaffordable. These models sometimes pay doctors fixed salaries. However. a large and complex staff. Hospitals These are complex organizations that require expensive capital investments. and inappropriate marketing strategies have made the pharmaceutical industry and its regulators [e. Nurses and other health professionals also have complex labor market issues. The Part D program in Medicare addresses a long-standing need to provide older persons with better access to pharmaceuticals. SUPPLY OF HEALTH CARE Physicians. In general. Incentives for physicians to provide services can lead to concerns about “demand inducement. In a competitive market with free entry. although incentives to see more patients are common. but there is active debate about whether NFP hospitals provide as much community benefit as would be expected based on the subsidies that they receive. undermine the ability of insurance to spread costs and risk among patient groups. and physician participation. Older persons whose incomes and assets are low enough to qualify may be eligible for both Medicare and Medicaid (“dual-eligible”). In addition. Most hospitals are not-for-profit (NFP). Health Professionals The economics of medical practice are shaped by the high level of investment in tuition and time (foregone earnings) that physicians must make during their training. Medicare Advantage is a program developed by Medicare to provide managed care options for Medicare beneficiaries. The rising cost of prescription drugs and concern that prices charged in the United States are above those charged in other countries have led to calls for efforts to control drug pricing in the United States. such as medications to treat hypertension. For patients and their families for whom high health care costs and insurance coverage are major concerns. with varying copayment rates depending on an individual’s prescription drug expenditures within the year. nurses and other health professionals. Established in 1965. Food and Drug Administration (FDA)] the subject of a great deal of recent scrutiny. the U. In 2006 Medicare also began offering a prescription drug benefit (part D).g. This tends not to happen because entry into medical specialties is often tightly controlled by a variety of accrediting agencies in collaboration with medical specialty societies. referral to a social worker.S. but the evidence for this being common is not compelling. as discussed below. manufacturers of pharmaceuticals and devices.g. Nevertheless. some specialties with the longest training periods still offer exceptionally high returns on investment. and close ties with physicians. In contrast. Attempts to bring down the costs of prescription drugs both in the United States and internationally must balance their short-term effects on the cost of health care with longer-term effects on the incen- PART 1 Introduction to Clinical Medicine Copyright © 2008 The McGraw-Hill Companies. One aspect of Medicaid coverage that is especially important for older persons and their families is that it pays for nursing home coverage for those whose income and assets are sufficiently low. reflect its origins in being modeled based on private health insurance in the 1960s. as well as within. Medicare covers both hospital care (part A) and physician fees (part B). The Pharmaceutical and Device Industries The pharmaceutical industry and its close cousin. which has recently been estimated to be in the vicinity of $1 billion per new chemical entity brought to market. meaning that any surplus left at the end of each year must be reinvested in the hospital or the health of the community it serves. Often the boundaries of practice between different forms of training (e.g. but online tools are available at www. Medicaid is an important source of insurance coverage for patients who lack private health insurance or Medicare and who cannot afford to purchase insurance on their own. These types of concerns greatly complicate the creation of successful insurance markets. staff. In the past. and researchers all provide key inputs into the health care system. Medicaid tends to have lower copayments than other types of health insurance. patient advocate. which is important because of the limited income of the recipients of Medicaid. direct-to-consumer advertising.

and AHRQ support basic. however. hospitals can be more profitable only if they lower their costs. and providing quality care within that diag. other experts have argued that variations in use across small areas may reflect differences in physician beliefs about appropriate practice patterns that are shaped by the influence of peers in their local area. consumer-driven health care will likely have only a modest effect on overall health care demand over the short run. However. often in close collaboration. or industry. Prospective Payment This is probably the most important cost-control strategy that has been adopted in the United States. COST-CONTROL STRATEGIES The rapid rise in health care costs over the past three decades has led to a variety of strategies to control costs. Competition This has been another important strategy used to attempt to control costs. a health care provider is provided a fixed amount of money to provide care for a patient over a specified episode of care. often called selective contracting. All rights reserved. but the increasingly competitive health care market place is making this progressively more difficult. or DRGs. in which Medicare reimbursed hospitals based on the specific services they provided with a system that provided a fixed payment for a hospital stay for any given diagnosis. Health maintenance organizations (HMOs) and other managed care organizations may emphasize prevention as a key aspect of their strategy for managing care and controlling costs. The causes of this excess utilization of services does not appear to result primarily from patient level factors or from differences in insurance coverage. Some have hypothesized that increased utilization of services results from increased capacity in some areas (“if you build it. philanthropy. with a fixed reimbursement. accordingly. The federal government also supports academic medicine through extra payments to academic medical centers through Medicare. This linkage of quality improvement and payment policy was an important move in the history of Medicare. For this reason. Other strategies have included direct regulation of payments through publicly established fee schedules for Medicare or Medicaid that often influence private payment rates. Some early programs focused on direct regulation of health care. successful implementation of managed care requires the ability to adjust payments to reflect the underlying cost of care so that providers are not systematically penalized for caring for certain classes of patients. However. in which a provider is paid based on the amount of care they provide. One example is the resource-based relative value scale (RBRVS). As with prospective payment of hospitals.tives to produce innovative new drugs and effects on access to patients within and across countries with varying incomes and ability to pay. These variations in spending are due to variations in the rate at which expensive care is provided and yet do not appear to result in improved outcomes. even in HMOs. is now common in medical care and provides a powerful strategy to encourage providers to lower their prices and. Pay for Performance Today’s interest in pay for performance. which often report on the rate at which various preventive care goals are met. it is possible that there could be much larger effects over time if greater consumer sensitivity to cost leads to changes in the way new technologies are developed and their use diffuses. Teaching hospitals have traditionally made profits on their clinical care that have allowed them to subsidize their educational and research activities. and clinical research as well as a wide range of programs to support the training and ongoing career development of researchers. NIH. . it is especially important that quality-of-care measures not neglect the special needs of the sickest patients. suggesting that much of the excess utilization in high-cost areas is of little value. sought to ensure that hospitals were acting appropriately in admitting patients according to the criteria for each DRG. competition between hospitals tended to increase costs as hospitals provided more and more services to attract patients and were well reimbursed for them. when hospital reimbursement was retrospective. the high rate at which individuals switch health care plans and the long period of time it takes for many preventive therapies (such as control of hypertension or diabetes) to exert their major benefits suggest that economic incentives for at least some forms of prevention are unlikely to be strong. This is one motivation for the use of report cards for health plans. could induce far more price sensitivity and cost control than was possible with traditional insurance arrangements. The most important example of such a system has been the Medicare Prospective Payment system. It was also coupled with the creation of Professional Review Organizations (PROs) that. Competitive bidding for contracts in which only the low-price bidders are able to provide services. This was established in 1983 and replaced the prior system. The combination of competition and prospective payment may be particularly powerful in reducing costs but can also create incentives to decrease the amount of care provided to the sickest patients within a given category. but often with more limited coverage of certain services. the costs of whose care may often exceed reimbursement. Therefore. which was developed with the intent to realign incentives to encourage physicians to enter needed medical specialties (such as primary care) and be rewarded based on the effort and complexity of the work they do. Given the evidence on the effect of health insurance on the demand for medical care. they may have more incentives and ability to provide integrated care. such as the requirement that a “certificate of need” be issued by a local health authority before construction of a new medical facility can proceed. This contrasts with a retrospective reimbursement system. classified according to one of several hundred diagnosis-related groups. Nevertheless. translational. they will come”). private foundations. competition has the opposite effect of lowering costs because hospitals can no longer charge insurers for added costs and because. Cost-Effectiveness Analyses In making medical decisions. among other things. For example. Prospective payment is a key idea underlying the use of managed care organizations to control costs by providing a fixed payment for providing care for a patient over a given period of time. It is also possible—though still unproven—that the development of novel new insurance mechanisms. costs.e9 nosis. Practice Variation Another major concern about health care spending is the large degree of variation in spending across small geographic areas around the United States. Under a prospective payment system. Sometimes fee schedules have been created with multiple policy goals. Likewise. In the era of prospective payment. in which providers receive higher reimbursement rates for care that meets specified quality indicators is an extension of this. especially in making decisions when costs are a concern. it is more important that research activities be supported by government. Competition does not always lower costs. development of tools to measure and reward the quality of care provided by managed care organization has arisen as a major priority for the field of health outcomes research. The National Institutes of Health (NIH) is the source of the vast majority of federal funding for health research. Innovation Medical innovation is also produced by academia and government. Consumer-Driven Care Another cost-containment strategy that has recently received increasing attention is the idea of consumer-driven care. This provided strong incentives to decrease hospital length of stay and costs and had large effects on hospital cost growth for several years. with the Centers for Disease Control and Prevention (CDC) a distant second and the Agency for Healthcare Research Quality (AHRQ) and a variety of other federal agencies further behind. in which patients select an insurance plan tailored to their personal needs. Because managed care organizations are responsible for all of the care of the patient over this time period. There are also loan repayment programs to encourage entry into research careers. such as health savings accounts paired with high-deductible health insurance coverage for catastrophic care. cost-effectiveness analy- CHAPTER e2 Economic Considerations in the Practice of Medicine Copyright © 2008 by McGraw-Hill Company. CDC. from serving merely as a payer to acting as an increasingly active manager of care.

2003 NEWHOUSE JP: Consumer-directed health plans and the RAND health insurance experiment. As a result. 2004 Primer on cost-effectiveness analysis. 2001 FISHER ES et al: The implications of regional variations in medicare spending. It is generally agreed that cost-effectiveness analysis take a societal perspective. 2005 CUTLER DM. 2003 MELTZER D et al: Does competition under Medicare Prospective Payment selectively reduce expenditures on high-cost patients? RAND J Econ 33(3):447. MCCLELLAN M: Is technological change in medicine worth it? Health Affairs 20(5):11. For example. All rights reserved. In countries (such as the United Kingdom) where cost-effectiveness analysis is used to inform coverage policy. Chicago. Nevertheless. for which most benefits are far in the future. In such a case. Part 1: The content. a great deal of effort has gone into approaches that may be used to change physician behavior and to create systems-level changes that can support the better use of evidence in clinical care. and their increasing use has already begun to show promise in addressing practice variations to improve meaningfully both the cost and effectiveness of care. University of Chicago Press. and accessibility of care. and from producers of new technologies. quality. which is a measure of life expectancy in which each year of life is weighted with a number between 0 (death) and 1 (perfect health) reflecting quality of life in that health state. In cost-effectiveness analysis. 253–255. cost-effectiveness theory suggests that interventions that cost less than some threshold value per QALY (often $50. Effect Clin Pract September/October. 2002 MURPHY KM. TOPEL RH: Measuring the Gains from Medical Research: An Economic Approach. Evidence-Based Medicine and Physician Practice Patterns To the extent that variation in practice patterns is an important contributor to higher health care costs. . the health benefits and costs of a medical intervention are compared to one or more other options by calculating a ratio of costs (C) to effectiveness (E). PART 1 Introduction to Clinical Medicine FURTHER READINGS BODENHEIMER T: High and rising health care costs. Ann Intern Med 142(12):996. There is also a strong case to be made for considering multiple perspectives in a cost-effectiveness analysis. though the appropriate threshold remains highly controversial. knowing that the business case for this valuable intervention is not strong might help target attention to developing quality indicators to ensure that plans are making good efforts to encourage intensive therapy for the appropriate patients. Costs and the Clinician Economic concerns arise in clinical care on a daily basis. where the C/E ratio = change in health benefits/change in costs. physicians need to develop and maintain an understanding of these economic considerations in the practice of medicine and to reflect them in their professional behavior. They range from patient–oriented concerns (such as outof-pocket costs or insurance purchase decisions) to system-oriented concerns (such as hospital or health plan management) to physicianoriented concerns (practice management and personal earnings). Ann Intern Med 138(4):273.000/QALY) would be considered cost-effective. Health Affairs 23(6):107. Often benefits will be measured using a metric of quality-adjusted life years.e10 sis and other approaches to technology assessment are an important source of evidence for decisions about when a medical technology is likely to be worthwhile. including expert judgment and political concerns emanating from patient and providers. is not cost-effective from a business perspective. it is well established that there are large gaps between the time evidence becomes available and the time it is incorporated into practice. In general. Cost-effectiveness analysis can also sometimes be used to assess when it would be valuable to do more research on a technology in order to better characterize how it should be used. To be fully effective. it is most commonly used as part of a broader process of technology assessment that may incorporate other forms of evidence. a costeffectiveness analysis done from the perspective of an HMO might find that intensive therapy for diabetes.000/QALY or $100. The scientific literature provides important data for such evidence-based practice. even if it is cost-effective from a societal perspective. Part 3: The role of health care providers. Health information systems provide a variety of tools. or QALYs. accounting for all costs and benefits of a medical intervention regardless of to whom they accrue. 2000 Copyright © 2008 The McGraw-Hill Companies. it becomes important to control practice vari- ations by improving alignment of practice patterns using evidence on the costs and benefits of care.

2 68. cardiovascular disease.1999. Native Americans/Alaska Natives.9 40. Multiple factors contribute to these racial and ethnic disparities in health. Composite is calculated by averaging the percentage of the population that received each of the five incorporated components of care. Our ability to prevent. First and foremost. and HIV/AIDS. diabetes) in the United States. and provide key recommendations to address them at both the health system and clinical level. e3-1). Second.9 40.9 Black women White women Black men White men 67. (From JZ Ayanian et al: N Engl J Med 341:1661. All rights reserved. even when confounders such as stage of presentation and comorbidities are controlled for and they have the same level of health insurance. and treat diseases in their early stages has allowed us to target and reduce morbidity and mortality.3 82. Disparities have also been found in the utilization of cardiac diagnostic and therapeutic procedures (African Americans being referred less than whites for cardiac catheterization and bypass grafting). 2002–2003. racial and ethnic minorities (Blacks. Hispanics/Latinos. cancer. NATURE AND EXTENT OF RACIAL AND ETHNIC DISPARITIES IN HEALTH AND HEALTH CARE Minority Americans have poorer health outcomes (compared with whites) from preventable and treatable conditions such as cardiovascular disease. and are more likely to report that they have not received needed care— Percent 80 2002 2003 e11 CHAPTER e3 60 40 Racial and Ethnic Disparities in Health Care 20 0 t To n No -H al a nic W hit e ic an Bl k ac As ian NA /A N sp Hi an ic isp n No -H isp FIGURE e3-2 Recommended hospital care received by Medicare patients with pneumonia. (From Institute of Medicine: Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care. emergency hospital care. David Blumenthal Over the course of its history. detect. health promotion. the United States has experienced dramatic improvements in overall health and life expectancy due largely to initiatives in public health. overall lower socioeconomic status. as uninsured individuals are less likely to have a regular source of care. This chapter will provide an overview of racial and ethnic disparities in health and health care. NA/AN. are more likely to report delaying seeking care. and surgical treatment of lung cancer (African Americans re- White Black Percentage of patients American Indian or Alaska Native Asian or Pacific Islander 200 150 100 50 0 Diseases of heart Cerebrovascular diseases Malignant neoplasms Diabetes mellitus Hispanic 100 80 60 40 20 0 Referred for evaluation 59. lack of access to care also takes a significant toll. among others (Fig. these environmental hazards have contributed to some of the highest rates of pediatric asthma among these populations. asthma.0001 for each comparison).Ethnic e3 Racial andCare Disparities in Health Joseph R. three of the five largest landfills in the country are found in African-American and Latino communities. diabetes.3 57. there is little doubt that social determinants—such as lower levels of education. . For instance. Washington. Research has highlighted that minorities may receive lower quality of care than whites in the health care setting. inadequate and unsafe housing. disease prevention. Despite interventions that have improved the overall health of the majority of Americans. cancer. identify root causes. National Academy Press. For example.) Copyright © 2008 The McGraw-Hill Companies. 271 black men. e3-2) and congestive heart failure (African Americans receiving less optimal care than whites when hospitalized for these conditions) and referral to renal transplantation (African Americans with end-stage renal disease being referred less often to the transplant list than whites) (Fig.) FIGURE e3-3 Referral for evaluation at a transplantation center or placement on a waiting list or receipt of a renal transplantation within 18 months after the start of dialysis among patients who wanted a transplant. (Adapted from Agency for Health Care Research and Quality: The 2005 National Health Care Disparities Report. Betancourt. 2000. there are racial/ethnic disparities in the quality of care for those with access to the health care system. racism. 280 white women. These differences in quality are called racial and ethnic disparities in health care. Asian/Pacific Islanders) have benefited less from these advances and suffer poorer health outcomes than whites from many major diseases (e. disparities have been found in the treatment of pneumonia (Fig. and adverse health outcomes.g.6 Placed on waiting list or received transplant FIGURE e3-1 Age-adjusted death rates for selected causes by race and Hispanic origin. prescription of analgesia for pain control (African Americans and Latinos receiving less pain medication than whites for long bone fractures and cancer). by race/ethnicity. e3-3). and 271 white men. DC. 2002.. Reference population is 239 black women. and living in close proximity to environmental hazards—disproportionately impact minority populations and thus contribute to poorer health outcomes.) all resulting in avoidable hospitalizations. In addition to the existence of racial and ethnic disparities in health. according to race and sex. Racial differences were statistically significant among the women and the men (p<.6 80. Reference population is Medicare beneficiaries with pneumonia who are hospitalized. Native American or Alaska Native. and chronic care management.

stereotyping. and delay in seeking care. Copyright © 2008 The McGraw-Hill Companies. (From AK Jha et al: N Engl J Med 353:683. Unequal Treatment went on to identify a set of root causes that included the following. Using data from enrollees in Medicare managed care plans. • Bias. patients. • A small number of studies suggest that certain patients may be more likely to refuse treatments. disparities for blacks are improving in some areas. in none of the measured areas have disparities been eliminated. the difference between the rates among whites and blacks increased significantly for five of the nine procedures.) measured between blacks and whites.5 0. 58% are narrowing. • Patient-level factors: These include patient’s refusal of services. The report found the following: • Racial and ethnic disparities in health care exist and. 41% are narrowing while 59% are widening. but disparities for Hispanic/Latino populations appear to be widening. (From V Vaccarino et al: N Engl J Med 353:671. yet these refusal rates are generally small and do not fully explain health care disparities. for disparities Reperfusion therapy 50 White men White women Black men 40 Black women 30 20 10 Total hip replacement 3. released by the Agency for Healthcare Research and Quality in January 2006.5 Rate (per 1000 enrollees) 3. All rights reserved. Overall.0 2. provider. Again.0 1992 Black men White women White men Percentage of patients Percentage of patients PART 1 Introduction to Clinical Medicine 1993 1994 1995 1996 1997 1998 1999 2000 2001 Year FIGURE e3-5 Racial trends in the use of total hip replacement.5 1. and in-hospital death after myocardial infarction have narrowed between 1994 and 2002 (Fig. The second National Healthcare Disparities Report (NHDR). 2005. and symptom expression are taken into account. age. the difficulty that minority patients may have in navigating this complex health system.0 0. there is evidence for a narrowing in racial disparities between 1997 and 2003 in several “report card” preventive care measures such as mammography and glucose and cholesterol testing.) • Health system factors: These include issues related to the complexity of the health care system. ROOT CAUSES FOR RACIAL/ETHNIC DISPARITIES IN HEALTH CARE The Institute of Medicine (IOM) report Unequal Treatment. and utilization managers—may contribute to racial and ethnic disparities in health care. Data from the National Registry of Myocardial Infarction found no evidence that the racial differences in rates of reperfusion therapy. For disparities measures between Hispanics/Latinos and whites. and narrowed significantly for only one procedure (Fig. the situation seems to be getting worse. 1994–2002. and the lack of availability of interpreter services to assist patients with limited English proficiency.0 Black women 1.e12 ceiving less curative surgery than whites for non-small cell lung cancer). including stereotyping. Using Medicare data from 1992–2001 on annual rates of receipt of nine surgical procedures (such as coronary artery bypass surgery and total hip replacement) previously shown to have disparities. Black women fared worst of all groups. A more detailed analysis of these root causes is presented here. and patient factors. Reference population is 598. remains the preeminent study of the issue of racial and ethnic disparities in health care in the United States. released in March 2002. remained unchanged for three procedures. while white men were significantly more likely to receive more aggressive interventions. among others: 0 1994–1996 Beta-blockers 50 40 30 20 10 1996–1998 1998–2000 2000–2002 White men White women Black men Black women 0 1994–1996 1996–1998 1998–2000 2000–2002 FIGURE e3-4 Sex and racial differences in the management of acute myocardial infarction. The IOM was charged to assess the extent of racial/ethnic differences in health care that are not otherwise attributable to known factors such as access to care. 2005. because they are associated with worse health outcomes. However. For example. comorbid conditions. and clinical uncertainty on the part of health care providers may contribute to racial and ethnic disparities in health care. e3-4). while some progress has been made in eliminating disparities in primary care process measures. • Many sources—including health systems. income. prejudice. the IOM studied health system. poor adherence to treatment.5 2. 1992–2001. Little progress has been made in addressing racial/ethnic disparities in cardiovascular procedures and other advanced surgical procedures. the impact of race/ethnicity on clinical decision-making. yet for Hispanics/Latinos.911 patients hospitalized with myocardial infarction between 1994 and 2002 who were ideal candidates for particular treatments. racial disparities in more complex items such as glucose control in diabetics and cholesterol levels in patients after a heart attack had actually worsened. For both populations. while 42% are widening. not better. e3-5). and clinical uncertainty due to poor communication. there were no meaningful or consistent reductions in the gaps in care between black and white Medicare enrollees. among others. found that in comparison to the previous year. • Provider-level factors: These include issues related to the health care provider. . coronary angiography. • Racial and ethnic disparities in health care occur in the context of (1) broader historic and contemporary social and economic inequality and (2) evidence of persistent racial and ethnic discrimination in many sectors of American life. Reference population is men and women enrolled in Medicare from 1992 through 2001. significant disparities persist. To provide recommendations regarding interventions to eliminate health care disparities. many of these disparities occurred even when variations in factors such as insurance status. are unacceptable. Ultimately. health care providers. data from the National Registry of Myocardial Infarction.

such as a mammogram. The survey found that 19% of all patients experienced one or more of these problems. Thus. and who have a high degree of health literacy. ethnicity. no prejudice). (From Commonwealth Fund Health Care Quality Survey. and plans for follow-up care. comprehension of management strategies. navigating the health care system can be complicated and confusing. patient satisfaction. expectations of care (including preferences for or against diagnostic and therapeutic procedures). In addition. If the doctor is caring for a patient for whom they have difficulty understanding the symptoms and are less sure of the “signal”—the set of clues and indications that physicians rely on to make clinical decisions—their decisions may not be the same for two patients who present with the exact same condition. and racial/ethnic disparities in care may result. whether they felt the doctor did not listen. sociocultural differences between patient and provider influence communication and clinical decision-making and are especially pertinent given evidence that clearly links provider-patient communication to improved patient satisfaction. . health care system. adherence. DC. Stereotyping can be defined as the process by which people use social categories (e. and the information they obtain from the patient. is recognized as a major challenge to effective health care delivery.) scribed medications.. African Americans. such as a colonoscopy. as well as assumptions about patients themselves. e3-7). and behaviors regarding health and well-being. Communication issues related to discordant language disproportionately affect minorities and others with limited English proficiency and likely contribute to racial/ethnic disparities in health care. may be at higher risk for receiving substandard care because of their difficulty navigating the complexities of the U. Hispanics/Latinos. provider-patient communication without an interpreter. Whites. feeling doctor listened.Health System Factors • HEALTH SYSTEM COMPLEXITY Even among those who are insured and educated. CLINICAL DECISION-MAKING Patient satisfaction Adherence Health outcomes FIGURE e3-6 The link between effective communication. better health outcomes (Fig. when sociocultural differences between patient and provider aren’t appreciated. and whether they had medical questions they were afraid to ask. and visit the emergency department for care. doctors—the overwhelming majority of whom are white—may understand symptoms best from patients of their own racial group. may contribute to racial and ethnic disparities in health care. and those who are mistrustful of the health care system. poor adherence. In addition. physicians who have access to trained interpreters report a significantly higher quality of patient-physician communication than physicians who used other methods. by race/ethnicity. or communicated effectively in the medical encounter. Faced with enormous information loads and the need to make many decisions. and adherence to preventive measures and medications. and. whether they felt the doctor did not listen. Given that the expression of symptoms may differ among and between cultural and racial groups. thresholds for seeking care. and limited English proficiency on health and clinical care. explored. values. A survey of 6722 Americans age 18 and older is particularly relevant given the important link between provider-patient communication and health outcomes. e3-6) . however.) Theory and research on clinical decisionmaking suggest that physicians’ understanding and interpretations of information obtained from patients. had questions but did not ask. Washington. doctors must depend on inferences about severity based on what they understand about illness. Differences in clinical decisions from this mechanism can arise when the doctor has the same regard for each patient (i. yet whites experienced them 16% of the time. Provider-Level Factors • PROVIDER-PATIENT COMMUNICATION S i g nificant evidence highlights the impact of sociocultural factors. race. and Asian Americans who had a medical visit in the last 2 years were asked whether they had trouble understanding their doctor. special instructions. Hispanic patients with language-discordant physicians are more likely to omit medication. and whether they had medical questions they were afraid to ask. Spanish-speaking patients discharged from the emergency room are less likely than their English-speaking counterparts to understand their diagnosis. People from these backgrounds may have difficulty knowing how and where to go for a referral to a specialist. 33% for Hispanics/Latinos. and health outcomes. subsequently.S. Health care professionals frequently care for diverse patient populations who present varied perspectives. poorer health outcomes. compared with 23% of the time for African Americans. 2002. preHow do we link communication to outcomes? Communication Percent of adults with one or more communication problems* 40 e13 CHAPTER e3 33% 27% 23% 20 19% 16% Racial and Ethnic Disparities in Health Care 0 Total White African American Hispanic Asian American Base: Adults with health care visit in past two years *Problems include understanding doctor. miss office appointments. and 27% for Asian Americans (Fig. in the setting of even a minimal language barrier. adherence. patient dissatisfaction.. and recalling information about others. National Academy Press. These individuals may include those from cultures unfamiliar with the Western model of health care delivery. The consequence is that white patients may be treated differently from minority patients. beliefs. more likely to report problems with their care. Two factors are central to this process: clinical uncertainty and stereotyping. understood. A doctor’s decision-making process is nested in clinical uncertainty—in sum. for example. or how to follow up on an abnormal test. how to prepare for a procedure. race.e. 2001. Some individuals. those with limited English proficiency. All rights reserved. gender) in acquiring. those with low health literacy. These include variations in recognition of symptoms. Reference population is 6722 Americans age 18 and older who had had a medical visit in the last 2 years and were asked whether they had trouble understanding their doctor. the inherent complexity of navigating our health care system has been seen as a root cause for racial/ethnic disparities in health care. and less satisfied with the patient-provider relationship. less likely to be satisfied with their care or willing to return if they have a problem. (From Institute of Medicine: Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care. The literature on social cognitive theory highlights the ways in which natural tendencies to stereotype may influence clinical decision-making.g. FIGURE e3-7 Communication difficulties with physicians. people subconsciously simplify the decision-making process and lessen cognitive effort by us- Copyright © 2008 The McGraw-Hill Companies. In addition. Since people of color in the United States tend to be overrepresented among the groups listed above. processing.

health care system. . documented alarming rates of medical errors and made patients feel vulnerable and less trustful of the U. The increased media and academic attention to problems of quality of care (and even disparities themselves) have clearly diminished trust in doctors and nurses. because of their origins in virtually universal social categorization processes.g. Kaiser Family Foundation. Sometimes. To Err Is Human: Building a Safer Health System. race/ethnicity. doctor-shopping. as well as favor them in terms of evaluation and resource allocation. Interestingly. Upon categorization of individuals into in-groups and out-groups. stereotyping can be systematically biased as people are automatically classified into social categories relating to dimensions such as race. As a result. Trust is a crucial element in the therapeutic alliance between patient and health care provider. if the media constantly present images of minorities as being less educated. ethnicity. should be excluded from consideration in the formulation of clinical decisions. A national survey by the Kaiser Family Foundation found that there is significant mistrust of the health care system among minority populations. they may also exist. these impressions may generate stereotypes that unnaturally and unjustly impact clinical decision-making. “these patients” engage in risky behaviors. culture. Although functional. an Institute of Medicine Report. Of the 3884 individuals surveyed. This in turn may lead doctors to misunderstand Past unfair Tx based on race/ethnicity Future unfair Tx based on race/ethnicity PART 1 Introduction to Clinical Medicine 15 35 36 Whites Blacks Latinos 22 65 58 0 20 40 Percent 60 80 FIGURE e3-8 Patient perspectives regarding how fairly they have been treated in the health care system. and ageism are experienced— consciously or unconsciously in our society—stereotypes may be created that impact the way doctors manage patients from these groups. violent. In the process of categorizing people into two different groups. segregation. For example. doctors may begin to equate certain races and ethnicities with specific health beliefs and behaviors (e. This may furthermore contribute to unconscious stereotyping. level of training. Patients who mistrust their health care providers are less satisfied with the care they receive. Based on historic factors of discrimination. which emphasizes social difference and group distinctiveness. and how fairly they feel they will be treated in the future based on their race/ethnicity. and under the time pressure—the hallmarks of the clinical encounter. and race/ethnicity). among people who strongly endorse egalitarian principles and truly believe they are not prejudiced. 2005. The result over time may be that doctors begin to believe that “these patients” don’t like invasive procedures. This lack of confidence in physicians also results in inconsistent care. Moreover. and an increased demand for referrals and diagnostic tests by patients. and medical experimentation. and discrimination is conscious and intentional disparate treatment. gender. This “conditioning” phenomenon may also occur if doctors are faced with certain racial/ethnic patient groups who don’t frequently choose aggressive forms of diagnostic or therapeutic interventions. The challenge is that if left unchecked. knowledgeable prejudgment of individuals that may lead to disparate treatment.S. gender. undergoing invasive procedures. self-medicating. 36% of Hispanics and 35% of African Americans (compared with 15% of whites) felt they were treated unfairly in the health care system in the past based on their race and ethnicity. Thus. This mistrust may contribute to wariness in accepting or following recommendations. often subconsciously. many medical students and residents are often trained—and minorities cared for—in academic health centers or public hospitals located in socioeconomically disadvantaged areas. as represented by outward racism or bigotry.. 65% of African Americans and 58% of Hispanics (compared with 22% of whites) were afraid of being treated unfairly in the future based on their race/ethnicity (Fig. socioeconomic status). both conscious processes. All individuals stereotype subconsciously. and mistrust of the health care system greatly affects patients’ use of services. and incentives). and age. and thus they may not offer them as options very ardently. It facilitates open communication and is directly correlated with adherence to physician recommendations and patient satisfaction. form of compensation. performance expectations. they tend to make a “snap judgment” in which they subconsciously and automatically assign the group’s characteristics to that individual.. as well as personal characteristics of the patient and the clinical setting. characteristics of the doctor (including the specialty. Perhaps even more alarming. It is important to differentiate stereotyping from prejudice and discrimination. ranging from the patient’s physical appearance to the organizational setting in which medical care is delivered. What is particularly salient is that stereotypes tend to be activated most in environments where the individual is stressed. Ethnicity & Medical Care: A Survey of Public Perceptions and Experiences. the cues that lead to particular stereotypes are also strongly influenced by the messages presented consciously and subconsciously in society. Public Health Service during the Tuskegee study left a legacy of mistrust that persists even today among this population.S. people may not be aware of their attitudes or they may consciously endorse stereotyping. despite the best intentions to treat every patient equitably. These biases may exist in overt forms. The exploitation of African Americans by the U. doctors are commonly taught that their own personal characteristics (race. age. Many nonmedical factors. if at all. by race/ethnicity. people typically classify themselves into one of the social categories and out of the other. this social categorization enhances perceptions of similarities within groups and differences between groups (particularly with respect to one’s own group). organization of practice. These nonmedical factors include characteristics of the patient (including patient age. clinical experience. In addition. however.g. when people assign someone to a particular class or group.) Copyright © 2008 The McGraw-Hill Companies. gender. based on training or practice location. African Americans may be especially mistrustful of providers. For example. or participating in clinical research. poverty) than a patient’s racial/ethnic background or cultural traditions. Nevertheless. and nonadherent to health care recommendations. and insurance status). people experience more positive feelings toward the in-group. may have as much influence on clinical decisions as the actual signs and symptoms of disease.e14 ing “categories” or “stereotypes” that group information and decisions into groups or types that can be more quickly processed and executed. language proficiency. and features of the practice setting (including location. Patient-Level Factors • MISTRUST Lack of trust has become a major concern for many health care institutions today. gender bias. In addition. stereotyping (especially based on stereotypes derived abnormally from conscious and subconscious societal cues. Reference population is 3884 individuals surveyed about how fairly they have been treated in the health care system in the past. multitasking. as signs of racism. socioeconomic status. All rights reserved. and class that may evolve into stereotypes. However. doctors may develop certain perceptions about race/ethnicity. or “those patients” tend to be noncompliant) that are more associated with the social environment (e. For instance. Although stereotyping may be a normal cognitive process. Prejudice is a conscious. those stereotypes are applied to individuals who are lumped together into groups to which certain beliefs and expectations are attached. e3-8). (From Race. classism. such as those related to race) may lead to lower quality of care for certain groups— such as minorities—who may be deemed less worthy of diagnostic or therapeutic procedures or resources.

and the community. African Americans 2. with a few notable exceptions. a national survey was conducted in which individuals were asked “Do all Americans receive the same quality of health care?” Most thought so. and on providing skills to understand and manage these factors in the medical encounter. as well as general recommendations. and the majority of physicians felt patients were treated equally regardless of their race or ethnicity. For instance. particular attention should be paid to the implementation of evidencebased guidelines for all patients. and as part of continuing education. HIV/AIDS.S. Collect and report health care access and utilization data by patient’s race/ethnicity Unequal Treatment found that the appropriate systems to track and monitor racial and ethnic disparities in health care are lacking. physicians whose race and ethnicity is known. do not collect data on the race.” and “other. the adoption and implementation of evidencebased guidelines broadly is a major recommendation to eliminate disparities. there now exist evidence-based guidelines for the management of diabetes. health care systems that lack interpreter services can lead to patient dissatisfaction.” Federal. and many health care systems and hospitals. lack of empowerment or involvement in the medical encounter by minorities can be a barrier to care as well. For example. The LCME—the body that accredits medical schools—now has a directive that medical education should teach how a patient’s race. even in the presence of well-delineated practice guidelines. and how to effectively communicate and negotiate across cultures.why African-American populations seem less adherent to or less interested in aggressive treatments. . minority students accounted for approximately 10% of medical school graduates in 2001. These include health systems interventions. These recommendations are described in more detail below. It should further be noted that approximately 20% of these faculty teach at the four historically black medical schools and the three Liaison Committee on Medical Education (LCME)-accredited medical schools in Puerto Rico. These curricula can be incorporated into health professions training in medical schools and nursing schools. and there is less known about the disparities for minority groups (Hispanics. or primary language of patients or enrollees. with minorities composing only 4. Health System Interventions 1. regardless of their race and ethnicity. and ineffective/lower-quality care for patients with limited English proficiency. and Alaska Natives) other than African Americans. and new immigrants. Hispanics make up 3. provider interventions. Efforts to incorporate cross-cultural education into undergraduate and graduate medical education will contribute to improving doctor-patient communication and to better quality of care. regardless of their background. as well as the attention it has attracted from medical education accreditation bodies.5%. All rights reserved. ethnicity. The ultimate goal is to generate discourse and mobilize action to address disparities in multiple areas. It will be difficult to develop a diverse health care workforce that can meet the needs of an increasingly diverse population without dramatic change in the racial and ethnic composition of medical student bodies. with the lack of awareness being greatest among whites. focusing on a broad set of stakeholders. In 2003. health systems. communicate with. including at the level of health policy. and asthma—all areas where significant disparities exist. a Kaiser Family Foundation survey of 2608 physicians whose primary activity is patient care found that the majority of respondents (mainly white) said that the health care system “never” (14%) or “rarely” (55%) treats people differently based on race/ethnicity. private. 4. poor comprehension and compliance. and Culture on Clinical Decision-Making Unequal Treatment found that stereotyping by health care providers might lead to disparate treatment based on a patient’s race or ethnicity. and state-supported data collection efforts are scattered and unsystematic. Ethnicity. Pacific Islanders. 2. most believed that all Americans deserve quality care. Support the use of language interpretation services in the clinical setting As described previously. Native Americans. CHAPTER e3 Racial and Ethnic Disparities in Health Care Incorporate Teaching on the Impact of Race.5% of U. and American Indian and Alaska Natives less than 0. or use indirect methods to obtain aggregate data on race.6%. Increase the proportion of underrepresented minorities in the health care workforce Recent data from the American Medical Association indicate that of the 70. Patient Interventions Educate Patients on How to Navigate the Health Care System and How to Be More Active in the Medical Encounter Difficulty navigating the health care system and obtaining access to care can be a hindrance to all populations. and care for patients from diverse backgrounds. shortly after the release of Unequal Treatment. Encourage the use of evidence-based guidelines and quality improvement Unequal Treatment highlights the subjectivity of clinical decision-making as a potential cause of racial and ethnic disparities in health care by describing how clinicians may offer different diagnostic and treatment options to different patients (consciously and unconsciously) based on their race or ethnicity. Data regarding the racial/ ethnic composition of medical school faculty are no different. Unequal Treatment’s recommendation to support the use of interpretation services has clear implications for delivery of quality health care by improving doctors’ ability to communicate effectively with patients with limited English proficiency. Similarly. Cross-cultural education includes curricula on health care disparities. additional research is needed Copyright © 2008 The McGraw-Hill Companies. ties in Health Care Conduct Further Research to Identify Sources of Disparities and Promising Interventions While the literature that formed the basis of the findings and recommendations of Unequal Treatment provided significant evidence for racial and ethnic disparities. particularly to minorities.2% nationally. a national survey of resident physicians by Weissman and colleagues found that more than one in five felt unprepared to deal with crosscultural issues. Asian Americans. ethnicity. These beliefs were held despite a large body of published research to the contrary. such education focuses on enhancing awareness of sociocultural influences on health beliefs and behaviors. Any effort to identify and address disparities must begin with the collection of race/ethnicity data and the stratification of quality measures by these groupings. only in the mid1980s did the Medicare database begin to collect data on patient groups outside the standard categories of “white. For instance.5% percent. Therefore. cancer screening and management. 3. KEY RECOMMENDATIONS TO ADDRESS RACIAL/ETHNIC DISPARITIES IN HEALTH CARE The publication Unequal Treatment provides a series of recommendations to address racial and ethnic disparities in health care. including caring for patients who have religious beliefs that may affect treatment. As part of ongoing quality improvement efforts. Despite the importance of this area of education. General Recommendations Increase Awareness of Racial/Ethnic DispariRecent surveys have shown that both physicians and the public tend to be unaware of the extent and severity of racial and ethnic disparities in health care in the United States. Despite composing 30% of the population. cardiovascular diseases. Interventions should be used to increase patients’ knowledge of how to best access care and participate in treatment decisions. patients with mistrust of the health care system. and culture might subconsciously impact on communication and clinical decision-making. A poll in 2005 showed that the majority of Americans were actually unaware that racial and ethnic minorities receive poorer care than whites. Despite this lack of awareness. Increasing awareness of racial and ethnic disparities among health care professionals and the public is an important first step in addressing disparities in health care. patients with health beliefs at odds with Western medicine.” “black. patients who use complementary medicine. Provider Interventions Integrate Cross-Cultural Education into the e15 Training of All Health Care Professionals The goal of cross-cultural education is to improve providers’ ability to understand. A Robert Wood Johnson Foundation survey found that 51% of health plans either ask members to provide their race voluntarily on enrollment and other forms. and patient interventions. how to use an interpreter.

gender. when broadly and uncritically applied. prejudice. Practice Culturally Competent Care Many have thought of “cultural competence” as simply the skills necessary for addressing language barriers in the clinical encounter. All rights reserved. another influential IOM report. and very little has been done to test interventions to address them. For example. Cultural competence has thus evolved from learning information and making assumptions about patients based on their background to focusing on the development of skills that follow the principles of patient-centered care. most of the literature on disparities focuses on black-versus-white differences. culture. participatory decision-making and the provider makes a concerted effort to understand the patient’s background. While the former is important and remains a key component of cultural competence. highlights the importance of equity—that there be no variations in quality of care by personal characteristics including race and ethnicity—as a central principle of quality. interpersonal skills and communication techniques that demonstrate honesty. openness. one can adjust their practice style accordingly to meet their specific needs. The problem of differences in quality of care across regions remains an important area of study and should remain a target of policy makers. for example. ethnicity. Improving the ability to collect racial and ethnic patient data should facilitate this process. values. the patient’s sense of vulnerability can be transformed into one of trust. The emergence of targeting disparities through quality improvement has gained significant traction nationally.” for example. and learning from. physicians can constantly ensure that they are offering the same things. by expanding the repertoire of knowledge and skills classically defined as patient-centered to include those that are especially useful in cross-cultural interactions (but remain vital to all clinical encounters). have begun to consider the importance of stratifying their quality data by race/ethnicity so as to identify disparities and develop interventions to address them. learning about a particular local community or cultural group can be helpful (following the principles of community-oriented primary care). These approaches are discussed here. assessing decision-making preferences and the role of family. values. in the same ways. PART 1 Introduction to Clinical Medicine • DISPARITIES AND QUALITY IMPROVENew Areas for Exploration MENT A major advance is that key health care stakeholders have begun to understand that disparities are an inequality in quality. Health plans and hospitals. and expressed preferences of the individual patient. we should aim to gain experiences working with. For instance. both with the release of the IOM report Unequal Treatment and with the many recent articles that have confirmed their persistence. Cultural competence aims to take this a step further. IMPLICATIONS FOR CLINICAL PRACTICE Individual health care providers can do several things in the clinical encounter to address racial and ethnic disparities in health care. There is clearly a need for a research agenda that identifies promising practices and solutions to disparities. Previous efforts in cultural competence have aimed to teach clinicians about the attitudes. a sense of camaraderie develops and prevents the future development of stereotypes based on race/ethnicity. ethnicity. when racially/ethnically/culturally/socially diverse teams are assembled (in which each member is given equal power) and are tasked to achieve a common goal. Second. There are many obvious opportunities for interventions to eliminate racial and ethnic disparities in health care. Since black or Hispanic populations tend to live in different areas from non-Hispanic white populations. simply being aware of the operation of social cognitive factors allows one to actively “check” or “monitor” behavior. By reframing the doctor-patient relationship as one of solidarity. especially given the fact that the IOM report Crossing the Quality Chasm highlighted among its six pillars of quality the concept of equity—the principle that health outcomes should not vary based on personal characteristics such as race. and racism. For example. but. both systemically and individually. Patient-centeredness encompasses the qualities of compassion. a diverse set of colleagues. There is no doubt that the quality approach to address disparities has great promise. from decreased patient satisfaction to the delay of care. and that we will serve as their advocates. providers must be aware that mistrust exists and may be more prevalent among minority populations given this nation’s history. and gender. determining the patient’s perception of biomedicine and complementary and alternative medicine. Be Aware That Disparities Exist Increasing awareness of racial and ethnic disparities among health care professionals is an important first step in addressing disparities in health care. Third. GEOGRAPHIC VARIATIONS IN CARE Where a patient lives can itself have a large impact on the level and quality of health care. location likely matters in the measurement and interpretation of health (and health care) disparities. it may be particularly crucial to understand the health beliefs of those who come from a different culture or have a different health care experience. and that we will do everything in our power to ensure that they always get the best care possible. the latter is an area in evolution. beliefs. providers must reassure patients that they come first. First. In certain situations. much of the literature on disparities to date has focused on defining areas where they exist. much less is known about the experiences of other minority groups. or class. high-quality care to all patients. our normal tendency to stereotype. Second. and being aware of mistrust. while others have equal treatment. or culture. This includes eliciting the patient’s understanding of his or her condition. Crossing the Quality Chasm. With the individual patient as teacher. but much less has been done to identify the multiple factors that contribute to disparities. to all patients. Work to Build Trust Patient mistrust of the health care system and health care providers impacts multiple facets of the medical encounter. Finally. and behaviors of certain cultural groups—the key practice “do’s and don’ts” for caring for “the Hispanic patient. while it is important to understand all patients’ health beliefs. patients indicate that trust is built when there is shared. and responsiveness to the needs. regardless of their race. identifying and negotiating different styles of communication. Understanding how we are susceptible to stereotyping—and how this may lead to disparities—is essential if we are to provide equitable. Greater attention to addressing the root causes Copyright © 2008 The McGraw-Hill Companies. empathy. several steps can be taken to build trust with patients and address disparities. For the process of eliminating disparities to be successful. compassion. among others. recognizing sexual and gender issues. racial and ethnic patient data may be collected prospectively in the setting of clinical or health services research to better understand disparities for other populations. First. or learning as much as you can about patients from specific cultures. In addition. but in instances where those systems are not yet in place. Avoid Stereotyping Several strategies can allow us to counteract. Furthermore. as reducing quality disparities would play a major role in improving the health care received by all Americans and by minority Americans in particular. this approach can also lead to stereotyping and oversimplification of culture without respect for its complexity. CONCLUSION The issue of racial and ethnic disparities in health care has gained national prominence.e16 in several areas. and respect on the part of the health care provider are essential tools in dismantling mistrust. Thus. Although the historic legacy of discrimination can never be erased. There is preliminary evidence to suggest wide variation in racial disparities across geographic lines: some areas have substantial disparities. we must utilize trust-building interventions and strengthen the doctor-patient relationship. . Only then can they be attuned to monitoring their behavior and clinical practice so as to ensure that all patients receive the highest quality of care.

Washington. 2005 STEWART M et al: Evidence on patient-doctor communication. 2000 SCHULMAN KA et al: The effect of race and sex on physicians’ recommendations for cardiac catheterization. 2005 VAN RYN M. All rights reserved. N Engl J Med 341:1198. 1999 CARRILLO JE et al: Cross-cultural primary care: A patient-based approach. DC. FURTHER READINGS AGENCY FOR HEALTH CARE RESEARCH AND QUALITY: The 2005 National Health Care Disparities Report. Curr Hypertens Rep 1:482. Ann Intern Med 130:829. Ann Intern Med 129:412. Med Care 37:1260. Washington. 2004 BERGER JT: Culture and ethnicity in clinical care. not just those who are racial and ethnic minorities. 1999 ——— et al: The effect of patients’ preferences on racial differences in access to renal transplantation. Arch Intern Med 158:2085. Rockville. JAMA 294:1058. N Engl J Med 353:683. 1999 ———. JAMA 288:82. 1996 PEREZ-STABLE EJ et al: The effects of ethnicity and language on medical outcomes of patients with hypertension or diabetes. Med Care 35:1212. DC. unanswered questions. 2005 CHAPTER e3 Racial and Ethnic Disparities in Health Care Copyright © 2008 The McGraw-Hill Companies. 2004 ———: In the Nation’s Compelling Interest: Ensuring Diversity in e17 the Health Care Workforce. 1998 BETANCOURT JR: Cultural competence—marginal or mainstream movement? N Engl J Med 351:953. Am J Pub Health 87:1773. 1991 BACH PB et al: Racial differences in the treatment of early-stage lung cancer. 2000 JHA AK et al: Racial trends in the use of major procedures among the elderly. National Academy Press. EPSTEIN AM: Differences in the use of procedures between women and men hospitalized for coronary heart disease. 1999 FLORES G et al: The health of Latino children: Urgent priorities. 2000 WEISSMAN JS et al: Resident physicians’ preparedness to provide cross-cultural care. 1999 TODD KH et al: Ethnicity as a risk factor for inadequate emergency department analgesia. N Engl J Med 353:671. and a research agenda. Soc Sci Med 42:769. N Engl J Med 341:1661.of disparities will improve the care provided to all patients. BURKE J: The effect of patient race and socio-economic status on physician’s perceptions of patients. Agency for Health Care Research and Quality. 1994-2002. 1999 SKINNER J et al: Mortality after acute myocardial infarction in hospitals that disproportionately treat black patients. MD. National Academy Press. Cancer Prev Control 3:25. 2004 ———: Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care. 2005 MCKINLAY JB et al: Non-medical influences on medical decisionmaking. National Academy Press. JAMA 269:1537. DC. 1997 PINCUS T et al: Social conditions and self-management are more powerful determinants of health than access to care. Am J Med 108:561. 1999 BAICKER K et al: Who you are and where you live: How race and geography affect the treatment of medicare beneficiaries. 1993 TRIVEDI AN et al: Trends in the quality of care and racial disparities in Medicare managed care. 2005 VACCARINO V et al: Sex and race differences in the management of acute myocardial infarction. 2002 ———: Crossing the Quality Chasm: A New Health System for the 21st Century. 1999 CARRASQUILLO O et al: Impact of language barriers on patient satisfaction in an emergency department. 2004 ——— et al: Hypertension in multicultural and minority populations: Linking communication to compliance. Soc Sci Med 50:813. Washington. DC. DC. Washington. N Engl J Med 340:618. 2002 GAMBLE V: Under the shadow of Tuskegee: African-Americans and health care. Health Aff (Millwood) Suppl Web Exclusive: VAR 33-44. 2006 ANDRULIS DP: Access to care is the centerpiece in the elimination of socioeconomic disparities in health. N Engl J Med 325:226. 2001 ———: To Err Is Human: Building a Safer Health System. Ann Intern Med 129: 406. 1998 RATHORE SS et al: The effects of patient sex and race on medical students’ ratings of quality of life. Washington. National Academy Press. 1998 AYANIAN JZ et al: Quality of care by race and gender for congestive heart failure and pneumonia. . 1997 INSTITUTE OF MEDICINE: Health Literacy: A Prescription to End Confusion. J Gen Intern Med 14:82. N Engl J Med 353:692. National Academy Press. Circulation 12:2634.

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misrepresenting it. However. such as hospitals or insurers. and simply being a good person do not guarantee that physicians can identify or resolve ethical dilemmas. Lying refers to statements that the speaker knows are false and that are intended to mislead the listener. and prevents discrimination. which is broader. informed patients may refuse recommended interventions and choose among reasonable alternatives. CONFLICTS BETWEEN BENEFICENCE AND AUTONOMY Patients’ refusals of care may thwart their own goals or cause them serious harm. If disagreements persist after discussions. the risks and benefits of each. Laypeople do not possess medical expertise and may be vulnerable because of their illness. Knowledge about common ethical dilemmas is also essential. and the likely consequences. needlessly complicated explanations. In most clinical settings different goals and approaches are possible. encourages them to seek treatment and discuss their problems candidly. the patient’s informed choices and view of his or her best interests should prevail. Hence. or the costs are e19 too high. patients traditionally are not told of a diagnosis of cancer or of other serious illness. Informed consent involves more than obtaining signatures on consent forms. The interests of the patient should prevail over physicians’ self-interest or the interests of third parties. no worthwhile goals can be Copyright © 2008 The McGraw-Hill Companies. Patients can be overwhelmed with medical jargon. medical providers have a legal duty to report victims of elder abuse. common sense. offering empathy and hope. and hope. Physicians can elicit patients’ expectations and concerns. For example. the alternatives. Confidentiality may be overridden in certain situations to prevent serious harm to third parties or to the patient. Such looser usages of the term are problematic because they may be inconsistent and mask important value judgments. Health care providers therefore should ask patients how they want decisions to be made. in the name of respecting autonomy. unless they have previously indicated otherwise. These regulations are not meant to inhibit transmission of information needed for patient treatment: disclosure of patient information to other health care providers for the purposes of treatment without having the patient sign an authorization form is permissible. Although such deception may be motivated by a desire to help the patient. make recommendations. which are characterized by “let the buyer beware. the adverse effects of overriding confidentiality are minimized. Experience. time-consuming. provides only limited guidance. Maintaining Confidentiality Confidentiality respects patients’ autonomy and privacy. Thus competent. many individuals in these groups want to know their diagnosis and prognosis. Emergency Care Informed consent is not required when patients cannot give consent and when delay of treatment would place their lives or health in peril. and emotionally draining. Simply to accept such refusals. physicians have a fiduciary duty to act in the best interests of their patients. answer questions. while often cited. People are presumed to want such emergency care. correct misunderstandings. disclosure of a grave diagnosis is believed to cause patients to suffer.” not by trust and reliance. while offering patients the option not to receive information or to turn over decision-making to someone else. Individuals place different values on health. while withholding information promotes serenity. The guideline of “do no harm” forbids physicians from providing ineffective interventions or acting without due care. or too much information at once. Nondisclosure of Information Physicians may consider withholding a serious diagnosis. cardiopulmonary resuscitation would be futile in a patient with progressive hypotension despite maximal therapy. while adjusting the pace of disclosure. medical care. However. For example. it is ethically problematic. This precept. For example. the health care provider may tell a patient that she has a “small growth” so that she does not think she has cancer. even if they are terminally ill. RESPECTING PATIENT AUTONOMY Treating patients with respect requires doctors to accept the medical decisions of persons who are informed and acting freely. These fiduciary obligations of physicians contrast sharply with business relationships. whether or not they are literally true. and these adverse effects are deemed acceptable by society. Informed Consent For patients to make informed decisions. Avoiding Deception Health care providers sometimes consider using lies or deception in order to protect the patient from bad news or to obtain benefits for the patient. and domestic violence. maintaining confidentiality is not an absolute rule. Or the provider may complete and sign a form for a patient to get a bus pass. saying that they usually provide information and make decisions together with patients. a young man with asthma may refuse mechanical ventilation for reversible respiratory failure. While refusing recommended care does not render a patient incompe- CHAPTER e4 Ethical Issues in Clinical Medicine FUNDAMENTAL ETHICAL GUIDELINES Physicians should follow two fundamental but frequently conflicting ethical guidelines: respecting patient autonomy and acting in the patient’s best interests. and help them deliberate.e4 Ethical Issues in Clinical Medicine Bernard Lo Physicians frequently confront ethical issues in clinical practice that are perplexing. In other situations. public health laws require reporting of tuberculosis and syphilis. Generally. These exceptions to confidentiality are justified because the risk is serious and probable. outcomes are uncertain. and try to persuade them to accept beneficial therapies. The recent HIPAA (Health Insurance Portability and Accountability Act) health privacy regulations have heightened awareness of the importance of confidentiality. and risk. They justifiably rely on physicians to provide sound advice and to promote their well-being. achieved. Physicians need to educate patients. deception undermines physicians’ credibility and trustworthiness. there are no lessrestrictive measures to avert risk. even though he does not meet the criteria for physical disability. But physicians should be wary of using the term “futile” in looser senses to justify unilateral decisions to forego interventions when they believe that the probability of success is too low. and helping patients cope with bad news. For example. security. ACTING IN THE BEST INTERESTS OF PATIENTS The guideline of beneficence requires physicians to act for the patient’s benefit. Patients should not be forced to receive information against their will. child abuse. Physicians are not obligated to provide futile interventions that have no physiologic rationale or have already failed. because many beneficial interventions also have serious risks. Deception. seems morally constricted. The person who is deceived cannot make informed decisions if they receive misleading information. In these cultures. even in the name of promoting informed decisions. the patient’s quality of life is unacceptable. or limiting discussions of prognosis or risks because they fear that a patient will develop severe anxiety or depression or refuse needed care. and an intervention may cause both benefits and harms. Physicians encourage such trust. physicians need to discuss with them the nature of the proposed care. All rights reserved. The law may require physicians to override confidentiality in order to protect third parties. Futile Interventions Autonomy does not entitle patients to insist on whatever care they want. may be defined as statements and actions that are intended to mislead the listener. physicians should provide relevant information. . In many cultures. and to obtain the patient’s agreement to care. Furthermore.

physicians can ensure that advance directives are informed. It is more flexible and comprehensive than the living will. are also justifications for withdrawing them.e20 tent. this distinction is not logical because all medical interventions have both risks and benefits. casual or vague comments may not be trustworthy. or feeding tubes. The courts should be used only as a last resort when disagreements cannot be resolved in the clinical setting. such choices should be respected. religion. competent patients can express a choice and appreciate the medical situation. the nature of the proposed care. While such substituted judgments try to respect the patient’s values. In addition. the alternatives. decisions should be postponed if possible until the patient recovers decision-making capacity. it is important to act consistently in cases that are similar in ethically relevant ways. Any intervention may be withheld. Extraordinary and Ordinary Care Some physicians are willing to forego “extraordinary” or “heroic” interventions. and consequences of each. or (2) who should serve as surrogate. there is no logical distinction between the two acts. When patients lack decision-making capacity. physicians usually determine that patients lack the capacity to make health care decisions and arrange for surrogates to make them. A surrogate may be mistaken about the patient’s preferences. Their choices should be consistent with their values and should not result from delusions or hallucinations. Most patients want their family members to be surrogates. Consultation with the hospital ethics committee or with another physician often helps resolve disputes. Legal Issues Physicians need to know pertinent state laws regarding patients who lack decision-making capacity. patients and surrogates might not even attempt treatments that might prove beneficial. Physicians can encourage patients to provide advance directives. PART 1 Introduction to Clinical Medicine PATIENTS WHO LACK DECISION-MAKING CAPACITY Patients may not be able to make informed decisions because of unconsciousness. applying whenever the patient is unable to make decisions. Psychiatrists may help in difficult cases because they are skilled at interviewing mentally impaired patients and can identify treatable depression or psychosis.” A health care proxy is someone appointed by the patient to make health care decisions if he or she loses decision-making capacity. Justifications for withholding interventions. mechanical ventilation. with access based on medical need rather than ability to pay. delirium. Withdrawing and Withholding Interventions Many health care providers find it more difficult to discontinue interventions than to withhold them in the first place. to indicate both what they would want and who should be the surrogate. or other conditions. In discussions with patients. dementia. such as refusal by patients or surrogates. and family members generally know the patient’s preferences and have the patient’s best interests at heart. Otherwise. it may lead the physician to probe further to ensure that the patient is able to make informed decisions. Living wills direct physicians to forego or provide life-sustaining interventions if the patient develops a terminal condition or persistent vegetative state. Patients may designate a particular individual to serve as proxy. A few state courts allow doctors to forego life-sustaining interventions only if patients have provided written advance directives or very specific oral ones. While such conversations are customarily followed in clinical practice. Oral conversations are the most frequent form of advance directives. JUSTICE The term justice is used in a general sense to mean fairness: people should receive what they deserve. If interventions could never be discontinued. informed patients may refuse life-sustaining interventions. The intervention may prove unsuccessful. and the risks. not what they would want for themselves. . the surrogate respects the patient’s autonomy. Competent. after an intervention has been started. Most patients with chronic illness rate their quality of life higher than their family members and physicians do. and to discuss their preferences with surrogates. CHOICE OF SURROGATE If a patient lacks decision-making capacity. All rights reserved. however. In practice. In addition. Generally patients may refuse only interventions that “merely prolong the process of dying. Best Interests When the patient’s preferences are unclear or unknown. Although such emotions need to be acknowledged. surrogates and physicians should try to decide as the patient would under the circumstances. using all information that they know about the patient. such as antibiotics. if others project their values onto the patient or weigh the perceived social worth of the patient. such as surgery. decisions should be based on the patient’s best interests. without involving the courts. The federal Patient SelfDetermination Act requires hospitals and health maintenance organi- DECISIONS ABOUT LIFE-SUSTAINING INTERVENTIONS Although medical technology can save lives. zations to inform patients of their right to make health care decisions and to provide advance directives. Patients generally take into account the quality of life as well as the duration of life when making decisions for themselves. if the burdens for the individual patient outweigh the benefits. or it may be learned that the patient did not want the intervention. However. They may indicate (1) what interventions they would refuse or accept. decisions would be arbitrary. Such consultation is also helpful when patients have no surrogate and no advance directives. they may be speculative or inaccurate. or gender and supports a moral right to health care. physicians routinely ask family members to serve as surrogates. benefits. it can also prolong the process of dying. Justice forbids discrimination in health care based on race. It is understandable that surrogates would also consider quality of life of patients who lack decisionmaking capacity. Bias or discrimination may occur. particularly when they have not been discussed explicitly. By definition. Physicians should ask two questions regarding such patients: Who is the appropriate surrogate? What would the patient want done? ASSESSING CAPACITY TO MAKE MEDICAL DECISIONS All adults are considered legally competent unless declared incompetent by a court. Such discussions are best carried out in the ambulatory setting. Judgments about quality of life are appropriate if they reflect the patient’s own values. Substituted Judgment In the absence of clear advance directives. new data may indicate that it is no longer appropriate. Copyright © 2008 The McGraw-Hill Companies. Physicians can remind everyone to base decisions on what the patient would want. Following the patient’s advance directives. Disagreements Disagreements may occur among potential surrogates or between the physician and surrogate. and unfair. Courts have ruled that foregoing life-sustaining interventions is neither suicide nor murder. When impairments are fluctuating or reversible. IV fluids. Some states have established a prioritized list of which relative may serve as surrogate if the patient has not designated a proxy. STANDARDS FOR SURROGATE DECISION-MAKING Advance Directives These are statements by competent patients to direct care if they lose decision-making capacity. and address likely clinical scenarios. such interventions may also be withheld on the basis of advance directives or decisions by appropriate surrogates. biased. or renal dialysis but insist on providing “ordinary” ones. up-to-date. MISLEADING DISTINCTIONS People commonly draw distinctions that are intuitively plausible but prove untenable on closer analysis.

Physicians should elicit and address any underlying problems. that suffering can generally be relieved. Opponents assert that such actions violate the sanctity of life. it can also disrupt a peaceful death. A helpful rule of thumb is to consider whether patients would approve of the gift if they knew physicians had accepted it. or psychiatric or medical illness place patients at risk. however. there is concern that physicians may withhold beneficial care in order to control costs. or hospitalizations. unless attending physicians are informed of trainees’ errors. or the insurer may deny coverage. and that such actions are outside the physician’s proper role. and makes it difficult for patients to make informed choices about their care. no more and no less. Physicians and students may fear that disclosing such errors could damage their careers. may lead to more elaborate deception. To prevent misunderstandings. Physicians may hesitate to order high doses of narcotics and sedatives. In contrast. except that physician-assisted suicide is legal in Oregon under restricted circumstances. such as physical symptoms. physicians should respond to patients’ inquiries about these actions with compassion and concern. listening to them. refuse to care for persons with HIV infection or multidrug-resistant tuberculosis. what benefits and burdens can be attributed to trainees. physicians have incentives to provide more care than indicated when they receive fee-for-service reimbursement or when they refer patients to laboratory or imaging facilities in which they have invested. tests. OCCUPATIONAL RISKS Some health care workers. society relies on physicians to regulate themselves. students may be introduced as physicians or patients may not be told that trainees will be performing procedures. and even fewer in certain subgroups. that abuses are inevitable. If colleagues of an impaired physician do not take steps to protect patients. loss of control. and how trainees are supervised. Often. Even the appearance of a conflict of interest may undermine trust in the profession. and after this is done patients generally withdraw their requests for these acts. All rights reserved. After CPR is attempted on a general hospital service. increase the cost of health care. Furthermore. Doctors might consider. and give the ap. These actions are illegal throughout the United States. and health care institutions should reduce occupational risk by providing proper training. and attending to their psychological distress. increasing the dose to levels that might suppress respiratory drive or lower blood pressure is ethically appropriate because the physician’s intention is to relieve suffering. drug abuse. only 14% of patients survive to discharge. The ethical ideal is to keep the patient’s interests paramount. patients cannot understand their clinical situation or make informed choices about subsequent care. While physicians understandably want to help patients. physicians should write DNR orders and the reasons for them in the medical record. physicians should provide appropriate care within their clinical expertise. cardiopulmonary resuscitation (CPR) is initiated unless a DNR order has been made. Physicians can also relieve suffering by spending time with dying patients. no one else may be in a position to do so. trying to help them obtain essential care. Patients should be told who is providing care. not hasten death. when informed. To ensure patient cooperation. additional efforts to relieve distress are successful. Without disclosure. Regardless of financial incentives. fearing they will hasten death. Whatever their personal views. Although a DNR order signifies only that CPR will be withheld. Although such incentives are intended to reduce inefficiency and waste. Such palliative sedation is distinguished ethically and legally from active euthanasia. However. LEARNING CLINICAL SKILLS Learning clinical medicine. protective equipment. DNR orders are appropriate if the patient or surrogate requests them or if CPR would be futile. may present inconvenience or risk to patients. Most patients. Discussing such dilemmas with more senior physicians can help trainees check their interpretation of the situation and obtain advice and assistance. “Slow” or “show” codes that merely appear to provide CPR are deceptive and therefore unacceptable. Critics contend that any gift from drug companies ALLOCATING RESOURCES JUSTLY Patient access to needed care is a moral aspiration rather than established public policy in the United States. IMPAIRED PHYSICIANS Physicians may hesitate to intervene when colleagues impaired by alcohol abuse. using lying or deception to help them gain such benefits. the reasons that justify DNR orders may lead to a reconsideration of other plans for care. terminally ill patients should have control over the end of life and that physicians should relieve refractory suffering. ASSISTED SUICIDE AND ACTIVE EUTHANASIA Proponents of these controversial acts believe that competent. CARE OF DYING PATIENTS Patients often suffer unrelieved pain and other symptoms during their final days of life. Similarly.DO NOT RESUSCITATE (DNR) ORDERS When a patient suffers a cardiopulmonary arrest. such misrepresentation undermines physicians’ credibility and trustworthiness. If this occurs. GIFTS FROM PHARMACEUTICAL COMPANIES Physicians may be offered gifts ranging from pens and notepads to lavish entertainment. particularly learning to perform invasive procedures. If lower doses of narcotics and sedatives have failed to relieve suffering. Avoiding deception is a basic ethical guideline that sets limits on advocating for patients.e21 pearance of conflict of interest. MEDICAL ERRORS Errors are inevitable in clinical medicine. can impair objectivity. They may cause serious harm to patients or result in substantial changes in management. To fulfill their mission of helping patients. CONFLICTS FOR TRAINEES Medical students and residents may fear that they will receive poor grades or evaluations if they act on the patient’s behalf by disclosing mistakes. despite some personal risk. physicians may serve as gatekeepers or bear financial risk for expenditures. Such misrepresentation undermines trust. which is administering a lethal dose with the intention of ending the patient’s life. Relieving pain in terminal illness and alleviating dyspnea when patients forego mechanical ventilation enhances patient comfort and dignity. or depression. Such fears about personal safety need to be acknowledged. CHAPTER e4 Ethical Issues in Clinical Medicine CONFLICTS OF INTEREST Acting in the patient’s best interests may conflict with the physician’s self-interest or the interests of third parties such as insurers or hospitals. Some patients with a clear need for medical care cannot pay for medications. patients are often outraged when physicians do not acknowledge errors. FINANCIAL INCENTIVES In managed care systems. physicians should advocate for patients. Physicians caring for underserved populations must act ethically in a health care system that has serious ethical shortcomings in access to and quality of care. avoiding misrepresentation of their role. they cannot provide optimal care and help trainees learn from mistakes. Allocation of health care resources is unavoidable because re- Copyright © 2008 The McGraw-Hill Companies. fearing fatal occupational infections. . allow trainees to play an active role in their care. physicians should recommend available care that is in the patient’s best interests. or patients might request. and reporting impaired colleagues. and supervision. Although CPR can restore people to vigorous health.

and ineffective. Lippincott Williams & Wilkins. with physician input. New York. a patient’s insurer may have a higher co-payment for non-formulary drugs. reasonable insurance coverage. New York. 2d ed. 2001 CHIONG W: Justifying patient risks associated with medical education. 5th ed. or the hospital ethics committee often clarifies issues and suggests ways to improve communication and to deal with strong emotions. LEFFLER C: Ethics and Humans Rights Committee of the American College of Physicians. tolerate uncertainty. All rights reserved. allocation decisions should be made as public policy. as when the formulary drugs are ineffective or not tolerated. John Wiley & Sons. At the bedside. Allocation of resources at the bedside is problematic because it may be inconsistent. Ann Intern Med 130:744. 2005 PART 1 Introduction to Clinical Medicine ASSISTANCE WITH ETHICAL ISSUES Discussing perplexing ethical issues with other members of the health care team. 2005 LO B et al: Discussing palliative care with patients. 2001 BERG JW et al: Informed Consent: Legal Theory and Clinical Practice. Ideally. 2002 LO B: Resolving Ethical Dilemmas: A Guide for Clinicians. Oxford University Press. 2d ed. New York. physicians may need to reevaluate their basic convictions. . and maintain their integrity while respecting the opinions of others. unfair. 2007 KITE S. physicians generally should act as patient advocates within constraints set by society. Ann Intern Med 142:560. Ethics Manual: Fifth Edition. Copyright © 2008 The McGraw-Hill Companies. WILKINSON S: Beyond futility: To what extent is the concept of futility useful in clinical decision-making about CPR? Lancet Oncol 3:638. colleagues. FURTHER READINGS BEAUCHAMP TL. It is reasonable for physicians to advocate for non-formulary drugs only if there are compelling reasons for an exception. 1995 SNYDER L. For example.e22 sources are limited. Oxford University Press. CHILDRESS JF: Principles of Biomedical Ethics. 3d ed. 1999 MEISEL A: The Right to Die. JAMA 298:1046. Baltimore. When struggling with difficult ethical issues. and evidence-based practice.

of Rashes e5 AtlasFever Associated with
Kenneth M. Kaye, Elaine T. Kaye
Given the extremely broad differential diagnosis, the presentation of a patient with fever and rash often poses a thorny diagnostic challenge for even the most astute and experienced clinician. Rapid narrowing of the differential by prompt recognition of a rash’s key features can result in appropriate and sometimes life-saving therapy. This atlas presents high-quality images of a variety of rashes that have an infectious etiology and are commonly associated with fever.

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Atlas of Rashes Associated with Fever
FIGURE e5-3 In measles, discrete erythematous lesions become confluent on the face and neck over 2–3 days as the rash spreads downward to the trunk and arms, where lesions remain discrete. (Reprinted from K Wolff, RA Johnson: Color Atlas & Synopsis of Clinical Dermatology, 5th ed. New York, McGraw-Hill, 2005, p 788.)

FIGURE e5-1 Lacy reticular rash of erythema infectiosum (fifth disease).

FIGURE e5-4 In rubella, an erythematous exanthem spreads from the hairline downward and clears as it spreads. (Photo courtesy of Stephen E. Gellis, MD; with permission.) FIGURE e5-2 Koplik’s spots, which manifest as white or bluish lesions with an erythematous halo on the buccal mucosa, usually occur in the first 2 days of measles symptoms and may briefly overlap the measles exanthem. The presence of the erythematous halo differentiates Koplik’s spots from Fordyce’s spots (ectopic sebaceous glands), which occur in the mouths of healthy individuals. (Source: CDC. Photo selected by Kenneth M. Kaye, MD.)

Copyright © 2008 The McGraw-Hill Companies. All rights reserved.

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PART 2
Cardinal Manifestations and Presentation of Diseases

FIGURE e5-5 Exanthem subitum occurs most commonly in young children. A diffuse maculopapular exanthem follows resolution of fever. (Photo courtesy of Stephen E. Gellis, MD; with permission.)

FIGURE e5-8 Erythema chronicum migrans is the early cutaneous manifestation of Lyme disease and is characterized by erythematous annular patches, often with a central erythematous papule at the tick bite site. (Courtesy of Yale Resident’s Slide Collection; with permission.)

FIGURE e5-6 Erythematous macules and papules are apparent on the trunk and arm of this patient with primary HIV infection. (Reprinted from K Wolff, RA Johnson: Color Atlas & Synopsis of Clinical Dermatology, 5th ed. New York, McGraw-Hill, 2005.)

FIGURE e5-9 Rose spots are evident as erythematous macules on the trunk of this patient with typhoid fever.

FIGURE e5-10 Systemic lupus erythematosus showing prominent, scaly, malar erythema. Involvement of other sun-exposed sites is also common. FIGURE e5-7 This exanthematous drug-induced eruption consists of brightly erythematous macules and papules, some which are confluent, distributed symmetrically on the trunk and extremities. Ampicillin caused this rash. (Reprinted from K Wolff, RA Johnson: Color Atlas & Synopsis of Clinical Dermatology, 5th ed. New York, McGraw-Hill, 2005.)
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.

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CHAPTER e5

FIGURE e5-11 Acute lupus erythematosus on the upper chest, with brightly erythematous and slightly edematous coalescence papules and plaques. (Courtesy of Robert Swerlick, MD; with permission.) FIGURE e5-14 Impetigo contagiosa is a superficial streptococcal or Staphylococcus aureus infection consisting of honey-colored crusts and erythematous weeping erosions. Occasionally, bullous lesions may be seen. (Courtesy of Mary Spraker, MD; with permission.)

Atlas of Rashes Associated with Fever

FIGURE e5-12 Discoid lupus erythematosus. Violaceous, hyperpigmented, atrophic plaques, often with evidence of follicular plugging (which may result in scarring), are characteristic of this cutaneous form of lupus. (Courtesy of Marilynne McKay, MD; with permission.)

FIGURE e5-15 Erysipelas is a streptococcal infection of the superficial dermis and consists of well-demarcated, erythematous, edematous, warm plaques.

FIGURE e5-13 The rash of Still’s disease typically exhibits evanescent, erythematous papules that appear at the height of fever on the trunk and proximal extremities. (Courtesy of Stephen E. Gellis, MD; with permission.)
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.

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PART 2
Cardinal Manifestations and Presentation of Diseases
FIGURE e5-16 Top: Petechial lesions of Rocky Mountain spotted fever on the lower legs and soles of a young, otherwise-healthy patient. Bottom: Close-up of lesions from the same patient. (Photos courtesy of Lindsey Baden, MD; with permission.) FIGURE e5-17 Primary syphilis with a firm, nontender chancre.

FIGURE e5-18 Secondary syphilis demonstrating the papulosquamous truncal eruption.

FIGURE e5-19 Secondary syphilis commonly affects the palms and soles with scaling, firm, red-brown papules.

FIGURE e5-20 Condylomata lata are moist, somewhat verrucous intertriginous plaques seen in secondary syphilis.

Copyright © 2008 The McGraw-Hill Companies. All rights reserved.

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CHAPTER e5

FIGURE e5-21 Mucous patches on the tongue of a patient with secondary syphilis. (Courtesy of Ron Roddy; with permission.)

Atlas of Rashes Associated with Fever

FIGURE e5-23 Tender vesicles and erosions in the mouth of a patient with hand-foot-and-mouth disease. (Courtesy of Stephen E. Gellis, MD; with permission.)

FIGURE e5-22 Petechial lesions in a patient with atypical measles. (Photo courtesy of Stephen E. Gellis, MD; with permission.) FIGURE e5-24 Septic emboli with hemorrhage and infarction due to acute Staphylococcus aureus endocarditis. (Courtesy of Lindsey Baden, MD; with permission.)

Copyright © 2008 The McGraw-Hill Companies. All rights reserved.

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PART 2
Cardinal Manifestations and Presentation of Diseases

FIGURE e5-25 Erythema multiforme is characterized by multiple erythematous plaques with a target or iris morphology and usually represents a hypersensitivity reaction to drugs or infections (especially herpes simplex virus). (Courtesy of the Yale Resident’s Slide Collection; with permission.)

FIGURE e5-27 Erythema progressing to bullae with resulting sloughing of the entire thickness of the epidermis occurs in toxic epidermal necrolysis. This reaction was due to a sulfonamide. (Reprinted from K Wolff, RA Johnson: Color Atlas & Synopsis of Clinical Dermatology, 5th ed. New York, McGraw-Hill, 2005.)

FIGURE e5-26 Scarlet fever exanthem. Finely punctuated erythema has become confluent (scarlatiniform); accentuation of linear erythema in body folds (Pastia’s lines) is seen here. (Reprinted from K Wolff, RA Johnson: Color Atlas & Synopsis of Clinical Dermatology, 5th ed. New York, McGraw-Hill, 2005.)

FIGURE e5-28 Diffuse erythema and scaling are present in this patient with psoriasis and the exfoliative erythroderma syndrome. (Reprinted from K Wolff, RA Johnson: Color Atlas & Synopsis of Clinical Dermatology, 5th ed. New York, McGraw-Hill, 2005.)

Copyright © 2008 The McGraw-Hill Companies. All rights reserved.

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CHAPTER e5
Atlas of Rashes Associated with Fever

FIGURE e5-31 Numerous varicella lesions at various stages of evolution: vesicles on an erythematous base, umbilical vesicles, and crusts. (Courtesy of R. Hartman; with permission.)

FIGURE e5-29 This infant with staphylococcal scalded skin syndrome demonstrates generalized desquamation. (Reprinted from K Wolff, RA Johnson: Color Atlas & Synopsis of Clinical Dermatology, 5th ed. New York, McGraw-Hill, 2005.)

FIGURE e5-32 Close-up of lesions of disseminated zoster. Note lesions at different stages of evolution, including pustules and crusting. (Photo courtesy of Lindsey Baden, MD; with permission.)

FIGURE e5-30 Fissuring of the lips and an erythematous exanthem are evident in this patient with Kawasaki’s disease. (Courtesy of Stephen E. Gellis, MD; with permission.) FIGURE e5-33 Herpes zoster is seen in this HIV-infected patient as hemorrhagic vesicles and pustules on an erythematous base grouped in a dermatomal distribution.
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.

e30 PART 2 Cardinal Manifestations and Presentation of Diseases FIGURE e5-34 Top: Eschar at the site of the mite bite in a patient with rickettsialpox.) Copyright © 2008 The McGraw-Hill Companies. edematous. . (Photo courtesy of Lindsey Baden. A liver transplant recipient developed six cutaneous lesions similar to the one shown. Biopsy and serum antigen testing demonstrated Cryptococcus. Bottom: Close-up of lesions from the same patient. MD. FIGURE e5-36 Urticaria showing characteristic discrete and confluent. 2002. All rights reserved. Kaye. Photos obtained by Kenneth M. FIGURE e5-37 Disseminated cryptococcal infection. (Reprinted from A Krusell et al: Emerg Infect Dis 8:727. Middle: Papulovesicular lesions on the trunk of the same patient. MD. with permission.) FIGURE e5-35 Ecthyma gangrenosum in a neutropenic patient with Pseudomonas aeruginosa bacteremia. erythematous papules and plaques. Important features of the lesion include a benign-appearing fleshy papule with central umbilication resembling molluscum contagiosum.

with permission. . with permission. erythematous. The lesion in the photograph is on the inner thigh and is several centimeters in diameter. with permission.) Copyright © 2008 The McGraw-Hill Companies.e31 CHAPTER e5 FIGURE e5-38 Disseminated candidiasis. All rights reserved.) FIGURE e5-41 Sweet’s syndrome: an erythematous indurated plaque with a pseudovesicular border. MD. Biopsy demonstrated infarction caused by Aspergillus fumigatus. (Courtesy of Lindsey Baden. with permission. with permission.) Atlas of Rashes Associated with Fever FIGURE e5-40 Erythema nodosum is a panniculitis characterized by tender deep-seated nodules and plaques usually located on the lower extremities. MD. Tender. Gellis. MD. nodular lesions developed in a neutropenic patient with leukemia who was undergoing induction chemotherapy.) FIGURE e5-42 Fulminant meningococcemia with extensive angular purpuric patches. (Photo courtesy of Lindsey Baden.) FIGURE e5-39 Disseminated Aspergillus infection. (Courtesy of Robert Swerlick. (Courtesy of Stephen E. MD. (Courtesy of Robert Swerlick. Multiple necrotic lesions developed in this neutropenic patient undergoing hematopoietic stem cell transplantation. MD.

MD. MD. with permission. .) PART 2 FIGURE e5-43 Erythematous papular lesions are seen on the leg of this patient with chronic meningococcemia. (From the Centers for Disease Control and Prevention. with permission. (Courtesy of Kenneth M. (Courtesy of Robert Swerlick.) Copyright © 2008 The McGraw-Hill Companies. All rights reserved.) FIGURE e5-44 Disseminated gonococcemia in the skin is seen as hemorrhagic papules and pustules with purpuric centers in a centrifugal distribution. MD.e32 FIGURE e5-46 The thumb of a patient with a necrotic ulcer of tularemia. Musher. MD.) FIGURE e5-45 Palpable purpuric papules on the lower legs are seen in this patient with cutaneous small-vessel vasculitis. Kaye. (Courtesy of Daniel M. with permission. Tularemia was diagnosed. (Courtesy of Lindsey Baden. and Elaine T.) Cardinal Manifestations and Presentation of Diseases FIGURE e5-47 This 50-year-old man developed high fever and massive inguinal lymphadenopathy after a small ulcer healed on his foot. Kaye. with permission. MD.

This process. vocabulary and knowledge of the associations between verbal concepts the neocortex learns slowly and has a very large storage capacity. a fundamental distinction has been made be. Bird. memories become “consolidated” in the neocortex and. and other details of a specific cortical regions. generic information that is acquired strengthened until the memory trace no longer depends on the MTL’s across many different contexts and accessed without accompanying activity but is instead entirely represented in the cortex. loss of sumption that memory is not a unitary phenomenon.nently stored within the same neocortical regions that are involved in ample. Episodic memory allows the recollection of hippocampal formation and between the MTL and neocortical regions unique personal experiences. All rights reserved.” The architecture of the hippocampus facts and events. This tem. Many episodic memories are kept for minutes and hours but the mental state of the person activates cells in the cortical regions. refers to cur. e6-1). In make up the bulk of semantic memory.” and “where it happened. as brain injury improves over time. One’s While the MTL learns quickly and has a limited capacity for storage. therefore. need not lead to the as. Natl Acad Sci U S A. 1996. e6 Memory Loss tive memory is supported by evidence that episodic and semantic e33 memory have distinctive anatomic substrates. as in Alzheimer’s disease (AD). and the temporal gradient for memory loss shrinks. Key structures involved with episodic the future. however. the soon discarded. an inability to commit new information to memory.” “when it haptween declarative memory. of a given memory. and occipital lobes via the parahippocampal cortex. habits.the unique ability to bind together “what happened. the hippocampus has memory but not others. memory include the hippocampus. Patients subiculum and back to the entorhinal cortex. This fractionation of declara.neocortical representation is strengthened. the person reex. points to the hippocampus as serving a critical function in the retrieval of detailed episodic memories. Semantic memory. in contrast. remembering a single practice session or even recognizing the teacher Each different cortical region makes a unique contribution to the storage who patiently works with him everyday.) Copyright © 2008 The McGraw-Hill Companies. In an effort to explain why focal brain damage affects some aspects of Given its anatomic placement and architecture. it is helpful to break down memory into simpler ing. Recent evidence. which refers to memory includes a circular pathway of neurons from the entorhinal cortex to the for skills.both regions. SM Zola: Proc tends to diminish. Others remain for the course of a lifetime. the retrograde memory impairment FIGURE e6-1 Fractionation of long-term memory. To delineate the neural cir. With episodic memory.bodies. the hippocampus that is to be remembered. and retrieve information. without initial processing and analyzing of sensory information (neocortex). Overly intense or painful episodic memories can result in posttraucomponents. and the way in which the brain will use the information in stimuli in our sensory world. retain. These parietal. and all regions participate together in the creation of a complete memory representation. Patients with injury to this system will exhibit anterograde amnesia. By contrast.” With repeated activations. As multiple reactivations occesses at work (see below). a devastating illness in which patients repeatedly reexperience unpleasant episodes from their lives. episodic and semantic memory tributions into a coherent memory trace. over time. Therefore.dentate gyrus and CA3 and CA1 neurons of the hippocampus to the pressed without awareness of what was learned (Fig. however. The neural circuits underlying these processes are dynamic. Memories that were established before the injury (remote memories) tend to be relatively preserved. sounds. which refers to the conscious memory for pened. details of the time when the words or facts were remembered. then. Bruce L. or other manifestations of learning that can be ex. although a retrograde amnesia. Also.MTL network that is associated with that cue is reactivated and the entire poral difference in storage probably reflects different physiologic pro. by which the burden of longterm (permanent) memory storage is gradually assumed by the neocortex. when a particular cue in the environment or event. (Adapted from LR Squire. 24: 13515. regardless of the age of the memory. This pathway is heavily with bilateral medial temporal lobe (MTL) damage show declarative damaged in AD. the connections between the relevant neocortical regions are slowly knowledge about the world. For ex. ensures that the MTL system is constantly available for the acquisition of new information. going back anywhere from minutes to years.are formed more rapidly than are the connections between disparate periences the sights. the hippocampal formation receives processed sensory information from association areas in the frontal. Injury anywhere along this septohippocampal pathway can lead to severe loss of episodic memory. Thomas D. and thalamus. episodic memories. The connections within the can be distinguished. The hippocampal formation. wire together. will prevent the individual from learning new things about the world and will eventually LONG-TERM MEMORY strip away the old memories that constitute a life biography. smells.Episodic Memory In the MTL. Memory allows us to store. and nondeclarative memory. Miller CHAPTER e6 Memory Loss .matic stress disorder. independent of the MTL. This categorization. DECLARATIVE MEMORY is saddled with the task of binding together these different regional conWithin the declarative memory system. the duration of time over which it must be is well placed to create associations between simultaneously occurring retained. whereby “cells that fire together. entorhinal cortex. mammillary reflecting the flexibility of memory itself. Larger lesions cause a more extensive retrograde memory deficit. Individual elements of episodic memories are permamemory deficits in the face of intact nondeclarative memory. Given three processes influence and are modified by the type of information these multiple cortical neuroanatomical connections. such a patient may learn to play the piano. learning occurs via Hebbian synapses. Alterations of episodic memory can be devastatcuitry underlying it. is usually evident.

basal ganglia activity is negatively correlated with MTL activity when both systems are engaged by a particular task. but the gravest deficits may be seen if the patient is unable to name common objects such as a pen or watch or less common objects such as a stethoscope or a fluorescent bulb. it often becomes difficult to verbalize how it was learned. a bike rider does not lose the skill entirely. we remember that a fork is a utensil that is used for eating food without remembering when we learned the word fork or when we discovered its use. Bilateral anterior temporal dysfunction is the anatomic substrate of semantic dementia. conscious awareness of learning is not necessary. once the information is acquired. These ideas are held together in the semantic memory system. in some cases. what is going on in the news. The hippocampus. Aside from semantic dementia. Additionally. leading to amnesia. For example. sometimes during positive but often during negative events. cerebellum.” then a “bird. Recent research now points to the basal ganglia as fundamental in motor skill learning. it is always necessary to have a historian who can verify that the recent memories are correct (not confabulated). Animal experiments have PART 2 Cardinal Manifestations and Presentation of Diseases Copyright © 2008 The McGraw-Hill Companies. suggesting that there are times when the two memory “systems” may compete for cognitive resources. In contrast. including the amygdala. For example. for example. That is. Emotionally charged events are more easily remembered than emotionally neutral episodes. in particular herpes simplex encephalitis. Bedside assessment of semantic memory is difficult. LTP occurs in the hippocampus and is mediated by N-methyl-D-aspartate (NMDA) receptors as well as the cyclic AMP– responsive element-binding (CREB) protein. can selectively attack the medial temporal regions. which begins in the entorhinal cortex and then spreads to the hippocampus. enhance or hasten the acquisition of skills and habits. and cognitive processes. While a fork may be useful in many different situations. Eventually all objects are classified with a series of simple stereotyped phrases. having lost access to specific exemplars. a subtype of the frontotemporal lobar degenerations. animals. The finding that children born with hippocampal sclerosis and lifelong episodic memory impairments can still function fairly well in school suggests that semantic memories are not wholly dependent upon intact episodic memory. the amygdala modulates memory processes during emotional experiences. One study. e6-1). however. Procedural memory is one type of nondeclarative memory. a hawk becomes a “hunting bird. All rights reserved. but deficits may be reported by patients or their families. In humans. The basal ganglia project to and receive projections from the frontal cortex. It is. While declarative memory can. Therefore. and prolonged seizures. One simple way to test episodic memory is to ask the patient to recall recent events such as what he did on the last big holiday. Furthermore. a parent’s attentiveness to his or her baby’s cry in a distant room involves perceptual learning. recent functional MRI work suggests that the MTL-based declarative memory and the corticostriatal procedural memory systems operate independently from each other and may in fact compete for cognitive resources. perceptual. With regard to personal episodic memories. is presumed to be involved in episodic memory acquisition and storage. Semantic memory is composed of a complex hierarchy of knowledge about the world. and that some foods are more easily eaten with a fork than another available utensil.” then an “animal. eating with only our hands is inappropriate. both the simple labeling process (naming) and knowledge about the identity of people and objects are lost. Parkinson’s disease (PD) causes damage to the basal ganglia and is associated with impairments in habit learning but spares declarative memory. and this corticostriatal loop has been implicated in the learning of skills and habits. . NONDECLARATIVE MEMORY Nondeclarative memory is an umbrella term for a heterogeneous collection of nonconscious memory abilities that involve multiple distinct neural regions. The amnesia of Korsakoff ’s syndrome is due to injury from hemorrhage into the mammillary bodies and dorsomedial nuclei of the thalamus. Here the attributes of an object are stored close to the regions of the cortex that mediate perception of those attributes. Cognitive psychologists have shown that in some cases. Procedural memory involves motor. if we are in a situation that requires using a fork as a tool in a novel manner. A common mechanism for hippocampal dysfunction is traumatic injury because the hippocampi sit adjacent to. Infections. Evidence that semantic memories are independent of the septohippocampal and mamillothalamic memory systems comes from humans with injury to these systems who maintain access to semantic knowledge despite profound deficits in episodic memory. The difference between declarative memory and procedural memory is the difference between “knowing that” and “knowing how. which spans across the association areas of the neocortex. the other disorders that lead to this syndrome include limbic encephalitis. suggesting that the representation of different parts of the body in the primary somatosensory cortex of humans depends on use and changes to conform to the current needs and experiences of the individual. Hence. Emotion plays a key role in enhancing the ability to remember personal episodes and other information encoded in a particular affective state. we can still call upon our semantic memory system to aid us in solving the problem. has shown that the cortical representation of the fingers of the left hand of musical string players is larger than that in nonmusicians. the recall of semantic memory does not lead to the retrieval of details of when. recent studies of patients with stroke in the left dorsomedial nucleus of the thalamus suggest that injury here alone will precipitate a severe amnesia. Because it requires extensive practice. flipping pancakes is a motor skill. basal ganglia. and are easily pushed against. or action) is organized as a distributed system. Vascular infarction can occur with occlusion of the hippocampal branches off the posterior cerebral arteries. Discrete cortical regions exist in the anterior temporal lobes in which object knowledge (such as words related to color. it is a slow and inflexible learning system that eventually takes on an automatic or reflexive quality. and sensory cortex (Fig. MOLECULAR AND NEUROCHEMICAL BASIS OF LONG-TERM MEMORY Long-term potentiation (LTP). is very sensitive to metabolic insults. In semantic dementia. Bedside testing of nondeclarative memory is outside the realm of the generalist. The forms of perceptual and motor learning that can occur without conscious recollections are mediated in part by contractions and expansions of representations in the sensory and motor cortex. severe loss of episodic memory can also be due to dysfunction in the mammillothalamic memory system. Knowing that a fork is generally used for eating depends on understanding that in certain social situations. a syndrome associated with neurodegenerative disease that begins in the anterior temporal lobes. the information was acquired. leading to severe and permanent deficits in episodic memory. fornix. or where. or medial temporal lobes. Finally. such as a spoon.e34 The most common cause for entorhinal dysfunction is AD. hypoglycemia.” and then a “thing” as the disease worsens. while the cerebellum is involved in the association of a visual cue with a motor action. Furthermore. declarative memory processes can hinder nondeclarative learning. tumors can injure the septum. and highly vivid “flashbulb” memories are often laid down during traumatic or emotional events. our semantic hierarchy reminds us that its main function is to facilitate eating. Semantic Memory Unlike episodic memory. or what she had for breakfast. patients with primarily anterior and lateral temporal lobe damage show intact episodic memory but impaired semantic memory. Patients with semantic dementia classify objects into increasingly superordinate categories. bone in the middle cranial fossa. particularly the CA1 and subicular region. including hypoxia. associated with viral or paraneoplastic processes. and increasing alacrity in solving Sudoku puzzles with practice requires cognitive skills. and herpes simplex encephalitis. which refers to a long-lasting enhancement of synaptic transmission resulting from repetitive stimulation of excitatory synapses.” Procedural learning describes the formation of skills and habits. long-lasting and reliable: even after years of absence from a bicycle. tools.

Hippocampus 15:535. with benefits thought to arise from increased levels of available acetylcholine. However. While some information is retained for only a few seconds—enough time to hear. The brains of AD patients show severe neuronal loss in the nucleus basalis of Meynert. In the most widely accepted conceptualization of working memory. GABA agonists including the benzodiazepines are associated with reversible but sometimes severe episodes of amnesia. while normal adults can generally repeat five digits backward. another major division of memory has used time as the distinguishing characteristic. Normal individuals can hold about seven (plus or minus two) “bits” of information in working memory. or behavioral neurologist. There are two ways of administering the test. Testing semantic and procedural memory is usually outside the realm of the generalist. (2) a visual system called the visuospatial scratchpad. The capacity for digit span forward is typically six numbers. but the most commonly used test is the Mini Mental Status Examination (Table 365-5). Nature 414:546. there are four main components: (1) a central executive that keeps track of and gathers information. (3) a phonologic “system” that holds verbal information. HODGES JR: Spectrum of memory dysfunction in degenerative disease. Nat Rev Neurosci 4:829. called digit span backward. 2004 Copyright © 2008 The McGraw-Hill Companies. Curr Opin Neurol 9:281. the major source of cholinergic input to the cerebral cortex. Choline acetyltransferase (the enzyme catalyzing the formation of acetylcholine) is known to be deficient in the cortex of patients with AD. ZOLA-MORGAN S: The medial temporal lobe memory system. Working memory (see below) is strongly modulated by dopamine. MOSCOVITCH M: Memory consolidation.e. These deficits in working memory have a profound effect on the organism by disrupting the learning process downstream to working memory. KNOWLTON BJ: Learning and memory functions of the basal ganglia. 1997 PACKARD MG. CHAPTER e6 Memory Loss SHORT-TERM MEMORY WORKING MEMORY While the fractionation of memory into declarative and nondeclarative systems has provided a reasonable framework for understanding many aspects of memory’s neurologic underpinnings. If the deficits are subtle. Also.. TESTING MEMORY AT THE BEDSIDE Testing of memory should be performed in anyone in whom memory deficits are a concern. Annu Rev Neurosci 27:279. . or health care workers. patients have intact working memory but cannot transfer information from working memory into long-term store. these bits can be manipulated and either discarded or associated and transferred into long-term memory. FURTHER READINGS BADDELEY A: Working memory: Looking back and looking forward. The most common bedside test of working memory involves asking patients to repeat a series of digits orally. the clinician may also ask the patient to repeat the digits in reverse order. 2001 SQUIRE LR. 2007 GILBOA A et al: Retrieval of autobiographical memory in Alzheimer’s disease: Relation to volumes of medial temporal lobe and other structures. The cholinergic system also plays an important role in memory. Working memory stores items only as long as the information is in consciousness and is either being rehearsed (subvocally) or manipulated in some other fashion (i. and anticholinergic agents such as atropine and scopolamine interfere with memory. while longer-term memory requires new protein synthesis and leads to physical changes at neuronal synapses. particularly Brodmann area 46. Digit span forward is a test of attention. Science 253:1380. Behavior and mood are modulated by noradrenergic. 1996 POLDRACK RA et al: Interactive memory systems in the human brain. but if deficits in these systems are suspected. In the classic amnesic syndrome. The capacity of working memory is limited by attention. Ann Rev Neurosci 30:123. Working memory is highly vulnerable to distraction and sometimes is even called working attention to emphasize the conscious and effortful processes that it entails. memory testing can be an extremely valuable component of the neurologic examination and performed effectively at the bedside. neuropsychiatrist. which holds visual representations of objects. Of all the memory processes. the testing may require a comprehensive consultation with a neuropsychologist. Annu Rev Neursci 25:563. 2002 PERRY RJ. further tests are warranted. while digit span backward is a simple probe of working memory. working memory is perhaps the easiest to assess at the bedside. 1991 ——— et al: The medial temporal lobe. 2005 NADEL L. In contrast. and norepinephrine has been shown to be reduced in the brainstem locus coeruleus in AD. whether these concerns are raised by the patient. or by affecting activities that directly depend on an intact working memory. Asking the patient to repeat the digits in the same order as they were delivered is called digit span forward. Similarly. There are a wide variety of brief standardized screens of cognition. retrograde amnesia and the hippocampal complex. functional imaging studies from humans show that the dorsolateral frontal lobes. Lesions that disrupt the structure or function of the dorsolateral frontal or posterior parietal regions decimate working memory. These findings form the basis for the use of cholinesterase inhibitors in the treatment of AD. a 30-point test that is strongly dependent on working (spell “world” backwards) and episodic memory (orientation and three-word recall). This brief type of memory differs from long-term memory. rotated or integrated with existing information in semantic memory). are critical for working memory. and (4) an episodic buffer that is capable of binding together information from different modalities into a coherent trace. serotonergic. Curr Opin Neurobiol 7:217. All rights reserved. with the clinician gradually increasing the number of to-be-retained digits. neurotrophins are postulated to play a role in memory in part by preserving cholinergic neurons. and dopaminergic pathways.shown that the formation of new episodic memories leads to physiologic changes in the synapse. These neurons appear to provide an important functional basis for working memory. Single-cell recordings have uncovered a network of neurons in the e35 posterior parietal and dorsolateral frontal lobes where activity is high only during periods when information is being held in memory for use over just a few seconds. not only in terms of duration of retention but also with regard to its function and neuroanatomy. 2003 EICHENBAUM H et al: The medial temporal lobe and recognition memory. remember and dial a phone number—other memories are seemingly remembered throughout a life span. family.

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periodontal tissues. Copyright © 2008 The McGraw-Hill Companies. FIGURE e7-4 Stevens-Johnson syndrome—reaction to nevirapine. and oral mucosa are all represented. FIGURE e7-5 Inflamed palate. diabetes.e7 Atlas of Oral Manifestations of Disease e37 Samuel C. Durso. All rights reserved. Conditions affecting the teeth. there is significant clinical value in examining the oral cavity for signs of disease. Jane C. Thus. and other systemic illnesses. . This chapter presents numerous outstanding clinical photographs illustrating many of the conditions discussed in Chap. Yellowitz. Janet A. Atkinson The health status of the oral cavity is linked to cardiovascular disease. 32. Oral Manifestations of Disease. FIGURE e7-1 Gingival overgrowth secondary to calcium channel blocker use. FIGURE e7-2 Oral lichen planus. CHAPTER e7 Atlas of Oral Manifestations of Disease FIGURE e7-3 Erosive lichen planus.

FIGURE e7-8 Sublingual leukoplakia. FIGURE e7-7 Angular cheilitis. Copyright © 2008 The McGraw-Hill Companies. All rights reserved. .e38 PART 2 Cardinal Manifestations and Presentation of Diseases FIGURE e7-6 Severe periodontitis.

FIGURE e7-11 Sublingual keratosis.e39 CHAPTER e7 Atlas of Oral Manifestations of Disease FIGURE e7-9 A. Epulis (gingival hypertrophy) under denture. FIGURE e7-13 Healthy mouth. B. Copyright © 2008 The McGraw-Hill Companies. Epulis fissuratum. FIGURE e7-12 Oral carcinoma. . FIGURE e7-10 Traumatic lesion inside of cheek. All rights reserved.

FIGURE e7-19 Heavy plaque and gingival inflammation.e40 PART 2 FIGURE e7-14 Geographic tongue. FIGURE e7-15 Moderate gingivitis. . All rights reserved. FIGURE e7-16 Gingival recession. Cardinal Manifestations and Presentation of Diseases FIGURE e7-18 Severe gingival inflammation and heavy calculus. FIGURE e7-17 Heavy calculus and gingival inflammation. Copyright © 2008 The McGraw-Hill Companies.

FIGURE e7-21 Osteonecrosis. B. Calculus. missing tooth. Teeth cleaned. All rights reserved. FIGURE e7-23 Salivary stone. very mobile teeth. .e41 CHAPTER e7 FIGURE e7-20 Ulcer on lateral border of tongue—potential carcinoma. Atlas of Oral Manifestations of Disease FIGURE e7-24 A. FIGURE e7-22 Severe periodontal disease. Copyright © 2008 The McGraw-Hill Companies. FIGURE e7-25 Traumatic ulcer.

All rights reserved.e42 PART 2 Cardinal Manifestations and Presentation of Diseases FIGURE e7-26 Fissured tongue. Copyright © 2008 The McGraw-Hill Companies. FIGURE e7-27 White coated tongue—likely candidiasis. .

Following completion of these initial steps. O’Gara. Intensity The intensity of a heart murmur is graded on a scale of 1–6 (or I–VI). Ltd. in which case the heart sounds can be distinguished by simultaneous palpation of the carotid arterial pulse. Accurate bedside identification of a heart murmur can also inform decisions regarding referral to a cardiovascular specialist. Presystolic murmur of mitral or tricuspid stenosis. such as a systolic click or diastolic snap. (Adapted from P Wood. Systolic murmur in pulmonic stenosis spilling through the aortic second sound. Holosystolic (pansystolic) murmur of mitral or tricuspid regurgitation or of ventricular septal defect. . London. Low velocity events. pulmonic valve closure being delayed. A grade 1 murmur is very soft and is heard with great effort. or plateau. Diastolic murmurs begin with or after the associated component of S2 and end at or before the subsequent S1. or the great vessels. e8-2). Careful attention to the characteristics of the murmur and other heart sounds during the Copyright © 2008 The McGraw-Hill Companies. The distinction between S1 and S2. Aortic or pulmonary diastolic murmur. Location and Radiation Recognition of the location and radiation of the murmur helps facilitate its accurate identification (Fig. Short mid-diastolic inflow murmur following a third heart sound. such as the “honking” sound appreciated in some patients with mitral regurgitation (MR) due to mitral valve prolapse (MVP). Small ventricular septal defects (VSDs). the degree of turbulence. The coarse systolic murmur of aortic stenosis (AS) may sound higher-pitched and more acoustically pure at the apex. clinical context. Diseases of the Heart and Circulation. A grade 4 murmur is very loud and accompanied by a thrill. usually grade 4 or greater. and a large pericardial effusion. noninvasive testing can be pursued to clarify any remaining ambiguity and to provide additional anatomic and physiologic information that will impact patient management.. All rights reserved. C. H. The diastolic murmur of chronic aortic regurgitation (AR) is a blowing. A grade 5 murmur is loud enough to be heard with only the edge of the stethoscope touching the chest. a phenomenon eponymously referred to as the Gallavardin effect. B. heard as a rumbling sound with the bell of the stethoscope. Duration The duration of a heart murmur depends on the length of time in the cardiac cycle over which a pressure difference exists between two cardiac chambers. or patent ductus arteriosus. but can be difficult in the setting of a tachyarrhythmia. and the need to restrict various forms of physical activity. the right ventricle and the pulmonary artery. The intensity of a heart murmur may also be diminished by any process that increases the distance between the intracardiac source and the stethoscope on the chest wall. and therefore systole and diastole. obstructive lung disease. crescendo-decrescendo. are accompanied by loud. respectively). such as left-to-right shunting across an atrial septal defect (ASD). S1 A S2 e43 B C A2 P2 CHAPTER e8 D E OS F Approach to the Patient with a Heart Murmur S3 G H FIGURE e8-1 Diagram depicting principal heart murmurs. such as obesity. A grade 3 murmur is loud. whereas the plateau configuration of the murmur of chronic rheumatic MR (Fig. The accurate timing of heart murmurs is the first step in their identification. but is not accompanied by a palpable thrill over the site of maximal intensity. high-frequency event. Systolic murmurs begin with or after the first heart sound (S1) and terminate at or before the component (A2 or P2) of the second heart sound (S2) that corresponds to their side of origin (left or right. They are traditionally defined in terms of their timing within the cardiac cycle (Fig. Aortic ejection murmur beginning with an ejection click and fading before the second heart sound. indicative of the left atrial–left ventricular diastolic pressure gradient. The frequency components of a heart murmur may vary at different sites of auscultation. is usually a straightforward process. The crescendo-decrescendo configuration of the murmur of AS reflects the changes in the systolic pressure gradient between the left ventricle and the aorta as ejection occurs. e8-1). The configuration of a heart murmur may be crescendo. The intensity of a murmur may also be misleadingly soft when cardiac output is significantly reduced. and the resulting frequency. Murmurs of grade 3 or greater intensity usually signify important structural heart disease and indicate high blood flow velocity at the site of murmur production. systolic murmurs as blood is ejected at high velocity from the left to the right ventricle. D. and associated findings provide additional clues by which the significance of a heart murmur is established. but rather begin in early systole and proceed through S2 into all or part of diastole. Eyre & Spottiswood. whereas the murmur of mitral stenosis (MS). Adventitious sounds. whereas a grade 6 murmur is loud enough to be heard with the stethoscope slightly off the chest. Eugene Braunwald The differential diagnosis of a heart murmur begins with a careful assessment of its major attributes and response to bedside maneuvers. The magnitude and variability of this pressure difference dictate the velocity of flow. F. Heart murmurs are caused by audible vibrations that are due to increased turbulence from accelerated blood flow through normal or abnormal orifices. E. decrescendo. G. the indications for antibiotic or rheumatic fever prophylaxis. Continuous murmurs are not confined to either phase of the cardiac cycle. is a low-frequency event. Long diastolic murmur of mitral stenosis following the opening snap.1968.e8 Approach to the Patient with a Heart Murmur Patrick T. Continuous murmur of patent ductus arteriosus. or backward flow through an incompetent valve. Some murmurs may have a distinct or unusual quality. The history. the left ventricle and the aorta. and intensity of the murmur. flow through a narrowed or irregular orifice into a dilated vessel or chamber. A. e8-1B) is consistent with the large and nearly constant pressure difference between the left ventricle and the left atrium. configuration. may provide additional clues.) A grade 2 murmur is easily heard. ventricular septal defect. e8-1E) can be understood in terms of the progressive decline in the diastolic pressure gradient between the aorta and the left ventricle. but not particularly loud. for example. The upstroke should closely follow S1. are usually silent. or abnormalities of S1 or S2. The decrescendo configuration of the murmur of chronic AR (Fig.

PJ Norton. and continuous heart murmurs (Table e8-1). relatively noncompliant left atrium results in an early. 2005. These characteristics reflect the progressive attenuation of the pressure gradient between the left ventricle and the left atrium during systole due to the rapid rise in left atrial pressure caused by the sudden volume load into an unprepared chamber. pulmonic stenosis Mid-Diastolic Murmurs Mitral Mitral stenosis Carey-Coombs murmur (mid-diastolic apical murmur in acute rheumatic fever) Increased flow across nonstenotic mitral valve (e. Post-MI mechanical complications of this nature mandate aggressive medical stabilization and prompt referral for surgical repair. atheroma. rheumatic fever. are discussed below in the context of specific systolic. arteriovenous. Elsevier. hypotension. aortitis Pulmonary Obstructive Supravalvular—pulmonary artery stenosis Valvular–pulmonic valve stenosis Subvalvular–infundibular stenosis (dynamic) Increased flow. 2003. TVP. acute myocardial ischemia Tricuspid TVP Holosystolic Atrioventricular valve regurgitation (MR. hypertrophic obstructive cardiomyopathy. or both. It can result in papillary muscle contusion and rupture. Copyright © 2008 The McGraw-Hill Companies. AR. annulo-aortic ectasia. 118). p 140. posterior. FA Davis. in E Braunwald. MVP. MVP may occur as an isolated phenomenon or the lesion may be part of a more generalized connective tissue disorder as seen. prolapse. Spontaneous chordal rupture can complicate the course of myxomatous mitral valve disease (MVP) and result in new-onset or “acute on chronic” severe MR. (From JB Barlow. aortic stenosis. JK Perloff. for example. These features. which allows bedside delineation of its etiology and pathophysiologic significance. TR. trauma. TR) Left-to-right shunt at ventricular level (VSD) Early Diastolic Murmurs Aortic regurgitation Valvular: congenital (bicuspid valve). rheumatic deformity. RA O’Rourke. It is often signaled by chest pain. PDA. pulmonary stenosis. Their causes are relatively few in number. post-valvulotomy Dilatation of valve ring: aorta dissection. VSD. and contrast sharply with the auscultatory features of chronic MR. ASD) Dilatation of pulmonary artery Late systolic Mitral MVP. ending well before S2. AS. MR. tricuspid regurgitation. mitral stenosis. mitral valve prolapse. chordal detachment. Philadelphia. in D Zipes et al (eds): Braunwald’s Heart Disease. ventricular septal defect. hypertrophic obstructive cardiomyopathy. in patients with Marfan syndrome. and (4) blunt chest wall trauma. tricuspid valve prolapse.. endocarditis. complete heart block Dilatation of ascending aorta. aortic regurgitation. sequential determination of oxygen saturations. Blunt chest wall trauma is usually self-evident. AV. left-to-right shunt (e. The distinction between acute MR and ventricular septal rupture can also be achieved with right heart catheterization. Acute severe MR as a consequence of infective endocarditis results from destruction of leaflet tissue. but a murmur may be absent in up to 50% of cases. (3) infective endocarditis (Chap. PDA. chordal rupture. Chap. mitral regurgitation. . atrial septal defect. Elsevier. HOCM. Aortic. VSD. highoutput states. or lateral MI and occurs 2–7 days after presentation. and pulmonary edema. MR. Acute severe MR into a normal-sized. and recommendations for further testing. The murmur is to be distinguished from that associated with post-MI ventricular septal rupture. Perspectives on the Mitral Valve. SYSTOLIC HEART MURMURS Early Systolic Murmurs Early systolic murmurs begin with S1 and extend for a variable period of time. severe MR occur include: (1) papillary muscle rupture complicating acute myocardial infarction (MI) (Chap.. mitral regurgitation. hyperkinetic states. Philadelphia. and complete heart block) Tricuspid Tricuspid stenosis Increased flow across nonstenotic tricuspid valve (e. (2) rupture of chordae tendineae in the setting of myxomatous mitral valve disease (MVP. 239). ankylosing spondylitis Widening of commissures: syphilis Pulmonic regurgitation Valvular: post-valvulotomy. ASD. MS. 7th ed. decrescendo systolic murmur best heard at or just medial to the apical impulse. Note: AR. diastolic. Clinical settings in which acute. Acute. VSD. severe MR from papillary muscle rupture usually accompanies an inferior. 2d ed. Source: E Braunwald.g. but may be disarmingly trivial. hyperkinetic states. 1987. ASD. 222). The posteromedial papillary muscle is involved six to ten times more frequently than the anterolateral papillary muscle. MR. Pulm. patent ductus arteriosus. which is accompanied by a systolic thrill at the left sternal border in nearly all patients and is holosystolic in duration.. TR. Philadelphia. 230). cystic medial degeneration. hypertension. coarctation of the aorta Valvular—AS and aortic sclerosis Subvalvular—discrete. ventricular septal defect.) respiratory cycle and the performance of simple bedside maneuvers when indicated complete the auscultatory examination. A new heart murmur following MI is an indication for transthoracic echocardiography (TTE) (Chap.g. carcinoid Dilatation of valve ring: pulmonary hypertension. endocarditis.e44 TABLE e8-1 PRINCIPAL CAUSES OF HEART MURMURS Systolic Murmurs Early systolic Mitral Acute MR VSD Muscular Nonrestrictive with pulmonary hypertension Tricuspid TR with normal pulmonary artery pressure Mid-systolic Aortic Obstructive Supravalvular—supravalvular aortic stenosis. L Goldman (eds): Primary Cardiology. Marfan syndrome Congenital: isolated or associated with tetralogy of Fallot. aortic stenosis. All rights reserved. and analysis of the pressure waveforms (tall v wave in the pulmonary artery wedge pressure in MR). VSD. tunnel or HOCM Increased flow. HOCM.g. and anomalous pulmonary venous return) Left and right atrial tumors (myxoma) Severe AR (Austin Flint murmur) Continuous Murmurs Patent ductus arteriosus Coronary AV fistula Ruptured sinus of Valsalva aneurysm Aortic septal defect Cervical venous hum Anomalous left coronary artery Proximal coronary artery stenosis Mammary souffle of pregnancy Pulmonary artery branch stenosis Bronchial collateral circulation Small (restrictive) ASD with MS Intercostal AV fistula Aortic Pulm VSD MR Vibratory HCM PART 2 Cardinal Manifestations and Presentation of Diseases FIGURE e8-2 Maximal intensity and radiation of six isolated systolic murmurs.

is heard in younger patients. Part IV. in older patients with stiffened arteries. Rarely. TTE is indicated in all cases of suspected acute severe MR to define its mechanism and severity. An early ejection sound. TTE is recommended for complete characterization. The murmur is softer in the setting of heart failure and low cardiac output. an early ejection sound (click) is usually audible. In rare patients. JJ Leonard. e8-3). as may occur with infective endocarditis. The murmur associated with the left-to-right shunt. noncalcified bicuspid valve (or one of its variants) and localizes the left ventricular outflow obstruction to the valvular (rather than sub. 229) leads to an increase in pulmonary blood flow and a grade 2–3 mid-systolic murmur at the mid to upper left sternal border with fixed Copyright © 2008 The McGraw-Hill Companies.or leaflet avulsion. crescendo-decrescendo murmur of congenital pulmonic stenosis (PS. such as a reduction in preload or afterload (Valsalva. left ventricular size. 220-2D) due to mid-systolic closure of the aortic valve. becomes limited to the first portion of systole as the elevated pulmonary vascular resistance leads to an abrupt rise in right ventricular pressure and an attenuation of the interventricular pressure gradient during the remainder of the cardiac cycle. small muscular VSD (Chap. The murmur is produced by both dynamic left ventricular outflow tract obstruction and MR. With prompt squatting. A small and delayed upstroke (parvus et tardus) is consistent with severe AS. signs of pulmonary hypertension (right ventricular lift. The Supine S1 C e45 S2 Standing CHAPTER e8 S1 C S2 Squatting Approach to the Patient with a Heart Murmur S1 C S2 FIGURE e8-3 A mid-systolic nonejection sound (C) occurs in mitral valve prolapse and is followed by a late systolic murmur that crescendos to the second heart sound (S2). The murmur is soft (grade 1 or 2). the heart becomes larger. an apical S4. 231. Mid-Systolic Murmurs Mid-systolic murmurs begin at a short interval following S1. paradoxical splitting of S2. and a late-peaking systolic murmur. Fig. loud and single or closely split S2) may predominate. these two lesions can be distinguished on the basis of their associated findings. such as the presence of LVH in HOCM or a non-ejection click in MVP. and provide an assessment of suitability for primary valve repair. American Heart Association. A sustained left ventricular apical impulse and an S4 may be appreciated. vasodilators) or to an augmentation of contractility (inotropic stimulation). 229) may be associated with an early systolic murmur. Maneuvers that increase preload (squatting. the intensity of which decreases with inspiration. and young adults with congenital valvular AS. e8-2 and e8-4). The murmur of AS is usually loudest to the right of the sternum in the second intercostal space (aortic area. If obtained. Assessment of the volume and rate of rise of the carotid pulse can provide additional information. In such instances. a systolic thrill and grade 4 or higher murmur suggest severe AS. best heard at the lower left sternal border. in the beat following a premature beat. C moves toward S2. is common (Gallavardin effect. Anatomically large and uncorrected VSDs. but usually does not exceed grade 3. Chap. Although the systolic murmur associated with MVP behaves similarly to that due to HOCM in response to the Valsalva maneuver and to standing/squatting (Fig. Other auscultatory findings of severe AS include a soft or absent A2. whereas the murmur of MR will remain of constant intensity from beat to beat. may lead to pulmonary hypertension. e8-2) and radiates into the carotids. which usually involve the membranous portion of the septum. The defect closes progressively during septal contraction and thus the murmur is confined to early systole. Fig. vasopressors) or that reduce contractility (β-adrenoreceptor blockers) decrease the intensity of the murmur. Examination of the Heart. In contrast to AS. The carotid pulse examination is less discriminatory. venous return increases. may produce an early systolic murmur. e8-2) and is usually of grade 4 or 5 intensity. passive leg raising. All rights reserved. The mid-systolic. It is localized to the left sternal border (Fig.or supravalvular) level. Copyright. A parasternal lift and ECG evidence of right ventricular hypertrophy indicate severe pressure overload. The intensity of the AS murmur also varies directly with the cardiac output. standing. The duration of the murmur lengthens and the intensity of P2 diminishes with increasing degrees of valvular stenosis (Fig. e8-1C). and following provocative maneuvers. is best appreciated in the second and third left intercostal spaces (pulmonic area) (Figs. 1990. With a normal cardiac output. C moves closer to the first heart sound (S1) and the mitral regurgitant murmur has an earlier onset. Differentiation of this apical systolic murmur from MR can be difficult. Auscultation of the Heart. A congenital. wall thickness and function. the chest x-ray may show poststenotic dilatation of the main pulmonary artery. American Heart Association. Suspicion of a VSD is an indication for TTE. and thus its configuration is a hybrid between ejection and regurgitant phenomena. and the duration of the murmur shortens. and the size and contour of the aortic root and proximal ascending aorta. Standing decreases venous return. and may increase in intensity with inspiration (Carvallo’s sign). see above). which may earlier have been holosystolic. TR in this setting is not associated with signs of right heart failure. it is bisferiens or bifid in contour (see Fig. the heart becomes smaller. e8-1D). or become louder. e8-2). (From JA Shaver. In children. The intensity of the murmur may vary from beat to beat. volume administration) or afterload (squatting. TTE is indicated to assess the anatomic features of the aortic valve. where it becomes higher pitched. Regurgitant “c-v” waves may be visible in the jugular venous pulse. DF Leon. however. p 13. Aortic stenosis is the most common cause of a mid-systolic murmur in an adult. adolescents. . Transmission of the mid-systolic murmur to the apex.) murmur will classically increase in intensity with maneuvers that result in increasing degrees of outflow tract obstruction. LVH is present on the ECG and the diagnosis is confirmed by TTE. and are usually crescendo-decrescendo in configuration. The murmur is best heard along the left sternal border but is softer. Dallas. more often along the left sternal border than at the base. the carotid upstroke is rapid and of normal volume. The obstructive form of hypertrophic cardiomyopathy (HOCM) is associated with a mid-systolic murmur that is usually loudest along the left sternal border or between the left lower sternal border and the apex (Chap. there may be reversed splitting of S2. 229). Significant left-to-right intracardiac shunting due to an ASD (Chap. end before S2 (Fig. The murmur of AS will increase in intensity. Signs of pulmonary hypertension or left ventricular volume overload are absent. The electrocardiogram (ECG) shows signs of left ventricular hypertrophy (LVH) as the severity of the stenosis increases. Tricuspid regurgitation (TR) with normal pulmonary artery pressures. delineate left ventricular size and systolic function. Its presence signifies a flexible. the severity of the stenosis.

It is usually high pitched and plateau in configuration because of the wide difference between left ventricular and left atrial pressure throughout systole. isometric contraction shortens until the pulmonary valvular ejection sound fuses with the first heart sound (S1). ascites.Ej S1 A2 S2 P2 S1 A2 S2 PART 2 S4 A2 P2 A. an enlarged and pulsatile liver. It is due to apical tethering and malcoaptation of the leaflets in response to structural and functional changes of the ventricle and mitral annulus. vibratory mid-systolic murmur at the lower left sternal border in normal children and adolescents (Fig. The severity of the MR is worsened by any contribution from apical displacement of the papillary muscles and leaflet tethering. and splitting becomes wider but more difficult to hear because A2 is lost in the murmur and P2 becomes progressively fainter and lower pitched. P2 is absent in severe tetralogy of Fallot. American Heart Association. and fainter. left ventricular preload and afterload are increased abruptly. As the pulmonic gradient increases. Often. A grade 2 or 3 mid-systolic murmur may also be heard best at the upper left sternal border in patients with idiopathic dilatation of the pulmonary artery. left atrial compliance is normal or even increased in chronic MR. mitral annular calcification. though the ECG may show abnormalities of sinus node function. The carotid upstrokes are normal and electrocardiographic LVH is not present. Auscultation of the Heart. Late Systolic Murmurs A late systolic murmur that is best heard at the left ventricular apex is often due to MVP (Chap. In contrast to acute MR. these responses to standing and squatting are similar to those observed in patients with HOCM. with increasing obstruction the murmur becomes shorter. All rights reserved. American Heart Association. gradual enlargement of the left atrium from chronic MR will result in further stretching of the annulus and more MR and thus. and peripheral edema. A large aortic root receives almost all cardiac output from both ventricular chambers. A grade 1 or 2 mid-systolic murmur can often be heard at the left sternal border with pregnancy. is most often a benign finding for which no further evaluation. Therefore. an increasing amount of right ventricular blood is shunted across the silent ventricular septal defect and flow across the obstructed outflow tract decreases. as leaflet prolapse is delayed. Leaflet flail is associated with a murmur of grade 3 or 4 intensity that can be heard throughout the precordium in thin-chested patients. e8-3). the resultant jet of MR is directed anteriorly and medially. e8-1B and e8-5) Holosystolic murmurs begin with S1 and continue through systole to S2. Dallas. the left-to-right shunt is usually not large enough to result in a systolic murmur. (From JA Shaver.Ej S1 A2 S2 S1 S2 P2 P. Holosystolic Murmurs (Figs.e46 S1 Pulmonic stenosis S2 S1 Tetralogy of Fallot S2 associated with accelerated blood flow. The presence of an S3 or a short. rumbling mid-diastolic murmur. Features suggestive of a primum ASD include the coexistence of MR due to a cleft anterior mitral valve leaflet and left axis deviation of the QRS complex on ECG. right ventricular systolic ejection becomes progressively longer. hyperthyroidism.) splitting of S2. TTE is indicated to evaluate a grade 2 or 3 mid-systolic murmur when there are other signs of cardiac disease. Causes of primary TR include myxomatous disease P. such as standing. In tetralogy of Fallot with increasing obstruction at pulmonic infundibular area. The abnormal jugular venous wave forms are the predominant finding and are very often seen in the absence of an audible murmur. Associated signs include “c-v” waves in the jugular venous pulse. enveloping the aortic component of the second heart sound (A2). The circumference of the mitral annulus increases as the left ventricle enlarges and leads to failure of leaflet coaptation with central MR in patients with dilated cardiomyopathy (Chap. Right. The intensity of the murmur varies as a function of left ventricular afterload and will increase in the setting of hypertension. there is only a small increase in left atrial pressure for any increase in regurgitant volume. With sinus venosus ASDs. e8-2). 231). and warrant TTE for further characterization. in some patients. heard in the absence of symptoms or signs of heart disease. An isolated grade 1 or 2 midsystolic murmur. e8-2). earlier.” Chronic severe MR results in enlargement and leftward displacement of the left ventricular apex beat and. Examination of the Heart. The holosystolic murmur of chronic MR is best heard at the left ventricular apex and radiates to the axilla (Fig. Standing also causes the murmur to become louder and longer.Ej A2 Cardinal Manifestations and Presentation of Diseases P. Because the mitral annulus is contiguous with the left atrial endocardium. including rheumatic scarring of the leaflets. 230). In valvular pulmonic stenosis with intact ventricular septum. As noted above. The pulmonic component (P2) occurs later. As a result. Anterior leaflet prolapse or flail results in a posteriorly directed MR jet that radiates to the axilla or left infrascapular region. Part IV. is necessary. In severe pulmonic stenosis with concentric hypertrophy and decreasing right ventricular compliance. apical systolic murmur indicative of MR may be heard transiently in the setting of acute myocardial ischemia. With squatting. and the click and murmur move away from the first heart sound. Copyright. 1990. this murmur is introduced by one or more nonejection clicks. Aortic sclerosis is defined as focal thickening and calcification of the aortic valve to a degree that does not interfere with leaflet opening. Ostium secundum ASDs are most common. heard at the second right interspace (Fig. A pulmonary ejection sound is present. The radiation of the murmur can help identify the specific mitral leaflet involved in the process of prolapse or flail. As a result. A late. With posterior leaflet prolapse or flail. will cause the click and murmur of MVP to move closer to the first heart sound. or anemia. and severe left ventricular chamber enlargement. physiologic states that are Copyright © 2008 The McGraw-Hill Companies. The most common example of a murmur of this type in an older adult patient is the crescendo-decrescendo murmur of aortic valve sclerosis. “MR begets MR. as leaflet prolapse occurs earlier in systole. Still’s murmur refers to a benign grade 2. and the aorta dilates and is accompanied by a root ejection sound that does not vary with respiration. JJ Leonard. including TTE.Ej = Aortic ejection (root) FIGURE e8-4 Left. is loudest at the left lower sternal border.Ej = Pulmonary ejection (valvular) A. e8-2). and usually increases in intensity with inspiration (Carvallo’s sign). The term flail refers to the movement made by an unsupported portion of the leaflet after loss of its chordal attachment(s). a diastolic filling complex as described previously. a fourth heart sound appears. with increasing obstruction to flow. signifies severe MR. despite Doppler echocardiographic verification of TR. There are several conditions associated with chronic MR and an apical holosystolic murmur. They are usually indicative of chronic mitral or tricuspid valve regurgitation or a VSD. p 45. DF Leon. TTE is recommended for assessment of late systolic murmurs. The murmur becomes softer and shorter in duration (Fig. Bedside maneuvers that decrease left ventricular preload. as a result of which the murmur radiates to the base of the heart and masquerades as AS. . The holosystolic murmur of chronic TR is generally softer than that of MR. the murmur becomes longer and louder.

1991. Ebstein’s anomaly. There is no change in the intensity of the murmur with inspiration. a water-hammer carotid upstroke (Corrigan’s pulse). endocarditis. ruptured chordae) Secondary mitral regurgitation (dilated cardiomyopathy. When AR is caused by aortic root disease. in K Chatterjee et al (eds): Cardiology: An illustrated Text/Reference. rheumatic disease. chronic severe AR is accompanied by several peripheral signs of significant diastolic run-off. S1. DIASTOLIC HEART MURMURS Early Diastolic Murmurs (Fig. with permission. carcinoid. With large defects. shunt flow is balanced. Radiation of the murmur may provide a clue as to the cause of the AR. restrictive VSDs. and the correspondingly rapid decline in the aortic–left ventricular diastolic pressure gradient. papillary muscle displacement. aortic component of the second heart sound. severe AR may also produce a lower pitched mid. early to middiastolic murmur (Graham Steell murmur) that begins after the pul- Copyright © 2008 The McGraw-Hill Companies. the diastolic murmur may radiate along the right sternal border. This maneuver brings the aortic root closer to the anterior chest wall. early to mid-diastolic murmur that begins following the aortic component of S2 (A2) and is best heard at the second right interspace (Fig. Philadelphia. decrescendo. e8-7) may either remain constant or increase with afterload reduction because of the reflex increase in cardiac output and mitral valve flow. pulmonic component of the second heart (prolapse). a grade 2 or 3 crescendo-decrescendo mid-systolic murmur is frequently heard at the base of the heart in patients with isolated severe AR.to late. Small. often difficult to differentiate from mitral regurgitant murmur Approach to the Patient with a Heart Murmur Primary mitral regurgitation (e. . blowing. This lower pitched apical diastolic murmur can be distinguished from that due to MS by the absence of an opening snap and the response of the murmur to a vasodilator challenge. or late stage of primary mitral regurgitation) Secondary to pulmonary hypertension FIGURE e8-5 Differential diagnosis of a holosystolic murmur. P2. the diastolic murmur tends to radiate along the left sternal border. and is due to an increased volume and rate of systolic flow. In the absence of heart failure. Causes include Marfan syndrome with aneurysm formation. annular dilatation. It can be very difficult to appreciate in the presence of a rapid heart rate. and thus the Austin Flint murmur of severe AR will become shorter and softer. as exemplified by the maladie de Roger. The holosystolic murmur of a VSD is loudest at the mid. The intensity of the murmur varies as a function of the anatomic size of the defect. and Quincke’s pulsations of the nail beds. including a wide pulse pressure. and aortic dissection. TR is more commonly a passive process that results secondarily from chronic elevations of pulmonary artery and right ventricular pressures. Left ventricular diastolic pressure may increase sufficiently to result in premature closure of the mitral valve and a soft first heart sound. unless auscultation is performed with the patient leaning forward at end-expiration. Accurate bedside identification of coexistent AS can be difficult. and chordal detachment following the performance of right ventricular endomyocardial biopsy. and failure of leaflet coaptation. e8-1G). prolapse. The distinction between post-MI ventricular septal rupture and MR has been reviewed previously. Lowering afterload with an agent such as amyl nitrite will decrease the duration and magnitude of the aortic–left ventricular diastolic pressure gradient. The intensity of the diastolic murmur of mitral stenosis (Fig. second heart sound. The murmur may be soft and difficult to hear. which is thought to reflect turbulence at the mitral inflow area from the admixture of regurgitant (aortic) and forward (mitral) blood flow (Fig. A2. Diseases of the aortic root cause dilatation or distortion of the aortic annulus and failure of leaflet coaptation. or endocarditis. the ventricular pressures tend to equalize. grade 1 or 2 diastolic murmur at the apex (Austin Flint murmur). e8-2) and radiates widely. sound. first heart sound. create a very loud murmur due to the significant and sustained systolic pressure gradient between the left and right ventricles. A thrill is present at the site of maximal intensity in the majority of patients. e8-6). ankylosing spondylitis. All rights reserved.to lower left sternal border (Fig.] Chronic. Although AS and AR may coexist. such as that due to congenital bicuspid disease. and a murmur is not appreciated. papillary muscle dysfunction. Lippincott. annulo-aortic ectasia. Pulmonic regurgitation (PR) results in a decrescendo. palpable thrill Decreased intensity with amyl nitrate No change in intensity during inspiration Wide splitting of S2 CHAPTER e8 Hyperdynamic left ventricular impulse Wide splitting of S2 Sustained left ventricular impulse Single S2 or narrow splitting of S2 Prominent left parasternal diastolic impulse Normal brief left parasternal systolic impulse Normal P2 Rarely paradoxical S2 Primary Sustained systolic left parasternal impulse Narrow splitting of S2 with marked increase in intensity of P2 Favors ventricular septal defect.g. [From C Chatterjee.e47 Onset with S1 terminates at or beyond S2 Maximum intensity over apex Radiation to axilla or base A 2 not heard over apex Decreased intensity with amyl nitrate Maximum intensity over left sternal border Radiation to epigastrium and right sternal border Increased intensity during inspiration Prominent cv wave with sharp y descent in jugular venous pulse Mitral regurgitation Tricuspid regurgitation Maximum intensity over lower left third and fourth interspace Widespread radiation. The diastolic murmur of acute severe AR (Fig. rheumatic. leading to right ventricular enlargement. S2. With primary valve disease.. These attributes reflect the abrupt rate of rise of diastolic pressure within the unprepared and noncompliant left ventricle. unless the carotid pulse examination is abnormal or the mid-systolic murmur is of grade 4 or greater intensity. e8-1E) Chronic AR results in a highpitched. Peripheral signs of significant diastolic run-off are absent. e8-6) is notably shorter in duration and lower pitched than the murmur of chronic AR.

and radiates along the left sternal border. The rumble may occur during either or both periods. It is usually of grade 1 or 2 intensity. Chronic Acute The duration of the murmur reflects the length of time over which left atrial pressure exceeds left ventricular SEM SEM pressure. e8-1G and e8-1H) Mid-diastolic murmurs result from obstruction and/or augmented flow at the level of the mitral or tricuspid valve. Examination of the Heart. PR in of increased tricuspid valve flow can occur with severe. S3 S3 The mid-diastolic murmur associated with tricuspid Apex stenosis is best heard at the lower left sternal border and increases in intensity with inspiration. Significant tachycardia is usually present. but may be absent when the cardiac output is severely reduced despite significant obstruction. the interval between A2 and the opening snap shortens. chronic AR has already been described. At the apex.to-late diastolic murmurs if atrial contraction occurs when These features also help distinguish PR from AR as the cause of a de. FIGURE e8-6 Contrast between the auscultatory findings in chronic and acute This murmur is very difficult to hear and often obscured aortic regurgitation. The murmur associFlint murmur (AF) is introduced by a prominent third heart sound (S3). electrocardiogram. An opening murmur may increase with inspiration. low-pitched 3 ventricle and aortic end-diastolic pressure. e8-1A. In mild mitral stenosis. Part IV. It is loudest at the left ventricular apex and often only appreciated when the patient is turned in the left lateral decubitus position. and the rumble persists throughout diastole. the diastolic gradient across the valve is limited to the two phases of rapid ventricular filling in early diastole and pre-systole.) of severe. Signs of pulmonary hypertension. secondary pulmonary hypertension develops and results in a loud P2 and the splitting interval usually narrows. S1 is loud and the murmur begins after an opening snap. e8-7). Pre-systolic accentuation does not occur in patients with atrial fibrillation.S. tent mid. The murmur of MS is low pitched and thus is best heard with the bell of the stethoscope. Copyright. e8-7). Augmented mitral diastolic flow can occur with markedly decreased in intensity because of premature closure of the mitral valve. the diastolic murmur is softer and Mitral Stenosis lower pitched than the classic Graham Steell murmur. TTE can also provide anatomic information regarding ECG the root and proximal ascending aorta. O. Aortic Regurgitation PART 2 Cardinal Manifestations and Presentation of Diseases Mid-Diastolic Murmurs (Figs. It is usually present following repair of tetralogy of Fallot in childhood. a large pressure gradient exists across the valve during the entire diastolic filling period. Longitudinal assessMild ment of the severity of the valve lesion and ventricular size and A2 A2 P2 P2 systolic function help guide the decision for surgical management. (From JA Shaver. which is a high-pitched sound that occurs shortly after S2. When pulmonary hyDiastolic Filling Murmur (Rumble) pertension is not present. DF Leon. The intensity Severe A2 P2 A2 P2 FIGURE e8-7 Diastolic filling murmur (rumble) in mitral stenosis. a prominent systolic ejection by left-sided acoustical events. A pre-systolic ated with an atrial myxoma may change in duration and component of the AF is also heard. Other signs or a congenitally deformed valve. the mid-diastolic component of Austin left ventricular inflow (Chap. In chronic aortic regurgitation. and the S1 S2 S2 S1 examiner can be misled as to the severity of the PR. p 55. TTE is indicated for the further evaluation of the patient with an early to mid-diastolic murmur. In younger patients with pliable valves. Dallas. astolic murmur at the base ends well before S1 because of equilibration of the left rapid filling sound (S ) followed by a short. O. The early di. Large left atrial myxomas may prolapse across the gitant murmur begins with S2 and continues in a decrescendo fashion. PR is most commonly due to snap is not present in the acute phase and the murmur dissipates with dilatation of the valve annulus from chronic elevation of the pulmo.) Copyright © 2008 The McGraw-Hill Companies. A short mid-diastolic murmur is rarely heard during monic component of S2 (P2). As the stenotic process becomes severe. O. The intensity of the due to enhanced flow through an edematous mitral valve. In acute aortic regurgitation there is a significant intensity with changes in body position. occurs in patients in sinus rhythm and is due to a late increase in transmitral flow S1 S1 S1 S2 S2 S1 with atrial contraction.murs.S. A prolonged y deAF AF scent may be visible in the jugular venous wave form. An opening decrease in the intensity of the systolic ejection murmur compared with that of snap is not present and there is no pre-systolic accentuachronic aortic regurgitation because of the decreased forward stroke volume. American Heart Association. Rheumatic fever is the most common cause of MS (Fig. As the left atrial pressure becomes greater. 1994. single or narrowly split S2.S. 233). are present.S. .resolution of the acute attack. In severe mitral stenosis. isolated severe MR or with a large left-to-right shunt at and at the apex the presystolic component of the AF murmur is absent. The Austin Flint murmur (From JA Shaver: Heart Dis Stroke 2:100. including a nous atrial and ventricular activation may be associated with intermitright ventricular lift and a loud. a phenomenon known as pre-systolic accentuation (Figs.e48 of the murmur increases during maneuvers that increase cardiac output and mitral valve flow. Auscultation of the Heart.the mitral valve is partially closed. The aortic diastolic regur. though computed tomographic or magnetic resonance angiography may be indicatS2 S1 S1 S2 ed for more precise characterization (Chap. All rights reserved. 222). The distance between the pulmonic component of the second heart sound (P2) and the opening snap is inversely related to the magnitude of the left atrial to left ventricular pressure gradient. Mid-diastolic murmurs indicative crescendo diastolic murmur heard along the left sternal border. ECG. mid-diastolic apical murmur.an episode of acute rheumatic fever (Carey-Coombs murmur) and is space. American Heart Association. S1 is tion. is best heard at the second left inter. JJ Leonard. terminating mitral valve and cause variable degrees of obstruction to before the first heart sound (S1). Complete heart block with dyssynchronary artery pressure. 1990. murmur resulting from the large forward stroke volume is heard at the base and the There are several other causes of mid-diastolic murapex and ends well before the second heart sound (S2). O. An increase in the intensity of the murmur just Base before S1. isolated TR the absence of pulmonary hypertension can occur with endocarditis and with large ASDs and significant left-to-right shunting. such as exercise.the ventricular or great vessel level and produce a soft.

Valsalva maneuver 6. (From JA Shaver. increase in intensity during inspiration. the aortic (A2) and pulmonic (P2) components of the second heart sound are separated by <30 ms and are appreciated as a single sound. including fixed-splitting of S2 and a mid-systolic murmur at the mid. A classic example of a to-fro murmur is aortic stenosis and regurgitation. 1990. right ventricular apical pacing. Copyright. and the murmur is indicative of a continuous pressure difference between the aorta and either the right ventricle or right atrium. DYNAMIC AUSCULTATION (Tables e8-2 and 220-1) Careful attention to the behavior of heart murmurs during simple maneuvers that alter cardiac hemodynamics can provide important clues as to their cause and significance. uncorrected shunts may lead to pulmonary hypertension. (From JA Shaver. Fixed splitting of S2 in the presence of a grade 2 or 3 mid-systolic murmur at the midor upper left sternal border indicates an ASD. Fig. CONTINUOUS MURMURS (Figs. HOCM. Rupture typically occurs into a right heart chamber. e8-9). and the splitting interval narrows. During expiration. The intensity of left-sided murmurs either remains constant or decreases with inspiration. JJ Leonard. A cervical bruit with both systolic and diastolic components (a to-fro murmur.to late diastolic murmur.. It is best appreciated in the right supraclavicular fossa and can be obliterated by pressure over the right internal jugular vein or by having the patient turn his/her head toward the examiner. During inspiration. A ruptured sinus of Valsalva aneurysm creates a continuous murmur of abrupt onset at the upper right sternal border. 229). At times. or acute myocardial ischemia. Wide physiologic splitting is caused by a delay in P2. Normal physiologic splitting. Reversed splitting can be a feature of severe AS. The mid-systolic ejection component decrescendos and disappears as it approaches S2. Left-sided murmurs may be best heard at end-expiration. Post-premature beat FIGURE e8-8 Comparison of the continuous murmur and the to-fro murmur. as more forceful movement of the chest tends to obscure the heart sounds. To-Fro Murmur S1 Continuous murmur S2 S1 S2 TABLE e8-2 DYNAMIC AUSCULTATION: BEDSIDE MANEUVERS THAT CAN BE USED TO CHANGE THE INTENSITY OF CARDIAC MURMURS (SEE TEXT) e49 S1 To-fro murmur S2 S1 S2 1. The continuous mammary souffle of pregnancy is created by enhanced arterial flow through engorged breasts and usually appears during the late third trimester or early puerperium. A continuous murmur may also be audible along the left sternal border with a coronary arteriovenous fistula and at the site of an arteriovenous fistula used for hemodialysis access. Narrow physiologic splitting occurs in pulmonary hypertension. A continuous murmur crescendos to around the second heart sound (S2). which is a combination of systolic ejection murmur and a murmur of semilunar valve incompetence. resulting in paradoxical movement. Auscultation of the Heart. whereas a to-fro murmur has two components. DF Leon. the splitting interval widens. peak near the second heart sound. with inspiration P2 moves towards A2. Bedside assessment should also account for the behavior of S2 with respiration and the dynamic relationship between the aortic and pulmonic components (Fig. attenuation or obliteration of the diastolic component of the murmur. CHAPTER e8 Approach to the Patient with a Heart Murmur Respiration Auscultation should be performed during quiet respiration or with a modest increase in inspiratory effort. Examination of the Heart. Respiration 2. The murmur is louder in systole. Not all continuous murmurs are pathologic. such as tricuspid or pulmonic regurgitation. American Heart Association. producing a continuous murmur. All rights reserved. i.) of an ASD are present (Chap. Isometric exercise (handgrip) 3.e. 1990. American Heart Association. Transient arterial occlusion 4. Part IV. and continue into all or part of diastole. American Heart Association. Murmurs of right-sided origin. American Heart Association. e8-8) usually indicates a high-grade carotid artery stenosis. The continuous murmur associated with a patent ductus arteriosus is best heard at the upper left sternal border. A classic example is patent ductus arteriosus. Copyright. This phenomenon is characteristic of the murmur of AR. Their presence throughout the cardiac cycle implies a pressure gradient between two chambers or vessels during both systole and diastole. Rapid standing/squatting 7.to upper left sternal border. Audible expiratory splitting. and both A2 and P2 are heard during expiration at a narrow splitting interval because of the increased intensity and high-frequency composition of P2. DF Leon. Auscultation of the Heart. Examination of the Heart. left bundle branch block. During abnormal communication between high-pressure and low-pressure systems. when lung volumes are minimized and the heart and great vessels are brought closer to the chest wall. a large pressure gradient exists throughout the cardiac cycle. Dallas. TTE is indicated for evaluation of the patient with a mid.Continuous Murmur vs. and A2 and P2 are clearly separated into two distinct sounds. e8-1H and e8-8) Continuous murmurs begin in systole. Large. Bottom. Part IV. Pharmacologic manipulation of preload and/or afterload 5. Reversed splitting is caused by a delay in A2.) Copyright © 2008 The McGraw-Hill Companies. p 17. and differential cyanosis of the lower extremities. A continuous venous hum can be heard in healthy children and young adults. Physiologic but wide splitting during the respiratory cycle implies either premature aortic Normal Physiological Splitting A2 P2 S1 S2 S1 S2 Audible Expiratory Splitting Expiration Wide physiological splitting S1 A2 P 2 Inspiration A2 P 2 S2 P2 A2 S1 S2 P2 A2 Reversed splitting S1 S2 A2 P2 Narrow physiological splitting (↑P2) S1 S2 S1 S2 S1 S2 FIGURE e8-9 Top. JJ Leonard. p 55. especially during pregnancy. Enhanced flow through enlarged intercostal collateral arteries in patients with aortic coarctation may produce a continuous murmur along the course of one or more ribs. reversal of shunt flow. Dallas. Firm pressure with the diaphragm of the stethoscope can eliminate the diastolic portion of the murmur. Findings specific to the diseases discussed above will help guide management. this type of murmur can be confused with a tofro murmur. .

Echocardiography should also be considered when there is a clinical need to verify normal cardiac structure and function in a patient whose symptoms and signs are likely noncardiac in origin. TEE. and asymptomatic young adult is most likely a benign finding for which no further evaluation is indicated. intracardiac shunt flow. whereas the latter two become softer after exposure to amyl nitrite. and/or a chest x-ray may have been obAsymptomatic and no associated findings Symptomatic or other signs of cardiac disease* Cardiac murmur Diastolic murmur Continuous murmur TTE TEE. in response to the abrupt lowering of systemic vascular resistance with amyl nitrite. grade • Early systolic louder murmur. cardiac MR. Chaps. The context in which the murmur is appreciated often dictates the need for further testing. petechiae. Routine echocardiography is not recommended for asymptomatic patients with a grade 1 or 2 mid-systolic murmur without other signs of heart disease. ECHOCARDIOGRAPHY (See Fig. should also undergo echocardiography. The click and murmur of MVP move away from S1 with squatting. The majority of murmurs decrease in intensity during the strain phase of the maneuver. A patient with suspected infective endocarditis. The diastolic murmur of AR becomes louder in response to interventions that raise systemic vascular resistance. ventricular function. Information regarding valve structure and function. In many instances. fatigue. the lungs. causing an increase in the gradient and a Midsystolic. the Austin Flint murmur of severe AR becomes softer. and extremities.e50 valve closure. and aortic flow can be readily ascertained. including those from ECG or chest x-ray. The increase in the intensity of the murmur of HOCM is predicated on the augmentation of the dynamic left ventricular outflow tract gradient that occurs with reduced ventricular filling. chamber size. for example. or holosystolic murmurs. Echocardiography is indicated for the evaluation of patients with early. and cardiac output. Squatting results in abrupt increases in both venous return and left ventricular afterload. PART 2 Cardinal Manifestations and Presentation of Diseases Post-Premature Ventricular Contraction A change in the intensity of a systolic murmur in the first beat after a premature beat. splenomegaly. referral to a cardiovascular specialist should be considered if doubt exists regarding the significance of the murmur after the initial examination. chills. Changes in Venous Return The Valsalva maneuver results in an increase in intrathoracic pressure. 220 and 222) Echocardiography with color flow and spectral Doppler is a valuable tool for the assessment of cardiac murmurs. followed by a decrease in venous return. estimated pulmonary artery pressures. grade 3 or more does not change in the post-premature beat as there is • Late systolic relatively little further increase in mitral valve flow or • Holosystolic change in the left ventricular to left atrial gradient. and positive blood cultures. Inhaled amyl nitrite is now rarely used for this purpose but can help to distinguish the murmur of AS or HOCM from that of either MR or VSD. other heart sounds. can help distinguish AS from MR. abdomen.) Copyright © 2008 The McGraw-Hill Companies. A new systolic murmur in a patient with a marked fall in blood pressure after a recent MI suggests myocardial rupture. (Adapted from Bonow et al. or infusion of a vasopressor agent. The intensity of the murmur of MR 2 or less • Midsystolic. On the other hand. both of which become louder during the Valsalva maneuver. pulmonic. increase in intensity in the beat following a Systolic murmur premature beat because of the combined effects of enhanced left ventricular filling and post-extrasystolic potentiation of contractile function. Two notable exceptions are the murmurs associated with MVP and obstructive HOCM. skin. as can occur with severe MR. e83). Systolic murmurs due to left ventricular outflow obstruction. e8-10. The performance of serial echocardiography to follow the course of asymptomatic individuals with valvular heart disease is a central feature of their longitudinal assessment and provides valuable information that may impact on decisions regarding the timing of surgery. catheterization if appropriate • Venous hum • Mammary souffle No further workup FIGURE e8-10 Strategy for evaluating heart murmurs. wall thickness. It is important to note that Doppler signals of trace or mild valvular regurgitation of no clinical consequence can be detected with structurally normal tricuspid. but the mid-diastolic rumble of MS becomes louder. simultaneous inflation of blood pressure cuffs on both upper extremities to pressures 20–40 mmHg above systolic pressure for 20 s. echocardiography is indicated. Patients with grade 1 or 2 mid-systolic murmurs. The murmurs associated with AS or HOCM will either become softer or remain unchanged with these maneuvers. and mitral valves. For this category of patients. the arterial pulses. All rights reserved. or delayed pulmonic valve closure due to PS or right bundle branch block. changes that predictably cause a decrease in the intensity and duration of the murmurs associated with MVP and HOCM. Such signals are not likely to generate enough turbulence to create a murmur. Both the click and the murmur of MVP move closer in timing to S1 on rapid standing (Fig. as should findings relevant to the jugular venous pressure and wave forms. or pulmonary disease should help focus the differential diagnosis. an ECG. ventricular filling. The murmur of MVP may also become longer as leaflet prolapse occurs earlier in systole at smaller ventricular volumes. including that due to AS. or in the beat after a long cycle length in patients with atrial fibrillation. Alterations of Systemic Vascular Resistance Murmurs can change characteristics following maneuvers that alter systemic vascular resistance and left ventricular afterload. TTE. active. THE CLINICAL CONTEXT Additional clues as to the etiology and importance of a heart murmur can be gleaned from the history and other physical examination findings. anorexia. The systolic murmurs of MR and VSD become louder during sustained handgrip. an isolated grade 1 or 2 midsystolic murmur at the left sternal border in a healthy. but other symptoms or signs of cardiovascular disease. transesophageal echocardiography. MR. and for patients with grade 3 or louder mid-systolic murmurs. transthoracic echocardiography. particularly in an older patient in whom the murmur of AS is well transmitted to the apex. Echocardiography is indicated for the evaluation of any patient with a diastolic murmur and for patients with continuous murmurs not due to a venous hum or mammary souffle. may have a murmur in the setting of fever. tained earlier and may contain valuable information. pulmonary and hepatic vein flow. *If an electrocardiogram or chest x-ray has been obtained and is abnormal. Opposite changes in systolic and diastolic murmurs may occur with the use of pharmacologic agents that lower systemic vascular resistance. Symptoms suggestive of cardiovascular. dyspnea. Forward flow accelerates. As noted previously. magnetic resonance. neurologic. . laboratory studies. These murmurs behave in a similar and parallel fashion with standing. late. The former two murmurs increase in intensity.

Fig. At least one study has suggested that initial referral of pediatric patients with heart murmurs to a specialist results in modest cost savings.pdf CHOUNDHRY NK. For some clinicians. although limited in its ability to display valvular morphology. risk factors. Although several reports attest to the improved sensitivity of such devices for the detection of valvular heart disease. chamber and great vessel size. Available at http://www. e8-10) In relatively few patients. INTEGRATED APPROACH The accurate identification of a heart murmur begins with a systematic approach to cardiac auscultation. Chest 126(2):470. OTHER CARDIAC TESTING (Chap. handheld or miniaturized cardiac ultrasound devices have replaced the stethoscope. especially when the TTE windows are limited by body size. 222.acc. P Libby et al (eds). Saunders Elsevier. in Braunwald’s Heart Disease. Correlation of the findings on auscultation with the noninvasive data provides an educational feedback loop and an opportunity for improving physical examination skills. TEE offers enhanced sensitivity for the detection of a wide range of structural cardiac disorders. ETCHELLS EE: Does this patient have aortic regurgitation? JAMA 281:2231. 8th ed. Arch Intern Med 166(6):610. associated cardiac findings. treatment. The use of electronic or digital stethoscopes with spectral display capabilities has also been proposed as a method to improve the characterization of heart murmurs and the teaching of cardiac auscultation. physicians and faculty: A multicenter study. 2008 MURGO JP: Systolic ejection murmurs in the era of modern cardiology. 2006 VUKANOVIC-CRILEY JM et al: Competency in cardiac examination skills in medical students. A Textbook of Cardiovascular Medicine. All rights reserved. especially when there is a suspicion of coronary artery disease predicated on symptoms. Philadelphia. American College of Cardiology Web Site. and outcome. allows the examiner to construct a e51 preliminary differential diagnosis. shunt flow. Additional study is required to assess the cost-effective application of newer imaging technology. Cost constraints mandate that noninvasive imaging be justified on the basis of its incremental contribution to diagnosis.org/clinical/guidelines/valvular/index. and the clinical context. and myocardial perfusion. Electrocardiographically gated cardiac magnetic resonance (CMR) imaging. chest configuration. 1998 TAVEL ME: Cardiac auscultation: A glorious past—and it does have a future! Circulation 113:1255. CHAPTER e8 FURTHER READINGS BARRETT MJ et al: Mastering cardiac murmurs: The power of repetition. regurgitant fraction. Coronary angiography is performed routinely in most adult patients prior to valve surgery. accuracy is highly operator dependent and incremental cost considerations have not been adequately addressed. 1999 ETCHELLS E et al: Does this patient have an abnormal systolic heart murmur? JAMA 277(7):564. O’GARA P: The history and physical examination. Characterization of its major at- tributes.The selective use of echocardiography outlined above has not been subjected to rigorous cost-effective analysis. What do we really know? J Am Coll Cardiol 32(6):1596. and/or age. The need for and urgency of further testing follow sequentially. Transesophageal echocardiography (TEE) can be considered for further evaluation. stenosis severity. ventricular function. clinical assessment and TTE do not adequately characterize the origin and significance of a heart murmur. as reviewed above. 2006 Approach to the Patient with a Heart Murmur Copyright © 2008 The McGraw-Hill Companies. which is then refined by integration of information available from the history. can provide quantitative information regarding valvular function. the general physical examination. 2004 BONOW RO et al: ACC/AHA 2006 Guidelines for the management of patients with valvular heart disease: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Patients with Valvular Heart Disease). 1997 FANG J. CMR has greater capability than cardiac computed tomography (CCT) in this regard and has largely supplanted the need for cardiac catheterization and invasive hemodynamic assessment when there is a discrepancy between the clinical and echocardiographic findings. trainees. . or intrathoracic pathology.

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This lesion may be idiopathic or associated with HIV infection and has a particularly poor prognosis.) Copyright © 2008 The McGraw-Hill Companies. the sine qua non of segmental sclerosis. (ABF/Vanderbilt Collection. There is a welldefined segmental increase in matrix and obliteration of capillary loops. (ABF/Vanderbilt Collection. The glomerular tuft shows proliferative changes with numerous PMNs. Eric G. In minimal change disease. e53 CHAPTER e9 Atlas of Urinary Sediments and Renal Biopsies FIGURE e9-1 Minimal change disease. Subepithelial hump-shaped deposits are seen by electron microscopy (right). Common urinalysis findings are also documented. with a crescentic reaction in severe cases (left).of Urinary Sediments e9 AtlasRenal Biopsies and Agnes B. (ABF/Vanderbilt Collection. with light. Neilson Key diagnostic features of selected diseases in renal biopsy and urinalysis are illustrated.) FIGURE e9-3 Collapsing glomerulopathy. All rights reserved. (EGN/UPenn Collection. immunofluorescence.) FIGURE e9-4 Postinfectious (poststreptococcal) glomerulonephritis. light microscopy is unremarkable (left). There is segmental collapse of the glomerular capillary loops and overlying podocyte hyperplasia. . while electron microscopy reveals podocyte injury evidenced by complete foot process effacement. These deposits localize in the mesangium and along the capillary wall in a subepithelial pattern and stain dominantly for C3 and to a lesser extent for IgG (middle). and electron microscopic images.) FIGURE e9-2 Focal segmental glomerulosclerosis. Fogo.

globular deposits within the mesangium. resulting in the appearance of spike-like projections on silver stain (left). there is a membranoproliferative pattern. There is variable mesangial expansion due to mesangial deposits. (ABF/Vanderbilt Collection. (EGN/UPenn Collection. with some cases also showing endocapillary proliferation or segmental sclerosis (left).e54 FIGURE e9-5 Membranous glomerulopathy. There is mesangial expansion and endocapillary proliferation resulting in the “tram-track” sign of cellular interposition along the glomerular basement membrane. By electron microscopy. with resulting basement membrane reaction.) FIGURE e9-8 Dense deposit disease (membranoproliferative glomerulonephritis type II). The deposits are directly visualized by fluorescent anti- IgG.) FIGURE e9-7 Membranoproliferative glomerulonephritis. with overlying foot process effacement (right). the subepithelial location of the deposits and early surrounding basement membrane reaction is evident. (ABF/Vanderbilt Collection.) PART 2 Cardinal Manifestations and Presentation of Diseases FIGURE e9-6 IgA nephropathy. only C3 staining is usually present. (ABF/Vanderbilt Collection. revealing diffuse granular capillary loop staining (middle).) Copyright © 2008 The McGraw-Hill Companies. All rights reserved. By immunofluorescence. By immunofluorescence. Membranous glomerulopathy is due to subepithelial deposits. By electron microscopy. By light microscopy. . deposits are evident (right). there is a dense transformation of the glomerular basement membrane with round.

manifests as endocapillary proliferation. These deposits typically stain for all three immunoglobulins. particularly in the subendothelial area (left). and both C3 and C1q (middle). along with extensive foot process effacement (right). ISN/RPS class III or IV. By electron microscopy. (EGN/UPenn Collection. molded outer contour due to their subendothelial location.) Copyright © 2008 The McGraw-Hill Companies. (ABF/Vanderbilt Collection. subendothelial. By immunofluorescence. and rare subepithelial dense immune complex deposits are evident. resulting from subendothelial deposits. IgM. (ABF/Vanderbilt Collection. mesangial. with some of the peripheral loop deposits having a smooth. and a crescent formed by proliferation of the parietal epithelium. IgA. as may be seen in mixed membranous and proliferative lupus nephritis (ISN/RPS class V and IV) or membranoproliferative glomerulonephritis type III. Note that the uninvolved segment of the glomerulus (at ~5 o’clock) shows no evidence of proliferation or immune complexes.) FIGURE e9-11 Wegener’s granulomatosis. which may result in segmental necrosis due to deposits. . IgG. Proliferative lupus nephritis. All rights reserved.) Atlas of Urinary Sediments and Renal Biopsies FIGURE e9-10 Lupus nephritis. This specimen shows pink subepithelial deposits with spike reaction and the “tramtrack” sign of reduplication of glomerular basement membrane.e55 CHAPTER e9 FIGURE e9-9 Membranoproliferative glomerulonephritis. This pauci-immune necrotizing crescentic glomerulonephritis shows numerous breaks in the glomerular basement membrane with associated segmental fibrinoid necrosis. chunky irregular mesangial and capillary loop deposits are evident.

e56 FIGURE e9-12 Anti-GBM antibody-mediated glomerulonephritis. with immunofluorescence showing monoclonal staining.) FIGURE e9-14 Light chain deposition disease. and a surrounding chronic interstitial nephritis with tubulointerstitial fibrosis.to 11-nm fibrils by electron microscopy (right).) Copyright © 2008 The McGraw-Hill Companies. and in the interstitium. The deposits are composed of randomly organized 9. the deposits show an amorphous granular appearance and line the inside of the glomerular basement membrane and are also found along the tubular basement membranes. often nodular by light microscopy (left). vessels.) FIGURE e9-15 Light chain cast nephropathy (myeloma kidney). . By electron microscopy (right). (ABF/Vanderbilt Collection. Amyloidosis shows amorphous. There is segmental necrosis with a break of the glomerular basement membrane and a cellular crescent (left).) PART 2 Cardinal Manifestations and Presentation of Diseases FIGURE e9-13 Amyloidosis. (ABF/Vanderbilt Collection. acellular expansion of the mesangium. All rights reserved. (ABF/ Vanderbilt Collection. more commonly with kappa than lambda light chain. with apple-green birefringence by polarized Congo red stain (left). There is mesangial expansion. of tubules (middle) and glomerular tufts. Monoclonal light chains precipitate in tubules and result in a syncytial giant cell reaction (left) surrounding the cast. (ABF/Vanderbilt Collection. with material often also infiltrating glomerular basement membranes. and immunofluorescence for IgG shows linear staining of the glomerular basement membrane with a small crescent at ~1 o’clock.

resulting in foamy podocytes by light microscopy (left). and arteriolar hyaline deposits (right). only extensive thinning of the GBM is seen by electron microscopy (right). All rights reserved. Due to deficiency of α-galactosidase.) Copyright © 2008 The McGraw-Hill Companies. These deposits can be directly visualized by electron microscopy (right). medial hypertrophy. microaneurysm formation in the glomerulus on the left. (ABF/Vanderbilt Collection. The vessels show disproportionately severe changes of intimal fibrosis. In Alport’s syndrome.e57 FIGURE e9-16 Fabry’s disease. (ABF/Vanderbilt Collection. with increased mesangial matrix and cellularity. and there may be segmental sclerosis (left). .) FIGURE e9-18 Diabetic nephropathy.) CHAPTER e9 Atlas of Urinary Sediments and Renal Biopsies FIGURE e9-17 Alport’s syndrome and thin glomerular basement membrane lesion. particularly in the podocytes.) FIGURE e9-19 Arterionephrosclerosis. or in early cases of Alport’s syndrome or female carriers. with accompanying and proportional tubulointerstitial fibrosis and pericapsular fibrosis. (ABF/Vanderbilt Collection. and prominent glomerular basement membranes without evidence of immune deposits and arteriolar hyalinosis of both afferent and efferent arterioles. Hypertension-associated injury often manifests extensive global sclerosis of glomeruli. where the glycosphingolipid appears as whorled so-called myeloid bodies. (ABF/Vanderbilt Collection. There is nodular mesangial expansion. there is irregular thinning alternating with thickened so-called basket-weaving abnormal organization of the glomerular basement membrane (left). there is abnormal accumulation of glycolipids. so-called Kimmelstiel-Wilson nodules. In benign familial hematuria.

) FIGURE e9-21 Hemolytic uremic syndrome. There are characteristic intratubular plugs and casts of PMNs with inflammation extending into the surrounding interstitium.) FIGURE e9-24 Acute tubular necrosis. . Acutely. There is extensive flattening of the tubular epithelium and loss of the brush border. this injury leads to intimal proliferation. Cholesterol emboli cause cleft-like spaces where the lipid has been extracted during processing.) Copyright © 2008 The McGraw-Hill Companies. (ABF/ Vanderbilt Collection. which is frequently associated with interstitial eosinophils (right) when caused by a drug hypersensitivity reaction. and surrounding fibrotic and mononuclear cell reaction in these arterioles. with smooth outer contours. All rights reserved. There are characteristic intraglomerular fibrin thrombi. (ABF/Vanderbilt Collection. (ABF/Vanderbilt Collection.e58 FIGURE e9-20 Cholesterol emboli. there is fibrinoid necrosis of interlobular and larger vessels. There is extensive interstitial lymphoplasmocytic infiltrate with mild edema and associated tubular injury (left).) FIGURE e9-23 Acute pyelonephritis. The remaining portion of the capillary tuft shows corrugation of the glomerular basement membrane due to ischemia. with a chunky pink appearance. (ABF/Vanderbilt Collection.) FIGURE e9-25 Acute interstitial nephritis.) PART 2 Cardinal Manifestations and Presentation of Diseases FIGURE e9-22 Progressive systemic sclerosis. with mild interstitial edema. the so-called onion-skinning appearance (right). Chronically. with intervening normal vessels and ischemic change in the glomeruli (left). (ABF/Vanderbilt Collection. (ABF/Vanderbilt Collection. and accompanying tubular injury.

There is chronic interstitial nephritis with numerous.) FIGURE e9-30 Fine granular cast. . (ABF/Vanderbilt Collection. All rights reserved. (ABF/Vanderbilt Collection. with flattening and regeneration of tubular epithelium (left).) FIGURE e9-28 Hyaline cast. non-necrotizing granulomas.) CHAPTER e9 Atlas of Urinary Sediments and Renal Biopsies FIGURE e9-27 Sarcoidosis.e59 FIGURE e9-26 Oxalosis. Calcium oxalate crystals have caused extensive tubular injury. but there is moderate tubular interstitial fibrosis. Crystals are well visualized as sheaves when viewed under polarized light (right).) FIGURE e9-31 Red blood cell cast. (ABF/Vanderbilt Collection.) FIGURE e9-29 Coarse granular cast. (ABF/ Vanderbilt Collection.) FIGURE e9-32 WBC cast. The glomeruli are unremarkable.) Copyright © 2008 The McGraw-Hill Companies. (ABF/Vanderbilt Collection. confluent. (ABF/Vanderbilt Collection. (ABF/Vanderbilt Collection.

e60 FIGURE e9-33 Triple phosphate crystals. (ABF/Vanderbilt Collection.) Copyright © 2008 The McGraw-Hill Companies. (ABF/Vanderbilt Collection.) PART 2 Cardinal Manifestations and Presentation of Diseases FIGURE e9-35 Uric acid crystals. All rights reserved. (ABF/ Vanderbilt Collection. .) FIGURE e9-34 “Maltese cross” formation in an oval fat body.

Psoriasis ranges from limited patches on the elbows and knees to severe erythrodermic involvement and associated psoriatic arthritis. virtually every clinician encounters patients with skin disease. a selected group of inflammatory skin eruptions and neoplastic conditions are grouped in the following manner: (A) common skin diseases and lesions. While most of these dermatoses usually present as a predominantly dermatologic process.) FIGURE e10-4 Atopic dermatitis with hyperpigmentation. (C) melanoma and pigmented lesions. (B) nonmelanoma skin cancer. lichenification. FIGURE e10-1 Acne vulgaris with inflammatory papules. with permission. Lawley. and scaling in the antecubital fossae. All rights reserved. MD. including asthma and sinusitis.e10 Atlas of Skin Manifestations of Internal Disease Thomas J. Atopic dermatitis is often present in patients with an atopic diathesis. (Courtesy of Kalman Watsky. Physicians of all specialties face the daily task of determining the nature and clinical implication of dermatologic disease. representing a pure dermatologic event. underlying systemic associations may be made in some settings. several common inflammatory skin diseases and benign neoplastic and reactive lesions are presented. one of the most common inflammatory dermatoses. Dermatologic conditions can be classified and categorized in many different ways. telangiectasias. and in this Atlas. or whether it is a manifestation of internal disease relating to the patient’s overall medical condition. (D) infectious disease and the skin. scattered papules. In patients with skin eruptions and rashes. Templeton e61 In the practice of medicine. and (F) skin manifestations of internal disease. Finally. (Courtesy of Robert Swerlick. the physician must confront the question of whether the cutaneous process is confined to the skin. Stephen F. (Courtesy of Robert Swerlick.) Copyright © 2008 The McGraw-Hill Companies. with permission. MD. (E) immunologically mediated skin disease. CHAPTER e10 Atlas of Skin Manifestations of Internal Disease FIGURE e10-2 Acne rosacea with prominent facial erythema. even acne vulgaris. FIGURE e10-3 Psoriasis is characterized by small and large erythematous plaques with adherent silvery scale. and small pustules.) COMMON SKIN DISEASES AND LESIONS (Figs. Some patients with alopecia areata may have an underlying thyroid abnormality requiring screening. and comedones. pustules. MD. e10-1 to e10-19) In this section. Evaluation and accurate diagnosis of skin lesions are also critical given the marked rise in both melanoma and nonmelanoma skin cancer. . with permission. can be associated with a systemic process such as polycystic ovarian syndrome.

MD.) FIGURE e10-7 Stasis dermatitis showing erythematous. characterized by deep-seated vesicles and scaling on palms and lateral fingers. Courtesy of Robert Swerlick. with permission. Nail dystrophy as seen in this patient’s thumbnail may also be a feature. Allergic contact dermatitis. (B. with permission. with permission. weeping. yellowish scale. (Courtesy of Jean Bolognia. MD. and oozing patches over the lower leg. MD. acute phase.) FIGURE e10-6 Seborrheic dermatitis showing central facial erythema with overlying greasy. chronic phase demonstrating an erythematous. Cardinal Manifestations and Presentation of Diseases FIGURE e10-8 A.) FIGURE e10-9 Lichen planus showing multiple flat-topped. Allergic contact dermatitis to nickel. scaly. weeping plaque on skin chronically exposed to a metal snap.e62 PART 2 FIGURE e10-5 Dyshidrotic eczema. Several stasis ulcers are also seen in this patient. lichenified. . is often associated with an atopic diathesis. eczematous plaques in a perioral distribution. All rights reserved. (Courtesy of Robert Swerlick. B. violaceous papules and plaques. Copyright © 2008 The McGraw-Hill Companies. with sharply demarcated.

MD. Dermatographism. FIGURE e10-13 Pityriasis rosea. All rights reserved. Multiple round to oval erythematous patches with fine central scale are distributed along the skin tension lines on the trunk.” waxy. with permission.) FIGURE e10-11 Vitiligo in a typical acral distribution demonstrating striking cutaneous depigmentation. FIGURE e10-12 Alopecia areata characterized by a sharply demarcated circular patch of scalp completely devoid of hairs. with permission. edematous.) Copyright © 2008 The McGraw-Hill Companies.e63 CHAPTER e10 Atlas of Skin Manifestations of Internal Disease FIGURE e10-10 Seborrheic keratoses are seen as “stuck on. indicating a nonscarring alopecia. Courtesy of Robert Swerlick. Urticaria showing characteristic discrete and confluent. (B. . MD. FIGURE e10-14 A. verrucous papules and plaques with a variety of colors ranging from light tan to black. Follicular orifices are preserved. as a result of loss of melanocytes. erythematous papules and plaques. Erythema and whealing that developed after firm stroking of the skin. B. (Courtesy of Robert Swerlick.

MD. surrounded by edema and erythema. cystic nodules are seen in this patient. .) Copyright © 2008 The McGraw-Hill Companies. Danzl. (Courtesy of Daniel F. Cardinal Manifestations and Presentation of Diseases FIGURE e10-16 Keloids resulting from ear piercing. They are characterized by multiple erythematous to dark purple papules. Several inflamed and noninflamed firm. with permission. surrounded by edema and erythema. with firm exophytic flesh-colored to erythematous nodules of scar tissue.e64 PART 2 FIGURE e10-15 Epidermoid cysts. Often a patulous follicular punctum is observed on the overlying epidermal surface. All rights reserved. (Courtesy of Daniel F.) FIGURE e10-19 Frostbite with vesiculation. usually located on the trunk. Danzl. with permission. FIGURE e10-17 Cherry hemangiomas are very common and arise in middle-aged to older adults. MD. FIGURE e10-18 Frostbite with vesiculation.

rolled. nonmelanoma skin cancer is increasing at an alarming rate. e10-20 to e10-27) In more fair-skinned ethnic populations. often ulcerated dermal nodules. including keratoacanthoma-type squamous cell carcinoma.NONMELANOMA SKIN CANCER (Figs. FIGURE e10-24 Metastatic carcinoma to the skin is characterized by inflammatory. “plum-colored” nodules. All rights reserved. Less common cutaneous malignancies include cutaneous T cell lymphoma (mycosis fungoides) and carcinoma and lymphoma metastatic to skin. telangiectatic tumor border. and tumor stages. FIGURE e10-20 Kaposi’s sarcoma in a patient with AIDS demonstrating patch. is the second most common skin cancer in most ethnic populations and is also most commonly linked to ultraviolet radiation. and plaque stage lesions are seen in this patient. Copyright © 2008 The McGraw-Hill Companies. FIGURE e10-21 Non-Hodgkin’s lymphoma involving the skin with typical violaceous. plaque. e65 CHAPTER e10 Atlas of Skin Manifestations of Internal Disease FIGURE e10-22 Basal cell carcinoma showing central ulceration and a pearly. Squamous cell carcinoma. with permission. Basal cell carcinoma is the most common cancer in humans and is strongly linked to ultraviolet radiation. MD. (Courtesy of Jean Bolognia. .) FIGURE e10-23 Mycosis fungoides is a cutaneous T cell lymphoma.

it is essential that all clinicians acquire some facility in evaluating pigmented lesions. Three of the clinicopathologic subtypes of melanoma. . and arms are other typical sites of involvement. black.e66 MELANOMA AND BENIGN PIGMENTED LESIONS (Figs.” Asymmetry—one half of the lesion varies from the other half. and acral lentiginous melanoma. PART 2 Cardinal Manifestations and Presentation of Diseases FIGURE e10-25 Keratoacanthoma is a low-grade squamous cell carcinoma that presents as an exophytic nodule with central keratinous debris. Border irregularity—the circumferential border exhibits an irregular. and color variation. may not manifest all these features but present as a more symmetric. and white within different areas of the lesion. FIGURE e10-27 Actinic keratoses consist of hyperkeratotic erythematous papules and patches on sun-exposed skin. Nevi are benign proliferations of nevomelanocytes characterized by regularly shaped hyperpigmented macules or papules of a uniform color. red.) Copyright © 2008 The McGraw-Hill Companies. e10-28 to e10-33) As the prognosis of melanoma is primarily related to microscopic depth of invasion. evenly pigmented or amelanotic lesion. They arise in middle-aged to older adults and have some potential for malignant transformation. (Courtesy of Robert Swerlick. lentigo maligna. with permission. sometimes jagged appearance. FIGURE e10-29 Dysplastic nevi are irregularly pigmented and shaped nevomelanocytic lesions which may be associated with familial melanoma. superficial spreading. Color—there is uneven coloration and tone to the pigmented lesion with varying shades of brown. Sun-exposed skin such as the head. All rights reserved. Dysplastic (atypical) melanocytic nevi may occur as solitary or multiple lesions as well as in the setting of familial melanoma. nodular melanoma. neck. The more uncommon subtype. Ordinary nevi may be acquired or congenital and are quite common. hands. They display some degree of asymmetry. border irregularity. Diameter—is typically >6 mm. typically display features noted in the “ABCD rule. FIGURE e10-28 Nevus. FIGURE e10-26 Squamous cell carcinoma seen here as a hyperkeratotic crusted and somewhat eroded plaque on the lower lip. MD. and early detection with surgical treatment can be curative in a high percentage of patients.

MD. Most sexually transmitted bacterial and viral diseases exhibit cutaneous involvement. All rights reserved. and condyloma accuminatum. (Courtesy of S. exposure to infectious agents occurs. warm plaques. Rocky Mountain spotted fever. FIGURE e10-31 Lentigo maligna melanoma occurs on sun-exposed skin as a large. viral. e10-34 to e10-59) One of the roles of the skin is to function as a barrier from the outside world. Wright Caughman. Lyme disease. FIGURE e10-32 Nodular melanoma most commonly manifests itself as a rapidly growing. with permission. .e67 CHAPTER e10 Atlas of Skin Manifestations of Internal Disease FIGURE e10-30 Superficial spreading melanoma is the most common type of malignant melanoma and demonstrates color variegation (black.) FIGURE e10-34 Erysipelas is a streptococcal infection of the superficial dermis and consists of well-demarcated. and white) and irregular borders. and examples include primary and secondary syphilis. FIGURE e10-33 Acral lentiginous melanoma is more common in blacks. (Courtesy of Alvin Solomon. often ulcerated or crusted black nodule. In addition the skin may be secondarily involved and provide diagnostic clues to systemic infections such as meningococcemia. genital herpes simplex. fungal. Lateral pigment diffusion is present. and bacterial. and parasitic infections may result. with permission. brown. MD. hyperpigmented macule or plaque with irregular borders and variable pigmentation. blue. The patient reported external ear pain. edematous. and septic emboli. erythematous. Asians. pink. A vesicular rash on the concha and antihelix suggested Ramsay Hunt syndrome. chancroid. In this capacity. Copyright © 2008 The McGraw-Hill Companies.) FIGURE e10-35 Spread of herpes zoster with chemotherapy. INFECTIOUS DISEASE AND THE SKIN (Figs. and Hispanics and occurs as an enlarging hyperpigmented macule or plaque on the palms or soles.

MD.) Copyright © 2008 The McGraw-Hill Companies. All rights reserved. with permission. (Courtesy of Stephen D. bullous lesions may be seen.) FIGURE e10-37 Herpes zoster is seen in this HIV-infected patient as hemorrhagic vesicles and pustules on an erythematous base grouped in a dermatomal distribution. (Courtesy of Yale Resident’s Slide Collection.e68 PART 2 Cardinal Manifestations and Presentation of Diseases FIGURE e10-36 Varicella showing numerous lesions in various stages of evolution: vesicles on an erythematous base. and crusts. (Courtesy of Robert Hartman.) FIGURE e10-38 Impetigo contagiosa is a superficial streptococcal or Staphylococcus aureus infection consisting of honey-colored crusts and erythematous weeping erosions. (Courtesy of Robert Swerlick. with permission. Occasionally.) FIGURE e10-40 Lacy reticular rash of erythema infectiosum (fifth disease). . with permission.) FIGURE e10-39 Tender vesicles and erosions in the mouth of a patient with hand-foot-and-mouth disease. MD. FIGURE e10-41 Molluscum contagiosum is a cutaneous poxvirus infection characterized by multiple umbilicated flesh-colored or hypopigmented papules. MD. MD. with permission. umbilicated vesicles. with permission. (Courtesy of Mary Spraker. Gellis.

(From K Wolff. RA Johnson. McGraw-Hill. with permission. with permission. (Courtesy of Gregory Cox.) FIGURE e10-44 Rocky Mountain spotted fever demonstrating pinpoint petechial lesions on the palm and volar aspect of the wrist. MD.accessmedicine. www. D Suurmond: Fitzpatrick’s Color Atlas & Synopsis of Clinical Dermatology.com.) FIGURE e10-43 Fulminant meningococcemia with extensive angular purpuric patches.e69 CHAPTER e10 Atlas of Skin Manifestations of Internal Disease FIGURE e10-42 Oral hairy leukoplakia often presents as white plaques on the lateral tongue and is associated with Epstein-Barr virus infection. New York. often with a central erythematous papule at the tick bite site. with permission. 5th ed.) Copyright © 2008 The McGraw-Hill Companies. (Courtesy of Yale Resident’s Slide Collection. All rights reserved. MD. Gellis. 2005. .) FIGURE e10-46 Primary syphilis with a firm.) FIGURE e10-45 Erythema chronicum migrans is the early cutaneous manifestation of Lyme disease and is characterized by erythematous annular patches. MD. (Courtesy of Robert Swerlick. nontender chancre. (Courtesy of Stephen D. with permission.

red-brown papules. (Courtesy of Alvin Solomon. MD.) FIGURE e10-49 Secondary syphilis demonstrating the papulosquamous truncal eruption. (Courtesy of Yale Resident’s Slide Collection. with permission. . with permission. FIGURE e10-48 Condylomata lata are moist. with permission.) Cardinal Manifestations and Presentation of Diseases FIGURE e10-51 Scabies showing typical scaling erythematous papules and few linear burrows. Copyright © 2008 The McGraw-Hill Companies. somewhat verrucous intertriginous plaques seen in secondary syphilis. seen here as an erythematous annular scaly plaque with central clearing. All rights reserved. Pranava Murthy.e70 PART 2 FIGURE e10-50 Tinea corporis is a superficial fungal infection.) FIGURE e10-52 Skin lesions caused by Chironex fleckeri sting. MD. firm. (Courtesy of V. FIGURE e10-47 Secondary syphilis commonly affects the palms and soles with scaling.

and loss of eyebrows. Copyright © 2008 The McGraw-Hill Companies. Ecthyma gangrenosum in a neutropenic patient with Pseudomonas aeruginosa bacteremia. A. Papule in a neutropenic patient with Candida tropicalis fungemia. D. Wright Caughman. with permission. MD. B. C. (Courtesy of Robert Gelber.) FIGURE e10-55 A patient with features of polar lepromatous leprosy.e71 CHAPTER e10 Atlas of Skin Manifestations of Internal Disease FIGURE e10-53 Chancroid with characteristic penile ulcers and associated left inguinal adenitis (bubo). Papules related to Escherichia coli bacteremia in a neutropenic patient with acute lymphocytic leukemia.) FIGURE e10-56 Skin lesions of neutropenic patients. (Courtesy of S. . FIGURE e10-54 Condylomata acuminata are lesions induced by human papillomavirus and in this patient are seen as multiple verrucous papules coalescing into plaques. The same lesion the following day. All rights reserved. particularly of the forehead. multiple nodular skin lesions. with permission. MD.

) FIGURE e10-60 A. (B.e72 PART 2 FIGURE e10-57 Septic emboli with hemorrhage and infarction due to acute Staphylococcus aureus endocarditis. Musher. and vasculitis. B. (Courtesy of Daniel M. (Courtesy of L.) Cardinal Manifestations and Presentation of Diseases IMMUNOLOGICALLY MEDIATED SKIN DISEASE (Figs.) FIGURE e10-58 Vegetations (arrows) due to viridans streptococcal endocarditis involving the mitral valve. with permission.) Copyright © 2008 The McGraw-Hill Companies. e10-60 to e10-71) Immunologically mediated skin disease may be largely localized to skin and mucous membranes and manifest with blisters and erosions such as pemphigus. dermatomyositis. MD. skin manifestations are often only one element of a widespread process. MD. FIGURE e10-59 Disseminated gonococcemia in the skin is seen as hemorrhagic papules and pustules with purpuric centers in an acral distribution. MD. scaly. In diseases such as systemic lupus erythematosus. Systemic lupus erythematosus showing prominent. All rights reserved. Acute lupus erythematosus on the upper chest demonstrating brightly erythematous and slightly edematous coalescence of papules and plaques. (Courtesy of AW Kerchner. pemphigoid. MD. Involvement of other sun-exposed sites is also common. Baden. and dermatitis herpetiformis. with permission. with permission. Courtesy of Robert Swerlick. malar erythema. . with permission.

MD.e73 CHAPTER e10 Atlas of Skin Manifestations of Internal Disease FIGURE e10-61 Discoid lupus erythematosus.) FIGURE e10-66 Erythema multiforme is characterized by multiple erythematous plaques with a target or iris morphology and usually represents a hypersensitivity reaction to drugs or infections (especially herpes simplex virus). MD. (Courtesy of James Krell. Violaceous.) FIGURE e10-63 Scleroderma characterized by typical expressionless.) FIGURE e10-64 Dermatomyositis often involves the hands as erythematous flat-topped papules over the knuckles (Gottron’s sign) and periungual telangiectasias. (Courtesy of Marilynne McKay. which may result in scarring. FIGURE e10-65 Scleroderma showing acral sclerosis and focal digital ulcers. hyperpigmented. Periorbital violaceous erythema characterizes the classic heliotrope rash. atrophic plaques. often with evidence of follicular plugging. with permission. All rights reserved. FIGURE e10-62 Dermatomyositis. (Courtesy of Yale Resident’s Slide Collection. Copyright © 2008 The McGraw-Hill Companies. with permission. mask-like facies. with permission. are characteristic of this cutaneous form of lupus. .

resulting in multiple erosions and crusted plaques. Palpable purpuric papules on the lower legs are seen in this patient with cutaneous small vessel vasculitis. Pemphigus vulgaris demonstrating flaccid bullae that are easily ruptured. Courtesy of Robert Swerlick. MD. with permission. .) FIGURE e10-71 Bullous pemphigoid with tense vesicles and bullae on an erythematous.) FIGURE e10-68 A. grouped vesicles in a typical location.) Copyright © 2008 The McGraw-Hill Companies. and posterior scalp. or the tongue. (Courtesy of Robert Swerlick. urticarial base. B. buccal mucosa.) FIGURE e10-70 Vasculitis. MD.e74 PART 2 Cardinal Manifestations and Presentation of Diseases FIGURE e10-67 Dermatitis herpetiformis manifested by pruritic. with permission. (Courtesy of Robert Swerlick. with permission. palate. posterior pharynx. The vesicles are often excoriated and may occur on knees. buttocks. (B. MD. All rights reserved. Pemphigus vulgaris almost invariably involves the oral mucosa and may present with erosions involving the gingiva. with permission. FIGURE e10-69 Erythema nodosum is a panniculitis characterized by tender deep-seated nodules and plaques usually located on the lower extremities. (Courtesy of Yale Resident’s Slide Collection.

with permission.) Copyright © 2008 The McGraw-Hill Companies. . which may be associated with hematologic malignancies. accompany. Malignant acanthosis nigricans may occur in association with several malignancies. (Courtesy of Robert Swerlick. MD. solid tumors. with permission. (Courtesy of Robert Swerlick. which is associated with thyroid disease. or follow diagnosis of systemic disease. MD. with permission. and Sweet’s syndrome. FIGURE e10-76 Neurofibromatosis demonstrating numerous fleshcolored cutaneous neurofibromas. infiltrated plaques in a patient with Graves’ disease. Other fatty areas such as buttocks and thighs are also common sites of involvement.) FIGURE e10-74 Plaque of Sweet’s syndrome demonstrating an erythematous indurated plaque with a pseudo-vesicular border. e75 CHAPTER e10 Atlas of Skin Manifestations of Internal Disease FIGURE e10-75 Bilateral rheumatoid nodules of the upper extremities. most commonly obesity and insulin resistance. All rights reserved. FIGURE e10-73 Pretibial myxedema manifesting as waxy. MD. It may also be associated with other endocrine disorders and several rare genetic syndromes. Other markers of internal disease in this section include pretibial myxedema. rheumatoid arthritis. FIGURE e10-77 Coumarin necrosis showing cutaneous and subcutaneous necrosis of a breast. The skin is also involved in many systemic inflammatory diseases such as sarcoidosis. lung. Acanthosis nigricans is a prototypical dermatologic process often occurring in association with underlying systemic abnormalities. Many of these dermatologic markers may precede. especially adenocarcinoma of the gastrointestinal tract. verrucous surface. or inflammatory bowel disease. e10-72 to e10-79) While many systemic diseases also have cutaneous manifestations. there are some well recognized dermatologic markers of internal disease. (Courtesy of Kim Yancey. and breast.SKIN MANIFESTATIONS OF INTERNAL DISEASE (Figs. and some are demonstrated in this section.) FIGURE e10-72 Acanthosis nigricans demonstrating typical hyperpigmented axillary plaques with a velvet-like. and lupus erythematosus.

) FIGURE e10-79 Pyoderma gangrenosum on the posterior-lateral aspect of the lower leg demonstrating multiple purulent draining ulcers on an infiltrated erythematous plaque. Sarcoid. Sarcoid. B. (B.e76 PART 2 Cardinal Manifestations and Presentation of Diseases FIGURE e10-78 A. All rights reserved. Infiltrated papules and plaques of variable color are seen in a typical paranasal and periorbital location. Courtesy of Robert Swerlick. (Courtesy of Robert Swerlick. and slightly erythematous coalescent papules and plaques on the upper arm.) Copyright © 2008 The McGraw-Hill Companies. . with permission. MD. MD. with permission. hyperpigmented. Infiltrated.

and contain large red granules. They can also be seen in renal failure and malnutrition and are often reversible. However. one examines the white blood cells. They are round. but they are also present in iron deficiency. Bands are immature neutrophils that have not yet completed nuclear condensation and have a U-shaped nucleus. and contain a lobulated nucleus with two to five lobes connected by a thin chromatin thread. certain rare inherited syndromes can produce large platelets. Systematic histologic examination of the bone marrow and lymph node are beyond the scope of a general medicine textbook. In the presence of viral infections. just barely touching each other but not overlapping. cholestatic liver disease. they can be seen in hereditary spherocytosis. My own approach is to look at the smallest cellular elements first. The best place to examine blood cell morphology is the feathered edge of the blood smear where red cells lie in a single layer. . When the red cells vary greatly in size. the platelets. and they also suggest a systemic inflammation. e18) CHAPTER e11 Atlas of Hematology and Analysis of Peripheral Blood Smears Copyright © 2008 The McGraw-Hill Companies. severe iron deficiency. In most individuals. every internist should know how to examine a peripheral blood smear. social history. The presence of 1. Polychromatophilia—the red cell cytoplasm has a bluish hue. and multiplies by 20. but they are also seen in iron deficiency. the cells get larger—they do not become darker. thalassemias. or bull’s eye. All rights reserved. Red cells that are smaller than the small lymphocyte nucleus may be microcytic. Lymphocytes can be present in several morphologic forms. Dacrocytes are teardrop-shaped cells that can be seen in hemolytic anemias. Another abnormal distribution involves red cells lying in single cell rows on top of one another like stacks of coins. In addition to hemoglobin content. averages the number per field. Eosinophils are slightly larger than neutrophils. There is usually 1 platelet for every 20 or so red cells. re. Acanthocytes are spiculated red cells with the spikes irregularly distributed. Elliptocytes are elliptical-shaped red cells that can reflect an inherited defect in the red cell membrane. It is useful to ask the laboratory to generate a Wright’s-stained peripheral blood smear and to examine it. can reflect infections. Longo 5. the cells lie side by side in a single layer. and some hemoglobinopathies. and thalassemias. but gross disparities between the automated and manual counts should be assessed. Both are normally about 8 μm wide. have bilobed nuclei. which will produce an MCV in the normal range but wide variation in red cell size. Diseases of eosinophils are associated with too many of them rather than any morphologic or qualitative change. about the size of neutrophils. called Dohle bodies. Similarly. “toxic granulations” are said to be present. One last feature of the red cells to assess before moving to the white blood cells is the distribution of the red cells on the smear. side by side. one examines the hemoglobin content of the cells. While advances in automated technology have made the examination of the peripheral blood smear by the physician seem less important. the technology is not a completely satisfactory replacement for blood smear interpretation by a trained medical professional who also knows the patient’s clinical history. Most common in healthy individuals are the small lymphocytes with a small dark nucleus and scarce cytoplasm. Neutrophils are generally the most abundant white cell. However. poikilocytosis is said to be present. Three types of granulocytes are usually present. myelofibrosis. burns. Parasites—red cell parasites include malaria and babesia (Chap. The presence of neutrophils with more than five nuclear lobes suggests megaloblastic anemia. it is seen in certain paraproteinemias and autoimmune hemolytic anemias. some patients may have both iron and vitamin B12 deficiency. Small red cells without the central pallor are spherocytes. hemolytic anemias of other causes. One can gauge their size by comparing the red cell to the nucleus of a small lymphocyte.e77 flecting the persistence of ribosomes still actively making hemoglobin in a young red cell Vital stains are necessary to see precipitated hemoglobin called Heinz bodies. Stomatocytes can indicate an inherited red cell membrane defect and can also be seen in alcoholism. Large platelets may be a sign of rapid platelet turnover. Vacuolated neutrophils may be a sign of bacterial sepsis.e11 Atlas of Hematology and Analysis of Peripheral Blood Smears Dan L. Platelet clumping visible on the smear can be associated with falsely low automated platelet counts. Schistocytes are helmet-shaped cells that reflect microangiopathic hemolytic anemia or fragmentation on an artificial heart valve. Some patients have red cell clumping (called agglutination) in which the red cells pile upon one another. enlarged lymph nodes. megaloblastic anemia. one first counts the platelets in five to six fields. as young platelets are often larger than old platelets. They can also be generated artifactually by improper slide making. anisocytosis is said to be present. After red cell size is assessed. neutrophils. the automated counter is much more accurate. in decreasing frequency. or other inflammatory states. They normally total less than one-thirtieth the number of neutrophils. they can represent an artifact of abnormal drying of the blood smear or reflect changes in stored blood. This process tends to be irreversible and reflects underlying renal disease. with abundant cytoplasm and a less condensed nuclear chromatin. Howell-Jolly bodies—dense blue circular inclusions that represent nuclear remnants—their presence implies defective splenic function 3. abetalipoproteinemia. Finally. Using an oil immersion lens that magnifies the cells 100-fold. The examination of the peripheral blood smear is one of the most informative exercises a physician can perform. Target cells have an area of central pallor that contains a dense center. and myelodysplastic syndromes. and clostridial sepsis. Basophils are even more rare than eosinophils in the blood. If the neutrophil granules are larger than normal and stain a darker blue. When the red cells vary greatly in shape. 10–14 μm wide. Neutrophils can provide clues to a variety of conditions. Red cell inclusions are the following: 1. They are either normal in color (normochromic) or they are pale in color (hypochromic). and physical findings. neutrophil fragmentation can be a source of falsely elevated automated platelet counts. Basophilic stippling—diffuse fine or coarse blue dots in the red cell representing usually RNA residue—especially common in lead poisoning 2. the red cells are examined for inclusions. alternatively.000 to get a rough estimate of the platelet count. The platelets are usually 1–2 μm in diameter and have a blue granulated appearance. Of course. myelodysplastic syndrome. or splenectomy. and work my way up in size to red cells and then white cells. Echinocytes are spiculated red cells with the spikes evenly spaced. and basophils. Next one examines the red blood cells. those larger than the small lymphocyte nucleus may be macrocytic. They are never “hyperchromic. The automated mean corpuscular volume (MCV) can assist in making a classification. and bone marrow are illustrated here. These Some of the relevant findings in peripheral blood. This is called rouleaux formation and reflects abnormal serum protein levels. These cells are seen classically in thalassemia. family history. Bands reflect a left shift in neutrophil maturation in an effort to make more cells more rapidly.to 2μm blue cytoplasmic inclusions. eosinophils. Large misshapen granules may reflect the inherited Chédiak-Higashi syndrome.” If more than the normal amount of hemoglobin is made. They have large dark-blue granules and may be increased as part of chronic myeloid leukemia. Stomatocytes are red cells in which the area of central pallor takes on the morphology of a slit instead of the usual round shape. All abnormally shaped red cells are poikilocytes. Red cells can take on a variety of different shapes. more of the lymphocytes are larger. Nuclei—red cells may be released or pushed out of the marrow prematurely before nuclear extrusion—often implies a myelophthisic process 4.

Small lymphocyte in field helps assess the red blood cell size. M Lichtman et al (eds). and rare epithelial malignant cells may be identified. Copyright © 2008 The McGraw-Hill Companies. and occasionally red cells. FIGURE e11-4 Iron deficiency anemia next to normal red blood cells. other types of tumors can get access to the blood stream. FIGURE e11-5 Polychromatophilia. In chronic lymphoid leukemia. 7th edition. and many of them are ruptured in making the blood smear. myeloid cells. the cytoplasm is gray. McGraw-Hill. 2005. The chances of seeing such abnormal cells is increased by examining blood smears made from buffy coats. ranging from 15–22 μm in diameter. McGraw-Hill. these are called large granular lymphocytes. This new methylene blue–stained blood smear shows large numbers of heavily stained reticulocytes (the cells containing the dark blue–staining RNA precipitates). leaving a smudge of nuclear material without a surrounding cytoplasm or cell membrane. ACKNOWLEDGMENT Figures in this e-chapter were borrowed from Williams Hematology. PART 2 Cardinal Manifestations and Presentation of Diseases FIGURE e11-3 Hypochromic microcytic anemia of iron deficiency. 2005. Abnormal cells may appear in the blood. Note large red cells with light purple coloring. RS Hillman. the layer of cells that is visible on top of sedimenting red cells when blood is left in the test tube for an hour. Monocytes are the largest white blood cells. Smears made from finger sticks may include rare endothelial cells. FIGURE e11-1 Normal peripheral blood smear. New York. More rarely. About 1% of the lymphocytes are larger and contain blue granules in a light blue cytoplasm. The nucleus can take on a variety of shapes but usually appears to be folded.e78 are called reactive lymphocytes. New York. 4th edition. Small lymphocyte in center of field. Note that the diameter of the red blood cell is similar to the diameter of the small lymphocyte nucleus. Hematology in General Practice. Microcytes (right panel ) are smaller than normal red blood cells (cell diameter < 7 μm) and may or may not be poorly hemoglobinized (hypochromic). the small lymphocytes are increased in number. All rights reserved. these are called smudge cells and are rare in the absence of chronic lymphoid leukemia. . KA Ault. Most often the abnormal cells originate from neoplasms of bone marrow–derived cells including lymphoid cells. FIGURE e11-2 Reticulocyte count preparation.

Small lymphocyte in center of field. FIGURE e11-11 Fragmented red cells. FIGURE e11-10 Red cell agglutination. Heart valve hemolysis. Small lymphocyte and segmented neutrophil upper left center. Hypersegmented neutrophils (multilobed polymorphonuclear leukocytes) are larger than normal neutrophils with five or more segmented nuclear lobes. . FIGURE e11-7 Hypersegmented neutrophils. These red cells align themselves in stacks and are related to increased serum protein levels. FIGURE e11-8 Spherocytosis. Copyright © 2008 The McGraw-Hill Companies.” FIGURE e11-9 Rouleaux formation. Note irregular collections of aggregated red cells. Some morphologists call these cells “macroovalocytes.e79 CHAPTER e11 Atlas of Hematology and Analysis of Peripheral Blood Smears FIGURE e11-6 Macrocytosis. They are commonly seen with folic acid or vitamin B12 deficiency. Note small hyperchromatic cells without the usual clear area in the center. All rights reserved. These cells are both larger than normal (mean corpuscular volume > 100) and are somewhat oval in shape.

Homozygous sickle cell disease. This is often seen as an artifact in a dehydrated blood smear. Howell-Jolly bodies are tiny nuclear remnants that are normally removed by the spleen. These cells can be seen in hemolytic anemias and in conditions in which the red cell is overhydrated or dehydrated. and in rare patients with McLeod blood group. A nucleated red cell and neutrophil are also in the field. usually due to mutations in spectrin. Copyright © 2008 The McGraw-Hill Companies. FIGURE e11-16 Acanthocytosis. FIGURE e11-17 Howell-Jolly bodies. Red cells characterized by a wide transverse slit or stoma. Echinocytes are found in patients with severe uremia. Acanthocytes are present in severe liver disease. Spiculated red cells are of two types: acanthocytes are contracted dense cells with irregular membrane projections that vary in length and width. and evenly spaced membrane projections. FIGURE e11-13 Target cells. FIGURE e11-15 Stomatocytosis. They appear in the blood after splenectomy (defect in removal) and with maturation/dysplastic disorders (excess production). Small lymphocyte in center of field. uniform. Target cells are recognized by the bull’seye appearance of the cell. echinocytes have small. All rights reserved. FIGURE e11-14 Elliptocytosis. Elliptical shape of red cells related to weakened membrane structure. . in patients with abetalipoproteinemia.e80 PART 2 Cardinal Manifestations and Presentation of Diseases FIGURE e11-12 Sickle cells. in glycolytic red cell enzyme defects. Larger numbers are typical of hemoglobin C disease. Small numbers of target cells are seen with liver disease and thalassemia. and in microangiopathic hemolytic anemia.

FIGURE e11-20 Reticulin stain of marrow myelofibrosis. Blood mixed with hypotonic solution of crystal violet. together with a marked increase in the platelet count. Coarsely stippled red cell. FIGURE e11-23 Giant platelets. Mild hypochromia. The stained material is precipitates of denatured hemoglobin within cells. especially primary thrombocythemia. are seen in myeloproliferative disorders. FIGURE e11-21 Stippled red cell in lead poisoning. A teardrop-shaped red blood cell (left panel ) and a nucleated red blood cell (right panel ) as typically seen with myelofibrosis and extramedullary hematopoiesis. FIGURE e11-22 Heinz bodies. Giant platelets. . FIGURE e11-19 Myelofibrosis of the bone marrow. All rights reserved.e81 CHAPTER e11 Atlas of Hematology and Analysis of Peripheral Blood Smears FIGURE e11-18 Teardrop cells and nucleated red blood cells characteristic of myelofibrosis. Total replacement of marrow precursors and fat cells by a dense infiltrate of reticulin fibers and collagen (H&E stain). Copyright © 2008 The McGraw-Hill Companies. Silver stain of a myelofibrotic marrow showing an increase in reticulin fibers (black-staining threads).

N. Döhle bodies are discrete. They represent aggregates of rough endoplasmic reticulum. fine neutrophilic granules are dispersed throughout the cytoplasm. or “pince-nez” configuration. neutrophil. Neutrophil band with Döhle body. blue-staining nongranular areas found in the periphery of the cytoplasm of the neutrophil in infections and other toxic states. FIGURE e11-25 Normal monocytes. PART 2 Cardinal Manifestations and Presentation of Diseases FIGURE e11-27 Normal basophil. The film was prepared from the buffy coat of the blood from a normal donor. the majority of granulocytes are bilobed. L. The film was prepared from the buffy coat of the blood from a normal donor. FIGURE e11-26 Normal eosinophils. basophil. clumped chromatin. FIGURE e11-30 Chédiak-Higashi disease. FIGURE e11-29 Döhle body. All rights reserved.e82 FIGURE e11-24 Normal granulocytes. E. N. B. The neutrophil with a sausage-shaped nucleus in the center of the field is a band form. neutrophil. Note giant granules in neutrophil. lymphocyte. . L. Copyright © 2008 The McGraw-Hill Companies. FIGURE e11-28 Pelger-Hüet anomaly. The nucleus frequently has a spectacle-like. In this benign disorder. M monocyte. eosinophil. The normal granulocyte has a segmented nucleus with heavy. lymphocyte. The film was prepared from the buffy coat of the blood from a normal donor.

All rights reserved. showing a mix of fat cells (clear areas) and hematopoietic cells. Note the characteristic paratrabecular location of the lymphoma cells. Marrow aspirate specimen showing a myeloid/erythroid ratio of ≥3:1. FIGURE e11-32 Aplastic anemia bone marrow. suggesting either a loss of red blood cell precursors or an expansion of myeloid elements. Marrow aspirate specimen with a myeloid/erythroid ratio (M/E ratio) of 1:1–2. Copyright © 2008 The McGraw-Hill Companies. In adults. FIGURE e11-36 Myeloid hyperplasia of the marrow. Nodular (follicular) lymphoma infiltrate in a marrow biopsy specimen. Marrow biopsy specimen infiltrated with metastatic breast cancer and reactive fibrosis (H&E stain). As we age. . Normal hematopoietic precursor cells are virtually absent. reticuloendothelial cells. normal marrow cellularity is 35–40%. the marrow cellularity decreases and the marrow fat increases. FIGURE e11-33 Metastatic cancer in the bone marrow.e83 CHAPTER e11 Atlas of Hematology and Analysis of Peripheral Blood Smears FIGURE e11-31 Normal bone marrow. Low-power view of normal adult marrow (H&E stain). typical for a patient with a hemolytic anemia or recovering from blood loss. cellularity may increase to meet the demand. FIGURE e11-35 Erythroid hyperplasia of the marrow. FIGURE e11-34 Lymphoma in the bone marrow. Patients >70 years may have a 20–30% marrow cellularity. leaving behind fat cells. and the underlying sinusoidal structure. The percentage of the space that is hematopoietic cells is referred to as marrow cellularity. If demands for increased marrow production occur.

Note giant dysmorphic erythroblasts. Maturation is delayed with late normoblasts showing a more immature appearing nucleus with a lattice-like pattern with normal cytoplasmic maturation. . FIGURE e11-41 Acute promyelocytic leukemia. Iron stores can be graded on a scale of 0 to 4+. C: minimal stores (1+). prominent nucleoli in each cell. Copyright © 2008 The McGraw-Hill Companies. High-power view of megaloblastic red blood cell precursors from a patient with a macrocytic anemia. Note two to four large. FIGURE e11-38 Prussian blue staining of marrow iron stores. Note prominent cytoplasmic granules in the leukemia cells. and D: absent iron stores (0). All rights reserved. An orthochromatic normoblast with a collar of blue granules (mitochondria encrusted with iron) surrounding the nucleus. FIGURE e11-40 Acute myeloid leukemia. B: normal stores (2–3+). Leukemic myeloblast with an Auer rod. A: a marrow with excess iron stores (>4+).e84 PART 2 Cardinal Manifestations and Presentation of Diseases FIGURE e11-37 Megaloblastic erythropoiesis. two are binucleate and one is multinucleate. FIGURE e11-39 Ringed sideroblast. FIGURE e11-42 Acute erythroleukemia.

Nodules vary in size and contain predominantly small lymphocytes with cleaved nuclei along with variable numbers of larger cells with vesicular chromatin and prominent nucleoli. All rights reserved. acute lymphoblastic leukemia. The normal nodal architecture is effaced by nodular expansions of tumor cells. FIGURE e11-47 Sézary’s syndrome. FIGURE e11-48 Adult T cell leukemia.e85 CHAPTER e11 Atlas of Hematology and Analysis of Peripheral Blood Smears FIGURE e11-43 Acute lymphoblastic leukemia. . FIGURE e11-46 Chronic lymphoid leukemia in the peripheral blood. FIGURE e11-44 Burkitt’s leukemia. Lymphocytes with frequently convoluted nuclei (Sézary cells) in a patient with advanced mycosis fungoides. FIGURE e11-45 Chronic myeloid leukemia in the peripheral blood. Copyright © 2008 The McGraw-Hill Companies. Peripheral blood smear showing leukemia cells with typical “flower-shaped” nucleus. FIGURE e11-49 Follicular lymphoma in a lymph node.

FIGURE e11-52 Erythrophagocytosis accompanying aggressive lymphoma. The lighter areas are macrophages attempting to clear dead cells. PART 2 Cardinal Manifestations and Presentation of Diseases FIGURE e11-51 Burkitt’s lymphoma in a lymph node. The majority of the cells are normal lymphocytes. FIGURE e11-55 Normal plasma cell. Fukuoka. Japan. and eosinophils that form a pleiomorphic cellular infiltrate. A Reed-Sternberg cell is present near the center of the field. All rights reserved. Burkitt’s lymphoma with starry-sky appearance. neutrophils. Kiyomi Tsukimori. . Kyushu University. (Courtesy of Dr.) FIGURE e11-54 Lacunar cell. and platelets. Reed-Sternberg cell variant in nodular sclerosing Hodgkin’s disease. a large cell with a bilobed nucleus and prominent nucleoli giving an “owl’s eyes” appearance. High-power view of single mononuclear lacunar cell with retracted cytoplasm in a patient with nodular sclerosing Hodgkin’s disease. The central macrophage is ingesting red cells. neutrophils. The neoplastic cells are heterogeneous but predominantly large cells with vesicular chromatin and prominent nucleoli. Copyright © 2008 The McGraw-Hill Companies. FIGURE e11-53 Hodgkin’s disease.e86 FIGURE e11-50 Diffuse large B cell lymphoma in a lymph node.

. All rights reserved.e87 CHAPTER e11 Atlas of Hematology and Analysis of Peripheral Blood Smears FIGURE e11-56 Multiple myeloma. The distinctive red coloration of plasma (hemoglobinemia) in a spun blood sample in a patient with intravascular hemolysis. FIGURE e11-57 Color serum in hemoglobinemia. Copyright © 2008 The McGraw-Hill Companies.

.

It is the site to which bone marrow precursors that are committed to differentiate into T cells migrate to complete their differentiation. stage III. The cortex of the thymus contains ~85% of the lymphoid cells and the medulla ~15%. stage III tumors are divided into A and B based upon whether disease was subtotally resected or only biopsied. stage II.” below). The majority of lymphoid tumors that develop in the thymus are derived from the precursor T cells. The French Study Group on Thymic Tumors (GETT. Like many organs. and B1 tumors are localized. Thymomas are most common in the fifth and sixth decades. PATHOLOGY AND ETIOLOGY Thymomas are epithelial tumors and all of them have malignant potential. % 86–100 5–100 47–60 0–11 Source: From A Masaoka et al: Cancer 48:2485. However. 1998) has proposed modifications to the Masaoka scheme based upon the degree of surgical removal because the extent of surgery has been noted to be a prognostic indicator. 310). 96%. Carcinoid tumors. If a lymphoid cell within the thymus becomes neoplastic.g. but thymic abnormalities are very rare. but the re- Copyright © 2008 The McGraw-Hill Companies. About 30% of patients with thymoma have myasthenia gravis. 70% of patients with thymoma were found to have another systemic illness (Souadjian et al. it is organized into functional regions—in this case. the disease that develops is a lymphoma. It is not worthwhile to try to divide them into benign and malignant forms. based on aberrant migration of the developing thymic enlage. Thymomas and lymphomas require sufficient tissue to examine the tumor architecture to assure an accurate diagnosis and obtain prognostic information. neoadjuvant chemotherapy may be warranted before surgery (see “Treatment. the key prognostic feature is whether they are noninvasive or invasive. 1999). stage IV. the tumor that develops is a thymoma. and thymic cysts may also produce radiographic masses. and panhypopituitarism. Once a diagnosis of thymoma is defined. MRI has a defined role in the staging of posterior mediastinal tumors.e12 Thymoma Dan L. and when these become neoplastic. DiGeorge syndrome. wheezing. night sweats. 1974). The thymus is composed of epithelial and stromal cells derived from the pharyngeal pouch and lymphoid precursors derived from mesodermal cells. are uncommon in children. 69%. or pleura but not the great vessels Macroscopic invasion into neighboring organs that includes great vessels Microscopic invasion outside of the capsule Macroscopic invasion into surrounding fat or grossly adherent to pleura or pericardium e89 Diagnostic Criteria Macroscopically and microscopically completely encapsulated. 105). Thymic carcinomas are invasive and carry a poor prognosis. The 5-year survival of patients in the various stages is as follows: stage I. systemic lupus erythematosus. The concurrence between the two systems is high. If invasion is present.. The epithelial component of the tumor may consist primarily of round or oval cells derived mainly from the cortex or spindle-shaped cells derived mainly from the medulla or combinations thereof (Table e12-2). germ cell tumors. Longo TABLE e12-1 MASAOKA STAGING SYSTEM FOR THYMOMAS Stage I II IIA IIB III IIIA IIIB IV IVA IVB Pleural or pericardial dissemination Lymphatic or hematogenous metastases Macroscopic invasion into neighboring organs. ulcerative colitis. However. accounting for ~40% of all mediastinal masses. 50%. When symptomatic. 1981. but genetic studies suggest that the lymphocytes are benign polyclonal cells. the cortex and the medulla. fatigue. the tumor is a mediastinal (thymic) B cell lymphoma (Chap. no invasion through capsule The thymus is derived from the third and fourth pharyngeal pouches and is located in the anterior mediastinum. Cytologic features are not reliable predictors of biological behavior. Chap. It is an anatomic system in which the stage is increased based on the degree of invasiveness. serious deficiencies in T cell development ensue and severe immunodeficiency is seen (e. chest CT scans can assess local invasiveness in some instances. If invasion is not distinguished by noninvasive testing. In one series. 105). About 90% of A. Rare B cells exist in the thymus. They may have a variable percentage of lymphocytes within the tumor. The genetic lesions in thymomas are not well characterized. The other major causes of anterior mediastinal mass are lymphomas. and ~5% have hypogammaglobulinemia. About 40% of patients with thymoma have another systemic autoimmune illness related to the thymoma. In their system. % 95–100 70–100 50–70 11–50 10-Year Survival. If the thymus does not develop properly. masses are detected incidentally on routine chest radiographs. . lipomas. Some data suggest that Epstein-Barr virus may be associated with thymomas (Dimery et al. and are distributed evenly between men and women. thymomas may obstruct the superior vena cava. molecular pathogenesis remains undefined. but it is not yet clear that it adds impor- CHAPTER e12 Thymoma Stage Distribution. Germ cell tumors and carcinoid tumors may occasionally arise in the thymus. patients may have cough. Thymoma more rarely may be associated with polymyositis. thyroiditis. About 40–50% of patients are asymptomatic. tant information to the CT scan in anterior mediastinal tumors. Addison’s disease. weight loss. chest pain. The staging system for thymoma was developed by Masaoka and colleagues (Table e12-1). and the tumor is a precursor T cell lymphoblastic lymphoma (Chap. An initial mediastinoscopy or limited thoracotomy can be undertaken to get sufficient tissue to make an accurate diagnosis. 1988). pericardium. Somatostatin receptor imaging with indium-labeled somatostatin analogues may be of value (Lin et al. an effort to resect the entire tumor should be undertaken. and substernal thyroid tumors. AB. or anorexia. Several things can go wrong with the thymus. Occasionally. A very small number of patients have aggressive histology features characteristic of carcinomas. CLINICAL PRESENTATION AND DIFFERENTIAL DIAGNOSIS Thymoma is the most common cause of an anterior mediastinal mass in adults. Fine-needle aspiration is poor at distinguishing between lymphomas and thymomas but is more reliable in diagnosing germ cell tumors and metastatic carcinoma. scleroderma. 86%. dyspnea. All rights reserved. fever. subsequent staging generally occurs at surgery. Among patients with myasthenia gravis. A thymoma susceptibility locus has been defined on rat chromosome 7. Medullary thymocytes have a phenotype that cannot readily be distinguished from mature peripheral blood and lymph node T cells. 5–8% have pure red cell aplasia. ~10–15% have a thymoma. Some tumors overexpress the p21 ras gene product. If the epithelial cells of the thymus become neoplastic. % I II III IV 65 25 5 5 5-Year Survival. a surgical procedure is required for definitive diagnosis. but some may be in other mediastinal sites or even the neck. Cowen et al. About 65% of thymomas are encapsulated and noninvasive and about 35% are invasive. stage I tumors are divided into A and B based on whether the surgeon suspects adhesions to adjacent structures. Sjögren’s syndrome. Some 90% of thymomas are in the anterior mediastinum. pernicious anemia. It appears that the primitive bone marrow progenitors enter the thymus at the corticomedullary junction and migrate first through the cortex toward the periphery of the gland and then toward the medulla as they mature. DIAGNOSIS AND STAGING Once a mediastinal mass is detected.

About 10% of patients with hypogammaglobulinemia have a thymoma. PART 6 Oncology and Hematology FURTHER READINGS BRIL V et al: The long-term clinical outcome of myasthenia gravis in patients with thymoma. cisplatin. 1998). Thymectomy produces at least some symptomatic improvement in ~65% of patients with myasthenia gravis. Clin Nucl Med 24:24. Thymectomy results in the resolution of pure red cell aplasia in ~30% of patients. and prednisone. and one patient whose c-kit locus was mutated responded dramatically to imatanib. lationship between this gene locus. Three cycles were given in 3to 4-week intervals. This multimodality approach appears to be superior to the use of surgery followed by radiation therapy alone. the use of neoadjuvant chemotherapy followed by radical surgery. 100 mg/d on days 1–5. continuous-infusion doxorubicin. 1999 [PMID: 9890489] PETRIE HT: Cell migration and the control of post-natal T-cell lymphopoiesis in the thymus. It is thought that the thymus plays a role in breaking self-tolerance and generating T cells that recognize the acetylcholine receptor as a foreign antigen. 1998 [PMID: 9781560] COWEN D et al: Natural history and treatment of malignant thymoma. Octreotide plus prednisone produces responses in about one-third of patients. which produces a 5-year survival of ≤50% in patients with advanced-stage disease. Type A AB B1 B2 B3 C Distribution. Survival at 7 years is 100%. but hypogammaglobulinemia rarely responds to thymectomy. Although patients with thymoma and myasthenia gravis are less likely to have a remission in the myasthenia as a consequence of thymectomy than are patients with thymic abnormalities other than thymoma. About 30–50% of patients with pure red cell aplasia have a thymoma. . 1974 [PMID: 4602050] WRIGHT CD: Management of thymomas. tumor was completely resected in nine and incompletely resected in two patients (one patient refused surgery and received radiation therapy only). complete resection is usually followed by 30–60 Gy of postoperative radiation therapy to the site of the primary tumor. 10 of the 12 patients were free of disease. At a median follow-up of 43 months. World Health Organization. Nat Rev Immunol 3:859. After surgery. Arch Intern Med 134:374. and 1 had a minor response. and the 2 patients who had local recurrence remain alive with disease. 2005 [PMID: 15725919] LIN K et al: Somatostatin receptor scintigraphy and somatostatin therapy in the evaluation and treatment of malignant thymoma. but the antibodies to the receptor and kinase inhibitors that block its action have not been systematically evaluated. INFLUENCE OF THYMECTOMY ON THE COURSE OF ACCOMPANYING DISEASES Patients with myasthenia gravis have a high incidence of thymic abnormalities (~80%) but overt thymoma is present in only ~10–15% of patients with myasthenia gravis. % 100 100 83 83 36 28 aWHO. complete resection is sufficient to cure 96% of patients. and additional consolidation chemotherapy has been associated with excellent survival in a small group of patients so treated (Shin et al. Oncology 12:1001. 1998 [PMID: 2835144] GIACCONE G: Treatment of malignant thymoma. For patients with stage III and IV disease. 30 mg/m2 per day on days 1–3 (total 90 mg/ m2). Many thymomas express epidermal growth factor receptors. THYMOMA Treatment is determined by the stage of disease. termed Tsr1. 1998 [PMID: 9669967] SOUADJIAN JV et al: The spectrum of diseases associated with thymoma. Induction chemotherapy consisted of cyclophosphamide 500 mg/m2 on day 1. 20 mg/m2 per day on days 1–3 (total 60 mg/m2). the course of myasthenia gravis is not significantly different in patients with or without thymoma (Bril et al. 8 had partial responses. These patients then underwent surgical resection. All rights reserved. all patients received radiation therapy (50–60 Gy) and three additional courses of chemotherapy at 80% of the doses used for neoadjuvant therapy. and human thymoma has not yet been examined. Crit Rev Oncol Hematol 64. Neurology 51:1198. Cancer 61:2475. For patients with stage II disease. For patients with encapsulated tumors and stage I disease. 1998 [PMID: 9684271] DIMERY IW et al: Association of Epstein-Barr virus with lymphoepithelioma of the thymus. % 8 17 27 8 12 28 Prognosis (10-year disease-free survival). radiation therapy. 3 had complete responses. 2003 [PMID: 14668802] SHIN DM et al: A multidisciplinary approach to therapy for unresectable malignant thymoma. Curr Opin Oncol 17:140. Of 12 patients treated with this regimen.e90 TABLE e12-2 WHO HISTOLOGIC CLASSIFICATION OF THYMUS TUMORS a Type A AB B1 B2 B3 C Histologic Description Medullary thymoma Mixed thymoma Predominantly cortical thymoma Cortical thymoma Well-differentiated thymic carcinoma Thymic carcinoma Some thymic carcinomas express c-kit. 2007 [PMID: 17570676] Copyright © 2008 The McGraw-Hill Companies. 1998). Ann Intern Med 129:100.

advanced age. to the uncertainty associated with changing a treatment that is known to work before having a replacement that works as well. Problems may be related to the cancer itself (e. and localized solid tumors have identified the features of >550 mg/m2 of doxorubicin will develop congestive heart failure cancer treatment that are associated with later morbidity and mortality. the risk of late complicatrastuzumab tions should not lead to the failure to apply poLung Bleomycin Pulmonary fibrosis tentially curative treatment. Bone Glucocorticoids Osteoporosis. Radiation therapy can damage organ function directly (salivary gland toxicity leading to dry mouth and dental caries). patients with primary cancers of the head and neck are at increased risk for subsequent lung cancer) or to the normal aging process (surviving one cancer does not necessarily alter the risk of other common tumors that increase in frequency with age). Adhesions Risk of obstruction would inform clinicians who assume the care Bowel anastomoses Malabsorption syndromes of cancer survivors of their previous treatRadiation Therapy Effect ments.Most anthracyclines damage the heart muscle. Drug toxicities and radiation therapy toxicities are discussed in Chap. coronary artery disease short. and treatment Salivary glands Dry mouth. avascular necrosis Late problems occurring in cured patients reBrain Methotrexate. including Intestine Malabsorption. psychosocial disturbances. the physiAny Secondary neoplasia cian(s) responsible for monitoring. and any Chemotherapy Effect identified psychosocial issues or concerns. dysgeusia received. others Decreased function. and childhood cancers. Therapy may produce subclinical damage that may only become recognized in the presence of a second inciting factor (such as the increased incidence of melanoma in patients with dysplastic nevus syndrome treated for Hodgkin’s disease with radiation therapy). who have published a monoAmputation Functional loss Lymph node dissection Risk of lymphedema graph on this subject—From Cancer Patient to Ostomy Psychosocial impact Cancer Survivor: Lost in Transition.CARDIOVASCULAR DYSFUNCTION pleteness of follow-up. Suggestions for monitoring for late toxKidney Decreased function.Consequences e13 Late Its Treatment of Cancer and Michael C. Organ An “End-of-Treatment Consultation Note” Bone Premature termination of growth. hypertension. and many will experience long-term complications. many of the problems affecting cured patients are related to the treatments. osteonecrosis would include the date. Infertility. ara-C. 81. All rights reserved. myocarditis. The challenge is to Methotrexate Pulmonary hypersensitivity Kidney Platinum. tes. Because of heterogeneity in treatment details and incom. physician’s name.eventually ventricular failure ensues. Cancer chemotherapy can produce damage to the bone marrow and immune system and induce a spectrum of organ dysfunctions. Neuropathy. premature menopause illness. fibrosis Brain Neuropsychiatric deficits. acute leukemia. act as a carcinogen (second solid tumors in radiation ports). lymphomas. (CHF). stricture recommendations for surveillance for recurGonads Infertility. cancer and its treatment are associated with psychosocial problems that can impair the survivor’s ability to adapt to life after cancer. hearing loss lems never develop in those who do not taxanes survive the cancer. stage. cognitive dysfunction of tissue diagnosis.” if uniformly carried out.and long-term effects of treatment deLung Pulmonary fibrosis tailed. cognitive decline? flect the success of such treatment. diagnosis. Surgical Bone marrow Various Aplasia. secondary leukemia procedures can create abnormal physiology Copyright © 2008 The McGraw-Hill Companies. others The mechanisms of damage vary. pathologic Thyroid Hypothyroidism. unusual or unexpected Eyes Cataracts toxicities would be noted and the expected Heart Pericarditis..g. TABLE e13-1 LATE EFFECTS OF CANCER THERAPY Survivorship issues have been addressed by Surgical Procedure Effect the Institute of Medicine and the National Research Council. The first task in a newly diagnosed patient is Organ Drug always to eradicate the diagnosed malignancy. guidelines for intervention. Late effects by treatment modality are shown in Table e13-1. and inability to find employment or insurance. Perry. (such as blind loops leading to malabsorption) or interfere with nor. myelodysplasia. where established. and. Morbidity and mortality Eyes Glucocorticoids Cataracts from iatrogenic disease should be avoided. hypertension Liver Decreased function icity should be given as well. A dose-dependent ted for many years. some treatment-related problems went undetec. Coexisting cardiac disease. premature menopause rence and second malignancies. Graves’ disease. and We have been somewhat slow to act in changing those aspects of prima.concomitant therapy with thoracic radiation therapy may hasten the ry treatment that contribute to these late problems. Finally. Individuals carefully followed for periods up to 30 years have taught us the spectrum of problems that can be CONSEQUENCES BY ORGAN SYSTEM encountered. studies of long-term survivors of dropout of myocardial cells is seen on endomyocardial biopsy. cancer findings. Their “SurSplenectomy Risk of sepsis vivorship Care Plan. however. signs and symptoms of late effects. including medical problems. In addition. caries. Dan L. This reticence is due onset of CHF. hypomagnesemia preserve or augment the cure rate while deLiver Various Altered function creasing the risk of serious treatment-related Gonads Alkylating agents. if Heart Anthracyclines. sexual dysfunction. Hodgkin’s disease. Longo Over 9 million Americans alive today have had cancer. Virtually all of these survivors will bear some mark of their diagnosis and its therapy. initial treatment plan. date Soft tissues Atrophy. However. Neuropsychiatric deficits. CHAPTER e13 Late Consequences of Cancer and Its Treatment . or promote accelerated aging-associated changes (atherosclerosis). About 5% of patients who receive ticular cancer. These probothers Peripheral nerves Vincristine. Anthracycline-induced CHF is not readily reversible.e91 mal organ function (splenectomy leading to impaired immune response). However. Cardiomyopathy possible. platinum.

hepatic venoocclusive disease is more common with high-dose therapy. Mediastinal radiation therapy that includes the heart can induce acute pericarditis. preexisting lung disease. are recognized complications of the successful therapy of childhood acute lymphoblastic leukemia. commonly lose both fertility and hormone production. A dose-related hearing loss can occur with the use of cisplatin. but not always. ENDOCRINE DYSFUNCTION Long-term survivors of childhood cancer who received cranial irradiation are shorter. an intracellular iron chelator. All rights reserved. The premature induction of menopause in a young woman can have serious medical and psychological consequences. The phenomenon has not yet been documented in adequately designed studies that take into account the normal age-associated decline in cognition. followed by Graves’ disease. reversible. LIVER DYSFUNCTION Clinically significant long-term damage to the liver from standarddose chemotherapy is relatively infrequent and mostly confined to patients who have received chronic methotrexate for maintenance therapy of acute lymphoblastic leukemia. NERVOUS SYSTEM DYSFUNCTION Although many patients experience peripheral neuropathy during chemotherapy. . Pericardial effusion may be present. Suicidal symptoms are reported by a significant minority of adult survivors of childhood cancer and represent treatable conditions requiring follow-up care. chemotherapy may produce infertility. perhaps because they have other coexisting diseases such as diabetes mellitus. Without saliva. Thyroid disease is common in patients who have received radiation therapy to the neck. Concern about antagonism of antitumor effects has restricted its use. and cancer. and the age of the child at the time of therapy. with potential exacerbation by age. This is irreversible. EYES Cataracts may be caused by chronic glucocorticoid use. Such patients should have frequent measurement of thyroid-stimulating hormone (TSH) levels to detect hypothyroidism early and suppress the TSH drive. or accelerated premature coronary atherosclerosis. Although rarely seen with standard-dose chemotherapy. Adjustment to normal expectations can be difficult. usually with doses >400 mg/m2. Women. such as that given to prepare patients for autologous or allogeneic stem cell transplantation. scoliosis. smaller amounts of chemotherapy will produce ovarian failure. especially following high-dose therapy such as that involved in hematopoietic stem cell transplantation. cognitive decline (“chemo brain”) can follow the use of adjuvant chemotherapy in women being treated for breast cancer. high concentrations of inhaled oxygen. such as those used before hematopoietic stem cell transplantation. Cognitive decline has been attributed to CNS radiation in the treatment of a variety of tumor types. Administration of doxorubicin by continuous intravenous infusion or encapsulated in liposomes appears to decrease the risk of heart damage. patients may be asymptomatic or have dyspnea on exertion. Radiation doses to the liver >1500 cGy can produce liver dysfunction. fever. myocardial fibrosis. Endothelial damage is probably the inciting event. and the concomitant use of other chemotherapeutic agents. with an incidence of up to 62% at 26 years post-therapy. Neurocognitive sequelae from intrathecal chemotherapy. prevention is the best approach. As a woman nears menopause. radiation of the carotids is associated with premature atherosclerosis of the carotids and can produce central nervous system (CNS) embolic disease. The obesity may be related to alterations in leptin biology. RAYNAUD’S PHENOMENON Up to 40% of patients with testicular cancer treated with bleomycin may experience Raynaud’s phenomenon varying in severity from mild and transient to severe. Similarly. only a few have chronic problems. it is usually asymptomatic but may render the patient more susceptible to other renal insults. In addition. MUSCULOSKELETAL DYSFUNCTION Late consequences of radiation therapy on the musculoskeletal system occur mostly in children and are related to the radiation dose. and several can cause pulmonary venoocclusive disease. which may contribute to thyroid cancer. and. Hypothyroidism is the most common abnormality. At very high doses. The mechanism is unknown. however. it is usually reversible with the cessation of therapy. and many patients have PART 6 Oncology and Hematology Copyright © 2008 The McGraw-Hill Companies. volume of tissue irradiated. particularly the alkylating agents. Compromised ejection fraction is noted in about 10% of patients. and short stature. The extent of the damage depends upon the patient’s age and the total dose administered. Chronic constrictive pericarditis can develop 5–10 years after treatment and usually presents with dyspnea on exertion. Dexrazoxane. Myocardial fibrosis may present as unexplained CHF with diagnostic evaluation showing restrictive cardiomyopathy. and coping with the usual stresses of daily life. valvular abnormalities. Trastuzumab (herceptin) has been associated with heart failure. and bone mineral density. cyclophosphamide can produce a hemorrhagic myocarditis. High doses of cisplatin can produce severe sensorimotor neuropathy. staying in a stable relationship. producing dry mouth. Patients who receive mantle field radiation therapy have a threefold increased risk of fatal myocardial infarction. with a peak about 9 months after treatment. thoracic radiation. ORAL COMPLICATIONS Radiation therapy can damage the salivary glands. a Fanconi-like syndrome that is usually. The incidence of acute pericarditis is 5–13%. may protect the heart against anthracycline toxicity by preventing iron-dependent free-radical generation.e92 mortality is as high as 50%. rarely. particularly in patients also receiving anthracyclines. Patients may have aortic insufficiency from valvular thickening or mitral regurgitation from papillary muscle dysfunction. more likely to be obese. thyroiditis. Vincristine may produce permanent numbness and tingling in the fingers and toes. and chest pain. Many patients suffer intrusive thoughts about cancer recurrence for many years after successful treatment. PULMONARY DYSFUNCTION Pulmonary fibrosis from bleomycin is dose-related. dental caries develop. by tamoxifen. thus. The gonads may also be permanently damaged by radiation therapy or by chemotherapeutic agents. Because the agents are given at modest doses and are not thought to cross the blood-brain barrier. Paroxetine and related drugs may be useful in controlling hot flashes. Cyclophosphamide cystitis may eventually lead to the development of bladder cancer. Mitoxantrone is a related drug that has less cardiac toxicity. Growth hormone deficiency is the most common hormone deficiency. the mechanism of the cognitive decline is not defined. Damage to the microvasculature of the epiphyseal growth zone may result in leg length discrepancy. RENAL/BLADDER DYSFUNCTION Reduced renal function may be produced by cisplatin. and have reductions in strength. chronic constrictive pericarditis. with or without radiation therapy. The onset is insidious. In men. Ifosfamide produces cystitis and a proximal tubular defect. exercise tolerance. but hormone production is not usually affected. radiation therapy to the head. Cancer survivors may often have more problems holding a job. such as patients with Hodgkin’s disease. Hormone replacement therapy is controversial. SEXUAL AND REPRODUCTIVE DYSFUNCTION Reversible azoospermia can be caused by many chemotherapy agents. Several other chemotherapy agents and radiation therapy can cause pulmonary fibrosis. and patients should be screened with audiometric examinations periodically during such therapy.

and it usually occurs 1. non-Hodgkin’s lymphomas. All rights reserved. Scoliosis and/or delayed growth due to radiation of the skeleton are more common. and those caused by chemotherapy. Patients who were treated with radiation therapy should be carefully examined on an annual basis and evaluated for any abnormalities in organs and tissues that were in the radiation field. Patients cured of Hodgkin’s disease seem to experience greater fatigue. In none of these examples does it appear that treatment of the primary cancer is the cause of the secondary cancer. The first occurs in patients treated with alkylating agents. About one-third of long-term survivors have moderate Copyright © 2008 The McGraw-Hill Companies. Usually these tumors are found at an early stage. Patients with head and neck cancers are at increased risk of developing a lung or esophageal cancer.or radiation-induced cardiomyopathy and acute leukemia. and in the lungs due to radiation therapy. HEAD AND NECK CANCER Patients frequently have poor dentition. CHAPTER e13 Late Consequences of Cancer and Its Treatment CONSEQUENCES BY CANCER TYPE PEDIATRIC CANCERS Quality of life is often excellent. TESTICULAR CANCER Depending on the modalities used for therapy. Those with nasopharyngeal cancer report the poorest long-term quality of life. to severe problems. while solid tumors are more likely to be seen with the use of radiation therapy. Patients treated with radiation therapy have an increasing and apparently lifelong risk of developing second solid tumors. Second malignancies can be grouped into three categories: those associated with the primary cancer.poor dentition. These predispositions should result in heightened surveillance in persons at risk. Those patients who have received chemotherapy may be at risk from doxorubicin. are at increased risk of second cancers of specific types. postsplenectomy sepsis. and retrograde ejaculation from retroperitoneal lymph node dissection. The incidence is <1%. Tamoxifen induces endometrial cancer in about 1–2% of women taking it for 5 years or longer. The major risk factor for hematologic malignancies is treatment with alkylating agents plus radiation therapy. possibly related to the volume of disease that is radiated. Cognitive function may be impaired. taste can be adversely affected and appetite can be suppressed. . and second malignancies. The second malignancies encountered include myelodysplasia and acute myeloid leukemia. Two types of acute leukemia have been described. and gut epithelium. Both forms of acute leukemia are highly refractory to treatment. mortality from endometrial cancer is very low compared to the benefit from tamoxifen use as adjuvant therapy in women with breast cancer. Functional impairments in the cardiovascular system due to radiation therapy and anthracyclines. and vice versa. and poor nutrition. Many survivors have psychosocial and sexual problems. Patients with Hodgkin’s disease are at increased risk of non-Hodgkin’s lymphoma. Second malignant neoplasms are a significant cause of death. SECOND MALIGNANCIES Second malignancies are a major cause of death for those cured of cancer. and melanoma. and infertility. In rare patients. are rare. STEM CELL TRANSPLANTATION Cured patients are at risk of second cancers. The development of premature ovarian failure from chemotherapy may cause hormone-deficient symptoms (hot flashes. The chances of curing the second malignancies hinge on early diagnosis. trismus. do not protect against osteoporosis and may increase the risk of this complication. The second type of acute leukemia occurs after exposure to topoisomerase II inhibitors such as doxorubicin or etoposide. dry mouth. especially over a protracted period. although the majority have at least one late effect. The alternatives to tamoxifen. Primary cancers increase the risk of secondary cancers in a number of settings. gonadal dysfunction. subnormal growth. but those <30 have a 19-fold increased risk. Sexual dysfunction is reported by 15% of patients cured of testicular cancer. with an immune-mediated attack against the skin. The lifetime risk is about 2%. They are also subject to gonadal damage and infertility. usually in or adjacent to the radiation field. BREAST CANCER Patients treated with adjuvant chemotherapy and/or hormonal therapy for breast cancer are at risk for endometrial cancer from the use of tamoxifen. those caused by radiation therapy. women receiving chest radiation therapy after age 30 have a small increased risk of breast cancer. such as multiple endocrine neoplasia type 1 or Lynch syndrome. such that populations followed for 25 years or more have a ≥25% chance of developing a second treatment-related tumor. dyspareunia) and places women at risk for osteoporosis and cardiovascular death. Hormonal manipulations can also cause second tumors. especially tobacco abuse. and report a poorer quality of life than patients cured of acute leukemia.5–3 years after treatment. A 25-year-old woman who received mantle-field radiation therapy for Hodgkin’s disease has an absolute risk of 29% of developing breast cancer by age 55 years. The malignant cells frequently carry genetic deletions in chromosomes 5 or 7. difficulty in eating. breast cancer. The risk is modest in the first decade after treatment but reaches 1–2% per year in the second decade. It is morphologically indistinguishable from the first but contains a characteristic chromosome translocation involving 10q23. Some organs differ in their susceptibility to radiation carcinogenesis with age. the risk is increased by the addition of radiation therapy and is about three times higher in people treated over age 40. Graft-versus-host disease is the leading factor contributing to the morbidity and mortality from allogeneic bone marrow transplantation. Chemotherapy produces two clinical syndromes that can be fatal: myelodysplasia and acute myeloid leukemia. lung cancer. and no preventive strategy has been developed. Chronic exposure to cyclophosphamide increases the risk of bladder cancer. HODGKIN’S DISEASE The patient cured of Hodgkin’s disease remains subject to long-term medical problems such as thyroid dysfunction. probably because of shared risk factors. Patients cured of lymphoma report a very good quality of life. liver. NON-HODGKIN’S LYMPHOMAS The patient cured of a non-Hodgkin’s lymphoma may be at increased risk of myelodysplasia and acute leukemia if high doses or prolonged courses of alkylating agents were used. have more psychosocial and sexual problems. Studies are needed to assess preventive measures in patients at high risk of second cancers. Symptoms in a patient cured of cancer should not be dismissed as they may be an early sign of second cancers. premature coronary artery disease. Trastuzumab (Herceptin) may contribute to heart failure. Late effects e93 are worse for those with poor socioeconomic status. decreased vaginal secretions. the risk returns to baseline if no disease has developed within 10 years of treatment. Patients with genetic syndromes. patients cured of testicular cancer can anticipate Raynaud’s phenomenon. Patients commonly report intrusive thoughts of cancer and psychological distress. neuropsychiatric difficulties. thyroid abnormalities. ACUTE LEUKEMIA The late effects of antileukemic therapy include second malignancies (hematologic and solid tumors). Patients with breast cancer are at increased risk of a second breast cancer in the contralateral breast. especially if radiation therapy was part of the treatment. but a role for treatment is difficult to exclude. renal and/or pulmonary damage from chemotherapy. the aromatase inhibitors. About half of patients report psychosexual problems. The risk of second cancer is often sufficiently high that cured cancer patients would make excellent candidates to assess chemoprevention strategies. It peaks in incidence 4–6 years after treatment.

825 breast cancer survivors. Blood 66:1393. N Engl J Med 336:897. FURTHER READINGS AHLES T et al: Neuropsychiatric impact of standard-dose chemotherapy in long-term survivors of breast cancer and lymphoma. 1988 ———: Long-term sequelae of therapy for childhood acute lymphoblastic leukaemia. 1992 DILLER L: Rhabdomyosarcoma and other soft tissue sarcomas of childhood. J Natl Cancer Inst 97:1428. The Childhood Cancer Survivor Study reported that survivors have a high rate of illness due to chronic health conditions.e94 COLON CANCER To date the major threat to patients with colorectal cancer treated with chemotherapy and/or radiation therapy remains the risk of a second colorectal cancer. ASCO Education Book. Bone Marrow Transplant 17:5. Am J Med 81:962. Acta Oncol 31:243. MC Perry (ed). Cancer Treat Res 62:45. Use of radiation therapy increases the risk of second cancers and may produce chronic prostitis or cystitis. J Clin Oncol 14:1718. MEADOWS AS: Cancer survivors: Future clinical and research issues. in The Chemotherapy Sourcebook. Lancet 355:1310. Adv Oncol Nurs 25:423. N Engl J Med 332:1738. 1992 PERRY MC. Curr Probl Pediatr 23:102. BYRNE J: Fertility and pregnancy after treatment for cancer during childhood or adolescence. Lippincott Williams & Wilkins. Baillieres Clin Haematol 7:365. 1988 BROWN LM et al: Risk of second non-hematologic malignancies among 376. JAMA 270:1949. 2006 MEISTER LA. BENJAMIN RS: Cardiotoxicity of chemotherapeutic drugs. Orlando. 3d ed. . 1995 BINES J et al: Ovarian function in premenopausal women treated with adjuvant chemotherapy for breast cancer. 1991 ——— et al: Cardiac disease following treatment of Hodgkin’s disease in children and adolescents. This incidence increases with time and does not appear to plateau. MEADOWS AT: Late effects of Hodgkin’s disease treatment in children. and about 10–15% develop some urine incontinence. 1985 CHATTERJEE R.) Washington. 2001. 1993 NICHOLSON HS. J Clin Oncol 23:7685. and cancers where chemotherapy and radiation therapy are used together in an organ-sparing approach. 2002 BOOKMAN MA et al: Late complications of curative treatment in Hodgkin’s disease. J Clin Oncol 20:485. 1997 DELAAT CA. in The Chemotherapy Sourcebook. Pediatr Clin North Am 44:1021. 1997 MEADORS. N Engl J Med 355:1572–1582. 1996 BJERGAARD JP et al: Acute nonlymphocytic leukemia. 3d ed. MULVIHILL JJ: Late effects of therapy in survivors of childhood and adolescent osteosarcoma. 1993 ——— et al: Factors affecting late mortality from heart disease after treatment of Hodgkin’s disease. 1996 CURTIS RE et al: Solid cancers after bone marrow transplantation. GOLDSTONE AH: Gonadal damage and effects on fertility in adult patients with haematological malignancy undergoing stem cell transplantation. Semin Oncol 33:98. JAMA 260:680. J Natl Cancer Inst 86:527. pp 115–117 LIPSHULTZ S et al: Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood. 1992 OCHS J. MEADOWS AT: Late effects of childhood cancer therapy. OUTLOOK The challenge for the future is to integrate new chemotherapy and biologic agents and newer techniques of delivering radiation therapy in a fashion that increases cure rates and lowers the late effects of treatment. LAMPKIN BC: Long-term survivors of childhood cancer: Evaluation and identification of sequelae of treatment. 1993 MOHN A et al: Thyroid function in children treated for acute lymphoblastic leukemia. Pediatr Clin North Am 32:835. J Clin Oncol 10:574. 1986 LANGE BJ. 1984. M et al: Pulmonary toxicity of chemotherapy. Philadelphia. pp 514–525 EWER MS. 2006 MACKIE E et al: Adult psychosocial outcomes in long-term survivors of acute lymphoblastic leukemia and Wilms’ tumor: A controlled study. 1990 JOHNSON DH et al: Acute nonlymphocytic leukemia after treatment of small cell lung cancer. PROSTATE CANCER Radical surgical treatment is often accompanied by impotence. in Toxicity of Chemotherapy. anal. National Academies Press. MULHERN RK: Late effects of antileukemic treatment. Breast Cancer Res Treat Feb 3. 1994 OEFFINGER KC et al for the Childhood Cancer Survivor Study. 1997 MORRIS JONES PH: The late effects of cancer therapy in childhood (editorial). 2005 FORBES JF: Long-term effects of adjuvant chemotherapy in breast cancer. Cancer Treat and Res 41:195. 1993 HENRY-AMAR M et al: Causes of death after therapy for early stage Hodgkin’s disease entered on EORTC protocols. 2000 TRAVIS LB et al: Cumulative absolute breast cancer risk for young women treated for Hodgkin lymphoma. J Endocrinol Invest 20:215. and solid tumors following intensive chemotherapy of small cell carcinoma of the lung. Lippincott Williams & Wilkins. Curr Opin Oncol 4:689. 1990 HYDZIK CA: Late effects of chemotherapy: Implications for patient management and rehabilitation. pp 458–468 FISHER B et al: Endometrial cancer in tamoxifen-treated breast cancer patients: Findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. NESBITT ME: Care and treatment of long-term survivors of childhood cancer. 2005 BIBLIOGRAPHY BEATY O et al: Subsequent malignancies in children and adolescents after treatment for Hodgkin’s disease. Philadelphia. 1991 —— et al: Female sex and higher drug dose as risk factors for late cardiotoxic effects of doxorubicin therapy for childhood cancer. FL. 1985 BYRD R: Late effects of treatment of cancer in children. 1994 FLOYD JD et al: Cardiotoxicity of cancer therapy. DC. Int J Radiat Oncol Biol Phys 19:1155. 2007 PMID:17277968 HEWITT M et al (eds): From Cancer Patient to Cancer Survivor: Lost in Transition. pp 1–19 PART 6 Oncology and Hematology Copyright © 2008 The McGraw-Hill Companies. 1991 NEGLIA JP. Cancer 71:3392. indicating that monitoring of survivors is a critical component of their overall health care. Br J Cancer 64:1. such as bladder. YARBRO JW: Complications of chemotherapy: An overview. Additional populations at risk for late effects include those with cancers where therapy is becoming more effective. Patients who have been cured of a cancer represent an important resource for cancer prevention studies. CA Cancer J Clin 42:263. 1992 DOLL DC: Vascular toxicity. Quality of life is reported as high in long-term survivors. Grune and Stratton. Spring 1998. Hematol Oncol Clin North Am 9:1317. J Clin Oncol 13:603. 1995 HANCOCK SL et al: Thyroid diseases after treatment of Hodgkin’s disease. such as ovarian cancer. Cancer 71:3386. 1989 LE CHEVALIER T: Review of toxicity and long-term sequelae in lung cancer. J Clin Oncol 11:1208. JW Yarbro (eds). preleukemia. 1993 NICHOLSON HS. Pediatr Clin North Am 35:815. and laryngeal cancers. N Engl J Med 325:599. N Engl J Med 324:808. 2006 OSANTO S et al: Long-term effects of chemotherapy in patients with testicular cancer. MC Perry. 2001. 1995 MARINA N: Long-term survivors of childhood cancer: The medical consequences of cure. 1988 LI F. Antibiot Chemother 41:199. MC Perry (ed). (Committee on Cancer Survivorship: Improving Care and Quality of Life. 1992 GREEN DM et al: Late effects of treatment for Wilms’ tumor. All rights reserved.

1996 VOGELZANG NJ et al: Raynaud’s phenomenon: A common toxicity after combination chemotherapy for testicular cancer. 2000 STEINHERZ L et al: Cardiac toxicity 4 to 20 years after completing anthracycline therapy. SCHWARTZ RS: Neoplasms and transplantation—Trading swords for plowshares (editorial). 2006 REID H et al: Late effects of cancer treatment in children. 1994 SOCIE G et al: New malignant disease after allogeneic marrow transplantation for childhood acute leukemia. 1997 SHAPIRO CL. . Ann Oncol 7:S67. Blood 70:1412. Hematol Oncol Clin North Am 8:213. and cardiac sequelae after treatment for Hodgkin’s disease. MURTHY A: Hodgkin’s disease: Long term effects of therapy. JAFFE N: Radiation-induced changes in long-term survivors of childhood cancer after treatment with radiation therapy. 1995 REID HL. Pediatr Dent 17:273. Baillieres Clin Haematol 7:57. 1992 VAN BASTEN JP et al: Current concepts about testicular cancer. J Clin Oncol 24:3852. 1994 ROWLAND KM. 1981 VON HOFF DD et al: Daunomycin-induced cardiotoxicity in children and adults: A review of 110 cases. 1986 SCHELLONG G: The balance between cure and late effects in childhood Hodgkin’s lymphoma: The experience of the German-Austrian Study Group since 1978. Ann Oncol 3:S111. RECHT A: Late effects of adjuvant therapy for breast cancer. Ann Intern Med 95:288. 1977 CHAPTER e13 Late Consequences of Cancer and Its Treatment Copyright © 2008 The McGraw-Hill Companies. J e95 Natl Cancer Inst Monogr 16:101. 1987 RECKLITIS CI et al: Suicidal ideation and attempts in adult survivors of childhood cancer. Am J Med 62:200. Med Pediatr Oncol 14:88. 1991 VALAGUSSA P et al: Thyroid. JAMA 266:1672. 1997 VAN LEEUWEN F et al: Second cancer risk following Hodgkin’s disease: A 20-year follow-up study. HENDERSON IC: Adjuvant therapy of breast cancer. 1996 SCHENKEIN DP. J Clin Oncol 18:348. pulmonary. All rights reserved.RATAIN MJ et al: Acute nonlymphocytic leukemia following etoposide and cisplatin combination chemotherapy for advanced non-small cell carcinoma of the lung. Eur J Surg Oncol 23:354. J Clin Oncol 12:312. 1994 ———: Risk of acute myelogenous leukaemia and myelodysplasia following cancer treatment. N Engl J Med 336:949. Semin Roentgenol 29:6. 1994 ———.

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This chapter discusses both the methods that are currently available and those that are being developed. Wet mounts with dark-field illumination are also used to detect spirochetes from genital lesions and to reveal Borrelia or Leptospira in blood. of turbidity changes as a measure of growth. making it easier to identify specific fungal structures. that is both sensitive and specific.e. Examples of biologic signals applicable to clinical microbiology include structural components of bacteria. BIOLOGIC SIGNALS A biologic signal is a material that can be reproducibly differentiated from other substances present in the same physical environment. Increasingly. and surface polysaccharides. or parasitic agents in tissues. and microscopic morphology for fungi and parasites. the use of nucleic acid probes is becoming a standard method for detection. fungal. These techniques enhance signal detection and decrease the background. DETECTION SYSTEMS A detector is used to sense a signal and to discriminate between the signal and background noise. . However. thorough testing is required before these methods are validated as diagnostic assays. toxins or other proteins. and clostridia (Fig. Clinical microbiology laboratories are responsible for processing these specimens and also for determining the antibiotic susceptibility of bacterial and fungal pathogens. The examination of CSF and joint. examination of stained stool specimens for leukocytes is useful as a screening procedure before testing for Clostridium difficile toxin or other enteric pathogens. and viruses. unique DNA or RNA base sequences. bacterial. Traditionally.e14 Laboratory Diagnosis of Infectious Diseases Alexander J. or excreta of the host. STAINING Gram’s Stain Without staining. for antigens and antibodies). an appropriate growth medium. Identification is generally based on phenotypic characteristics. fungi. Gram’s stain may prove useful for specimens from areas with a large resident microflora if a useful biologic marker (signal) is available. Cellular morphology and Gram’s stain characteristics can often be used to categorize stained organisms into groups such as streptococci. of enzyme activity as a change in light absorbance. and/or identification in the clinical microbiology laboratory. chemiluminescence for DNA/RNA probes. Although simple one-step stains can be used. enzymes. The advantage of growth as an amplification method is that it requires only Copyright © 2008 The McGraw-Hill Companies. Similarly. staphylococci. Staining techniques permit organisms to be seen more clearly. cytopathic effects in tissue culture for viral agents. quantitation. AMPLIFICATION Amplification enhances the sensitivity with which weak signals can be detected. the disadvantage is the amount of e97 time required for amplification. Detection systems range from the trained eyes of a technologist assessing morphologic variations to sensitive electronic instruments. differential stains are more common. and of particle agglutination as a measure of antigen presence. The simplest method for microscopic evaluation is the wet mount. for example. detection of pathogenic agents has relied largely on either the microscopic visualization of pathogens in clinical material or the growth of microorganisms in the laboratory. the presence in “sputum” samples of >10 epithelial cells per low-power field and of multiple bacterial types suggests contamination with oral microflora. The most common microbiologic amplification technique is growth of a single bacterium into a discrete colony on an agar plate or into a suspension containing many identical organisms. CHAPTER e14 Laboratory Diagnosis of Infectious Diseases DETECTION METHODS Reappraisal of the methods employed in the clinical microbiology laboratory has led to the development of strategies for detection of pathogenic agents through nonvisual biologic signal detection systems. It is essential to use a detection system that discerns small amounts of signal even when biologic background noise is present—i. All rights reserved. with India ink as a background against which to visualize large-capsuled yeast cells. More rapid specific amplification of biologic signals can be achieved with techniques such as polymerase chain reaction (PCR) or ligase chain reaction (LCR. e14-1). such as fermentation profiles for bacteria. metabolic end products. antibody capture methods (for concentration and/or separation). enzyme immunoassays (EIAs. Onderdonk The laboratory diagnosis of infection requires the demonstration—either direct or indirect—of viral. Gram’s staining of vaginal swab specimens can be used to detect epithelial cells covered with gram-positive bacteria in the absence of lactobacilli and the presence of gram-negative rods—a scenario regarded as a sign of bacterial vaginosis. Although a variety of methods are available for the amplification and detection of biologic signals in research. electronic amplification (for gas-liquid chromatography assays). specific antigens. This simple method is particularly useful for examination of CSF for bacteria and white blood cells or of sputum for acid-fast bacilli (AFB). fluids. with lactophenol cotton blue stain for fungal elements—is often used for morphologic identification. flame ionization detection of short. Staining of wet mounts—e. Much of this methodology is based on the use of either electronic detection systems involving relatively inexpensive but sophisticated computers or nucleic acid probes directed at specific DNA or RNA targets. Centrifugation is often performed before staining to concentrate specimens thought to contain low numbers of organisms. DIRECT DETECTION MICROSCOPY The field of microbiology has been defined largely by the development and use of the microscope. to examine cerebrospinal fluid (CSF) for the presence of Cryptococcus neoformans. The pellet is examined after staining. gradually replacing phenotypic characterization and microscopic visualization methods.or long-chain fatty acids. Gram’s stain differentiates between organisms with thick peptidoglycan cell walls (gram-positive) and those with thin peptidoglycan cell walls and outer membranes that can be dissolved with alcohol or acetone (gram-negative). bacteria are difficult to see at the magnifications (400× to 1000×) used for their detection. such as gas-liquid chromatographs coupled to computer systems for signal analysis. pleural. Andrew B. of cytopathic effects in cell lines. for DNA/RNA). which is used. The examination of specimens by microscopic methods rapidly provides useful diagnostic information. McAdam. Gram’s stain is particularly useful for examining sputum for polymorphonuclear leukocytes (PMNs) and bacteria. Despite the difficulty of discriminating between normal microflora and pathogens. Key issues in the use of a biologic (or electronic) signal are distinguishing it from background noise and translating it into meaningful information. The sensitivity with which signals can be detected varies widely. and detection of substrate utilization or end-product formation as color changes. and selective filtration or centrifugation. Sputum specimens from immunocompetent patients with ≥25 PMNs and <10 epithelial cells per low-power field often provide clinically useful information..g.. The sensitivity is such that >104 bacteria per milliliter should be detected. These techniques are reliable but are often time-consuming. Skin scrapings and hair samples can be examined with use of either 10% KOH wet-mount preparations or the calcofluor white method and ultraviolet illumination to detect fungal elements as fluorescing structures. Common detection systems include immunofluorescence. or peritoneal fluid with Gram’s stain is useful for determining whether bacteria and/or PMNs are present.

Gram-Negative Organisms PART 7 Infectious Diseases Copyright © 2008 The McGraw-Hill Companies. Fluorochrome Stains Fluorochrome stains.. The acid-fast stain is applied to sputum. amplified). it is important to seek advice from the microbiology form of staining is called indirect because a two-antibody system is laboratory when in doubt about a particular situation. Such tests are usually reasonably specific but may have only modest sensitivity. such as peritoneal dialysis fluid.To culture bacterial. an appropriate sample must be placed into the proper medium for growth (amplificaistic structures. The success of efforts to identify a specific pathogen often Immunofluorescent Stains The direct immunofluorescent antibody depends on the collection and transport process coupled to a laboratotechnique uses antibody coupled to a fluorescing compound. The identification of the pink/red AFB against the blue but do not quantify the antigen.a weak biologic signal. the basis for antigen detection is antigen-antibody binding.g. mycotic. may be used for the DETECTION OF PATHOGENIC AGENTS BY CULTURE detection of mycoplasmas in cell cultures. the visual signal can be intensified (i. or samples in which anaerof protein and polysaccharide antigens. and viral agents by means ria. Modifications of this procedure allow the differen. Others Techniques such as direct agCoccus Neisseria Veillonella glutination of bacterial cells with Branhamella Acidaminococcus specific antibody are simple but Megasphaera relatively insensitive.. Because there are many pathogen-specific paradigms for antibody. Some cell-associated Branching Spores Acid-Fast Catalase + Catalase – antigens. such as capsular polysaccharides and lipopolysacRod Nocardia Clostridium Mycobacterium Corynebacterium Lactobacillus charides. other with the detection system changed to accommodate the biologic signal. appropriate conditions..product. C. without a specialized diagnostic laboratory. Deep tissue or fluid (pus) samples are more likely stained with fluorescein-labeled polyclonal antibody directed at the to give useful culture results than are superficial swab specimens. An alternative method is the au. such as Dappe’s stain. Other specialized stains.g. which employ FIGURE e14-1 Interpretation of Gram’s stain. Capsular. Because each unlabeled target antibody attached to ble e14-1 lists procedures for collection and transport of common the appropriate antigen has multiple sites for attachment of the second specimens. it is better for specimens to be plated at the time of ganisms or subcellular structures. such as ry-processing algorithm suitable for the specific sample/agent. the sensitivity of such assays is often high. yeasts. even when the specimen has been Rapid and simple tests for antigens of group A Streptococcus.). and respiratory viruses) within cultured cells or Isolation of suspect pathogens from clinical material relies on the use clinical specimens as well as many difficult-to-grow bacterial agents of artificial media that support bacterial growth in vitro. to support the growth of the species of interest. acid-fast organisms. The general use of directly on clinical samples or after growth of organisms on agar plates liquid medium for all specimens is not worthwhile. such as acridine orange. Myco. extracellular toxins. used to generate the signal for detection of the antigen. In fluorescein. influconcentrated by centrifugation..ISOLATION OF BACTERIAL PATHOGENS pes simplex virus. since few AFB rial toxins—e. ting. while latex agglutination and EIAs are more Gram-Positive Organisms sensitive. or viral pathogens. this method is useful for Micrococcus typing of the somatic antigens of Others Shigella and Salmonella... Both direct and indirect methods detect viral antigens (e. her. . and directed at a specific antigenic target to visualize or. This these procedures. an unlabeled is plated onto appropriate media. flagellar.) are Most such assays provide information as to whether antigen is present suspected. are used to identify white blood cells. difficile toxins A and B in stool. Broth is employed for MACROSCOPIC ANTIGEN DETECTION Latex agglutination assays and EIAs are rapid and inexpensive methods growth (amplification) of organisms from specimens with few bactefor identifying organisms. the better the chance for isolating (target) antibody binds a specific antigen. may be detected in an entire smear. Because the coupling of an enzyme to the antibody can amplify bacterium spp. Legionella pneumophila) directly in clinical specimens. and SPECIMEN COLLECTION AND TRANSPORT spore stains are used for identification or demonstration of character.. which is not metabolized by bacteria.e. Monoclonal or polyclonal antibodies couRod Pseudomonas Enterobacteriaceae Haemophilus Bacteroides Vibrio pled to a reporter (such as latex Aeromonas Others Legionella Prevotella Campylobacter Pasteurella Bordetella Fusobacterium particles or an enzyme) are used Others Brucella Others for detection of antibody-antiFrancisella gen binding reactions. can be detected by Actinomyces Bacillus Listeria Others agglutination of a suspension of Bifidobacterium Others bacterial cells when antibody is Coccus Streptococcus Staphylococcus added. and respiratory syncytial virus can be used in the clinic setramine-rhodamine combination fluorescent dye technique. Tatarget antibody. CSF. antibodies coupled to an enzyme. Such media are composed of agar. In systems such as EIAs. Mycobacterium spp.g. an antigen-antibody reacAcid-Fast Stain The acid-fast stain identifies organisms that retain tion results in the conversion of a colorless substrate to a colored carbol fuchsin dye after acid/organic solvent disruption (e.g. The specimen is then bacterial pathogens. All rights reserved. cytomegalovirus. Such assays may be performed obes or other fastidious organisms may be present. In each tiation of Actinomyces from Nocardia or other weakly (or partially) instance.g. the fluorescing compound absorbs ultraviolet urethral swabs being cultured for Neisseria gonorrhoeae or sputum light and reemits light at a higher wavelength visible to the human eye. tion). the more rapidly a specimen In the indirect immunofluorescent antibody technique.some instances. and bacteria in body fluids. and tissue samples when AFB (e. The biologic signal in each case is the anGRx only Oxidase + Oxidase – Fastidious Anaerobic Curved tigen to be detected. EIAs are also useful for detecting bactebackground of the counterstain requires a trained eye. and sometimes substances to inhibit the growth of other bacteria. In general.g. nutrients (e. fluids. specimens for pneumococci). When samples are examined under collection rather than first being transported to the laboratory (e.e98 or in viral cell cultures.enza virus.

d Vaginal swab samples for “routine culture” should be discouraged whenever possible unless a particular pathogen is suspected.g. ulcerations. Do not refrigerate. stool for Salmonella. Plastic-coated cardboard cup or plastic cup with tight-fitting lid Plastic-coated cardboard cup or plastic cup with tight-fitting lid If Vibrio spp. or other fastidious aerobes and for elimination of antibiotics from cultured blood in which organisms are concentrated by centrifugation. Special precautions may be required. routine (blood culture for aerobes. and Tissues Spinal fluid Cerebrospinal fluid (lumbar puncture) Body fluids Aseptically aspirated body fluids 1 mL for routine cultures. Chlamydia. with number of epithelial cells and PMNs noted. 0. cervical swabs. randomly collected stool Fresh. Specimen Whole blood Minimum Volume 10 mL in each of 2 bottles for adults and children. Other leak-proof containers are also acceptable.. For some body fluids (e.g.. in aerobic bottles for infants. E. Specimen may be left in syringe used for collection if the syringe is capped before transport. Copyright © 2008 The McGraw-Hill Companies. or bronchial aspirate Rectal swab or (preferably) fresh. the laboratory must be notified. and Campylobacter Stool for Yersinia. etc. depending on diagnostic considerations (e. Pneumocystis). Limitations: Stool should not be cultured for these organisms unless also cultured for other enteric pathogens.a Other Considerations See below. ≥5 mL for Mycobacterium 1 mL for routine cultures Sterile tube with tight-fitting cap Sterile tube with tight-fitting cap. randomly collected stool 1 mL of aspirate or brush in transport medium Sterile aspirate or bronchoscopy tube. 1 swab per test should be obtained. Limitations: Procedure requires enrichment techniques. bronchoscopy specimen. or areas of suspected purulence Fresh sputum (not saliva) 1 swab 1 swab Sterile culturette or similar transport system containing holding medium Sterile culturette or similar swab specimen collection system containing holding medium Commercially available sputum collection system or similar sterile container with screw cap Swabs made of calcium alginate may be used. coli O157 Stool for Aeromonas and Plesiomonas Urogenital Tract Urine Urogenital secretions 1 g of stool or 2 rectal swabs 1g 1g Plastic-coated cardboard cup or plastic cup with tight-fitting lid. group B Streptococcus. bronchoscopy brush in a separate sterile container Cause for rejection: Care must be taken to ensure that the specimen is sputum and not saliva. Stool Stool for routine culture. increased volumes are helpful for isolation of small numbers of bacteria. Use mainly for isolation of fungi.5 mL of fluid Sterile. Aspirates. Shigella. 5 mL.g. or in Isolator tube requested from laboratory 10 mL Container See below. as for routine blood cultures.c Sputum 2 mL Bronchial aspirates Transtracheal aspirate. uterine fluid. Induced sputum specimens should not be rejected. or Candida spp.5 mL 1 swab or 0.” since fungal agents may require ≥4 weeks to grow. anaerobes. . Examination of Gram’s stain. direct inoculation preferred for Neisseria gonorrhoeae Body Fluids. This information determines the selection of culture media and the length of culture time. leak-proof container with screw cap or special urine transfer tube Vaginal and rectal swabs transported in Amies transport medium or similar holding medium for group B Streptococcus. prostatic fluid. peritoneal lavage samples). For detection of multiple organisms (e. (continued) Clean-voided urine specimen or urine collected by catheter Vaginal or urethral secretions. Blood.. randomly collected stool Fresh. if possible. less for neonates 10 mL in each of 2 bottles. are suspected. and yeasts) Blood for fungi/Mycobacterium spp.b Whole blood Same as for routine blood culture Specify “hold for extended incubation.TABLE e14-1 INSTRUCTIONS FOR COLLECTION AND TRANSPORT OF SPECIMENS FOR CULTURE Note: It is absolutely essential that the microbiology laboratory be informed of the site of origin of the sample to be cultured and of the infections that are suspected. All rights reserved. e99 Type of Culture (Synonyms) Blood Blood. See below. Isolator (lysis centrifugation) Whole blood Isolator tubes CHAPTER e14 Laboratory Diagnosis of Infectious Diseases Respiratory Tract Nose Throat Swab from nares Swab of posterior pharynx. and appropriate collection/transport methods should be used. Trichomonas. See below. can be an important part of the evaluation process. transfer to laboratory as soon as possible. Mycobacterium.).

gastric aspirates. and Staphylococcus spp. (acid-fast bacilli) body fluids 1 mL or as specified above for individual listing of specimens. overwhelming sepsis. Collection containers for aerobic culture (such as dry swabs) and inappropriate specimens (such as refrigerated samples. a special culture request is recommended. if requested.. Many specimens should be kept cool but not frozen. peritoneal. Multiple cultures from the same patient are encouraged. a first morning specimen is usually preferred. eAspirated specimens in capped syringes or other transport devices designed to limit oxygen exposure are suitable for the cultivation of obligate anaerobes. stool samples (in some cases) 1 mL of fluid. bone. Swabs should not be used.. Aerobic culture of the throat (“routine”) includes screening for and identification of beta-hemolytic Streptococcus spp.g. Sterile bottle or jar should be used for tissue specimens. Collection: Abscess contents or other fluids should be collected in a syringe (rather than with a swab) when possible to provide an adequate sample volume and an anaerobic environment..5 mL of aspirated pus Special Recommendations Fungi Specimen types listed above may be used. Smears and cultures of pleural. freezing at −80°C is usually adequate. Do not allow air bubbles to get into anaerobic broth bottles. or another appropriate broth and the other with thioglycollate or another broth containing reducing agents appropriate for isolation of obligate anaerobes. rectum.g. Most samples for culture are transported in holding medium containing antibiotics to prevent bacterial overgrowth and viral inactivation. d(1) Clean-voided specimens. from whom only limited volumes of blood can be obtained. throat. and the early stages of salmonellosis and brucellosis) or intermittently (as in most other bacterial infections. swab specimens from suspicious skin lesions. different blood collection systems may be used (Isolator systems. 1 swab. or other specimens from normally sterile areas Purulent material or abscess contents obtained from wound or abscess without contamination by normal microflora Minimum Volume 1 mL of fluid or a 1-g piece of tissue Container Sterile “culturette”-type swab or similar transport system containing holding medium. . — Wounds 2 swabs or 0. saprophytic Neisseria spp. Contamination of specimens with normal microflora from the skin. Rapid transport to laboratory is critical. Bacteria may be present in blood either continuously (as in endocarditis. For children. send specimen in anaerobic transport device or closed syringe. For simultaneous anaerobic cultures. with additional sets obtained if fastidious organisms are thought to be involved. is improved by use of concentration techniques. Most blood culture systems employ two separate bottles containing broth medium: one that is vented in the laboratory for the growth of facultative and aerobic organisms and a second that is maintained under anaerobic conditions. rectum. Large volumes may be useful for urinary fungi. A variety of commercially available transport devices may be used. 1 mL of aspirated fluid. In cases of suspected continuous bacteremia/fungemia. Aspirated specimens from abscesses or body fluids Respiratory secretions. Sterile. If specimens are to be shipped or kept for a long time. fLaboratories generally use diverse methods to detect viral agents. and Streptococcus pneumoniae will be identified by most laboratories. nasal swabs. Procedures and transport media vary with the agent to be cultured and the duration of transport. 10 mL of fluid or small piece of tissue. provided they are transported promptly to the laboratory. Fluid or tissue is preferred to swabs. For intermittent bacteremia.5-g sample should be obtained when possible. or 2 swabs 1 mL of fluid. and Foley or indwelling catheter specimens that yield ≥50. Plasma samples and buffy coats in sterile collection tubes should be kept at 4−8°C. and vaginal.e Fluid or stool samples in sterile containers or swab samples in viral culturette devices (kept on ice but not frozen) are generally suitable. and other potentially pathogenic organisms. see table). expectorated sputum. or mycobacteremia). vaginal vault. nose. cNormal microflora includes alpha-hemolytic streptococci. any size tissue sample. Enough tissue should be collected for both microbiologic and histopathologic evaluations. anticoagulated bone marrow. culture-negative endocarditis. Copyright © 2008 The McGraw-Hill Companies. Neither indwelling catheter tips nor urine from the bag of a catheterized patient should be cultured. Special considerations: There is no more important clinical microbiology test than the detection of blood-borne pathogens. Detection of Mycobacterium spp. Collection: Specimen should be transported to microbiology laboratory within 1 h of collection. organisms such as Staphylococcus aureus. midvoid specimens. two bottles (smaller for pediatric samples) should be used: one with dextrose phosphate. tissue. blood samples (including buffy coats). (3) Certain clinical problems (e. and rectal swabs) should be rejected as unsuitable. When urine or sputum is cultured for fungi. Contamination with normal flora from skin. diphtheroids. bronchial/ transbronchial biopsy. in which bacteria are shed into the blood on a sporadic basis). Specimens cultured for obligate anaerobes should be cultured for facultative bacteria as well. vaginal tract.g. two or three samples should be obtained at least 1 h apart during the first 24 h. lung biopsy. regardless of colony count. vaginal and rectal swabs. Haemophilus influenzae. All rights reserved. bronchoalveolar lavage fluid. and pericardial fluids often have low yields. (2) Straight-catheterized. Sterile container with tight-fitting cap PART 7 Infectious Diseases Legionella Anaerobic organisms Virusesf Pleural fluid.. Mycobacterium Sputum. bladder-tap. although a 0. Culturing in liquid media shortens the time to detection. aFor samples from adults. stool. The rapid identification of bacterial and fungal agents is a major determinant of patients’ survival. with abdominal infections). biopsy samples. tryptic soy.000 organisms/mL. urine. 1 g of tissue. wash aspirates from respiratory tract. leak-proof container with tight-fitting cap Other Considerations Accurate identification of specimen and source is critical. acute dysuria in women) may warrant identification and susceptibility testing of isolates present at concentrations of <50. or another body site should be avoided. two or three samples should be drawn before the start of therapy. or other body surfaces should be avoided. Although considered components of the normal microflora. Culturette swab or similar transport system or sterile tube with tight-fitting screw cap. bCollection: An appropriate disinfecting technique should be used on both the bottle septum and the patient. and similar urine specimens should undergo a complete workup (identification and susceptibility testing) for all potentially pathogenic organisms. only an aerobic culture should be done unless there is specific concern about anaerobic sepsis (e.000 organisms/mL and from which no more than three species are isolated should have organisms identified. or 1 g of stool in each appropriate transport medium — An appropriate anaerobic transport device is required. When Neisseria gonorrhoeae or Corynebacterium diphtheriae is suspected.e100 TABLE e14-1 INSTRUCTIONS FOR COLLECTION AND TRANSPORT OF SPECIMENS FOR CULTURE (CONTINUED) Type of Culture (Synonyms) Biopsy and aspirated materials Specimen Tissue removed at surgery. suspected fungal infection. and the specific requirements for each specimen should be checked before a sample is sent. For special situations (e.

subculture to chocolate agar or 7H10 for TB. vancomycin-resistant Enterococcus faecium. Two basic strategies are used to isolate pathogenic bacteria. MRSA. cytomegalovirus. e14-2). report MRSA. use enrichment and selective agar Blood: Specify site and time of collection. such as herpes simplex virus. a positive culture is often detected more rapidly than by manual techniques. DFA. gas-liquid chromatography. Shigella. urine Stool: Gram’s stain for fecal leukocytes. cytomegalovirus and varicella-zoster virus) can be detected quickly by shell-vial culture. Mycobacterium tuberculosis. Conventional viral culture is useful for detection of rapidly propagated agents. These systems measure CO2 concentration as indicative of microbial growth. and Kingella kingae. Tergitol agars for pathogens. Virus may be detected by direct observation of the cultured cells for cytopathic effects or by immunofluorescent detection of viral antigens following incuba- Haemophilus aphrophilus/parainfluenzae/paraphrophilus. Gram’s stain for sputum or vaginal swab DNA/RNA amplification for Chlamydia. organisms that grow on such media are further characterized to determine whether they are pathogens. ISOLATION OF VIRAL AGENTS (See also Chap.. and important information. GBS. The first is to employ enriched media that support the growth of any bacteria that may be present in a sample such as blood or CSF. group B Streptococcus. perform susceptibility tests. VREF. selective agar for common pathogens. HE. VREF. blood agar plate. identification of pathogens. ESBL Anaerobes: Group with Gram’s stain. use other tests as appropriate (serology) Use immunofluorescence for viral agents in cultures. use fermentation profile for identification Isolation from subculture. test for substrate assimilation. examine specialized media for other pathogens Evaluate MacConkey’s. with a light-emitting diode and photodiode employed to detect a color change in a CO2-sensitive indicator built into the bottom of the culture bottle. report MRSA. or sputum—sites that contain many bacteria under normal conditions. Eikenella corrodens. serum. stool. difficile: Cell culture assay or EIA for toxins A and B Isolation. including the result of Gram’s stain and pre- Copyright © 2008 The McGraw-Hill Companies. tissue. systems that rely on the detection of gas (usually CO2) produced by bacteria and yeasts in blood culture medium have allowed the automation of the detection procedure. Hektoen enteric medium. human immunodeficiency virus. direct DNA/RNA probes. culture and identify yeast isolates from blood and CSF Virology specimen: use cell culture or serologic methods. hepatitis C virus. examine sporulation medium. All rights reserved. Neisseria gonorrhoeae. in which the specimen is centrifuged on a monolayer of cells that is then incubated for 1–2 days and finally stained for viral antigens with fluorochrome-conjugated antibodies. Abbreviations: BAP. GC.g. Such methods are no more sensitive than the human eye in detecting a positive culture. wound. which contain no bacteria under normal conditions. The most common systems involve either (1) the measurement of gas pressure in the headspace to indicate bacterial gas production or consumption or (2) the use of reflectance optics. Selection for organisms that may be pathogens from the normal microflora shortens the time required for diagnosis (Fig. VREF. because the bottles in an automated system are monitored more frequently. The biologic signal—virus—is amplified to a detectable level. Pneumocystis Mycology specimen: Use fluorochrome stain for fungal elements in tissue. direct fluorescent antibody. ESBL FIGURE e14-2 Common specimen-processing algorithms used in clinical microbiology laboratories. Over the years. extended-spectrum β-lactamase. and chocolate agar for pathogens. GLC. use other identification methods. cerebrospinal fluid. Broths that allow the growth of small numbers of organisms may be subcultured to solid media when growth is detected. use Isolator cultures for fungus. cytopathic effects. CMV. an essential element is a monolayer of cultured mammalian cells sensitive to infection with the suspected virus. Viruses that grow more slowly (e. however. bronchial wash. genital tract secretions. . Although a number of techniques are available. methicillin-resistant Staphylococcus aureus. These cells serve as the amplification system by allowing the proliferation of viral particles. such as direct DNA/RNA probes CHAPTER e14 Laboratory Diagnosis of Infectious Diseases Evaluate MacConkey’s. perform susceptibility tests. Antimicrobial agents or other inhibitory substances are incorporated into the agar medium to inhibit growth of all but the bacteria of interest. samples include buffy coat. ESBL. and GLC. The second strategy is to use selective media to isolate (amplify) specific bacterial species from stool. BAP. and skin scrapings. HACEK. use rapid DFA where possible Assess microscopic morphology. HE. identification of pathogens. TB. HepC. spore test. examine wet mount Examine cell cultures for CPE. or sputum: Specify site and collection method. prepare sample for culture. CPE. enzyme immunoassay. Cardiobacterium hominis. HepC. AUTOMATION OF MICROBIAL DETECTION IN BLOOD The detection of microbial pathogens in blood is difficult because the number of organisms present in the sample is often low and the organisms’ integrity and ability to replicate may be damaged by humoral defense mechanisms or antimicrobial agents. specialized media for other pathogens Urine. TB. hair. tion. GC. Mycobacterium Sample preparation: Culture to Sabouraud’s and other media. use other enrichment media for HACEK Perform fungal susceptibility tests for yeasts and molds when necessary to detect resistance Viral load testing: Use for CMV. CSF. direct stain for infectious agents such as Legionella. serogroup Salmonella. HIV. Actinobacillus actinomycetemcomitans. BAP. use Gram’s stain or other rapid tests Examine both aerobic and anaerobic liquid medium.e101 Suspected Infectious Agent Obtain Appropriate Specimen Bacteriology specimen for rapid diagnosis or routine culture methods for common and fastidious pathogens Rapid diagnosis: Latex agglutination for Cryptococcus. 170) Pathogenic viral agents often are sought by culture when the presence of serum antibody is not a criterion for active infection or when an increase in serum antibody may not be detected during infection. use liquid medium for fastidious pathogens. After incubation. blood. stain with lactophenol cotton blue or other stain. use serology to detect antibody in acute and convalescent sera. EIA. use DNA/RNA amplification for genotyping C. HIV.

Use of nucleic acid tests generally involves lysis of intact cells or viruses and denaturation of the DNA or RNA to render it single-stranded. IgM may be useful as a measure of an early. can be detected in certain automated systems if appropriate liquid media are used for culture. particularly gram-negative bacteria. coding to simplify recording of results. and thus the likelihood of laboratory contamination is decreased. parasitic.g. Histoplasma capsulatum. Automated systems allow rapid phenotypic identification of bacterial pathogens. acute-phase antibody response. however. Mycobacterium spp. Because the types and relative concentrations of volatile acids differ among the various genera and species that make up this group of organisms. In situ hybridization of a probe to a target is also possible and allows the use of probes with agents present in tissue specimens. such information serves as a metabolic “fingerprint” for a particular isolate. Haemophilus. and EIA) and unique systems such as hemolysis inhibition and complement fixation.e102 liminary susceptibility assays. Last. DETECTION OF PATHOGENIC AGENTS BY SEROLOGIC METHODS Measurement of serum antibody provides an indirect marker for past or current infection with a specific viral agent or other pathogens. nucleic acid tests are used to determine whether two or more isolates of the same pathogen are closely related (belonging to the same “clone” or “strain”). Several systems use preformed enzymes for even speedier identification (within 2–3 h). acute. lysis-centrifugation culture is recommended for filamentous fungi. and many common organisms can be identified on the first day of growth. Rickettsia. most laboratories test for antibody directed at both viral capsid antigens and antigens associated with recently infected host cells to determine the stage of infection.S. or the production of certain metabolites. and/or quantify the target-probe complex (Fig. such as Epstein-Barr virus. Most such systems are based on biotyping techniques. and some fastidious bacteria (Legionella and Bartonella). Probe(s) or primer(s) complementary to the pathogen-specific target sequence may be hybridized to the target sequence in a solution or on a solid support. One advantage of automated blood culture systems is that the bottles are scanned continuously in a noninvasive monitoring procedure. such as rubella virus or varicella-zoster virus. microscopic appearance) may suggest a species. odor. Several factors affect the yield of blood culture from bacteremic patients. Quantitative serologic assays to detect increases in antibody titers most often employ paired serum samples obtained at the onset of illness and 10–14 days later (i. depending on the system employed. Current technology encompasses a wide array of methods for amplification and signal detection. specific pathogens in clinical specimens. A fourfold increase in total antibody titer or in EIA activity between the acute. such tests are used for identification of organisms (usually bacteria) that are difficult to identify by conventional methods. assays for this purpose normally use one or two dilutions of serum for a qualitative determination of protective antibody levels. If the biotyping approach is automated and the reading process is coupled to computer-based data analysis. Cardiobacterium. The biologic signal is usually either IgM or IgG antibody directed at surface-expressed antigen. and fungal infections. Second. immunofluorescence. Determination of an antibody response as a measure of current immunity is important in the case of viral agents for which there are vaccines. Increasing the volume of blood tested increases the chance of a positive culture. NUCLEIC ACID TESTS Techniques for the detection and quantitation of specific DNA and RNA base sequences in clinical specimens have become powerful tools for the diagnosis of bacterial. Obtaining multiple cultures (up to three per 24-h period) also increases the chance of detecting a bacterial pathogen. GAS-LIQUID CHROMATOGRAPHY Gas-liquid chromatography is often used to detect metabolic end products of bacterial fermentations. hemolytic reactions. e14-3). which is still the most common approach. the production of specific enzymes. a variety of strategies may be employed to detect. CLASSIC PHENOTYPING Classic phenotypic identification of bacteria entails tests for protein or carbohydrate antigens. Automated systems have also been applied to the detection of microbial growth from specimens other than blood. Rapid versions of some of these tests are available. can be obtained sooner. All rights reserved. the ability Copyright © 2008 The McGraw-Hill Companies. including Brucella. this effect is less pronounced in patients with bacterial endocarditis. For any given species. such as peritoneal and other normally sterile fluids.e. characteristics that are readily detectable after growth on agar media (colony size. amplify.. some systems use fluorogenic substrate/end-product detection methods to increase sensitivity (through signal amplification). either manual or automated. Nucleic acid tests are used for four purposes. and commercially available systems include miniaturized fermentation. nucleic acid tests are used to predict the sensitivity of organisms (typically viruses) to chemotherapeutic agents. Since the incubation period before symptoms are noted may be long enough for an antibody response to occur. in which isolates are grown on multiple substrates and the reaction pattern is compared with known patterns for various bacterial species. Prolonged culture and blind subculture for detection of most fastidious bacteria (e.) are not needed with automated blood culture systems. The detection systems include those used for bacterial antigens (agglutination reactions. One common application is identification of short-chain fatty acids produced by obligate anaerobes during glucose fermentation. This procedure is relatively fast. they are used to detect. Eikenella. color. An increase from 10 to 20 mL of blood increases the proportion of positive cultures by ~30%. Although automated blood culture systems are more sensitive than lysiscentrifugation methods (Isolator) for yeasts and most bacteria.and convalescent-phase samples). to metabolize specific substrates and carbon sources (such as carbohydrates). Food and Drug Administration (FDA) for clinical diagnosis. require more extensive testing. Serologic methods generally fall into two categories: those that determine protective antibody levels and those that measure changing antibody titers during infection. and Kingella spp. the antibodies produced may be directed at different antigens during different phases of the infection. An organism may be identified definitively within a few hours after detection of growth on appropriate media. For this reason. First. rapidly growing organisms (such as Enterobacteriaceae) can be identified within hours of detection on agar plates. Gas-liquid chromatography can be coupled to a sophisticated signal-analysis software system for identification and quantitation of long-chain fatty acids (LCFAs) in the outer membranes and cell walls of bacteria and fungi. LCFA analysis is one of the most advanced procedures currently available for phenotypic characterization. PART 7 Infectious Diseases IDENTIFICATION METHODS Once bacteria are isolated. and more sophisticated methods such as gas chromatography and nucleic acid tests.and convalescent-phase samples is also regarded as evidence for active infection. In such circumstances. and probability calculations for the most likely pathogens. Third. some of which have been approved by the U. the demonstration of acute-phase antibody alone is often insufficient to establish the diagnosis of active infection as opposed to past exposure. Actinobacillus. the types and relative concentrations of LCFAs are distinctive enough to allow differentiation even from closely related species. They employ a heavy inoculum in which specific bacterial enzymes are present in amounts sufficient to convert substrate to product rapidly. but definitive identification requires additional tests. Other organisms. Such systems do not rely on bacterial growth per se to determine whether a substrate has been used. Once the probe(s) or primer(s) have been hybridized to the target (biologic signal).. viral. Identification methods include classic biochemical phenotyping. Legionella. For certain viral agents. In addition. . and Helicobacter pylori. and sometimes to quantify.

Hybrid capture as- probe. target amplification using the PCR for complementary strand extension. Such tests detect a relatively short sequence of bases specific for a particular pathogen on single-stranded DNA or RNA by hybridization of a complementary sequence of bases (probe) coupled to a “reporter” system that serves as the signal for detection. Many laboratories have developed their own probes for pathogens. In an alternative probe assay. or bDNA). cytomegalovirus. Campylobacter spp. and Candida spp. hybridization of a primer sequence to the appropriate target sequence.) has also been approved. of which there are many more copies than there are of any single genomic DNA sequence in a bacterial cell. Streptococcus spp.. they may be amplified by repetitive cycles of complementary strand extension (polymerase chain reaction) before attachment of a reporter Probes for Direct Detection of Pathogens in Clinical Specimens Nucleic acid probes are used for direct detection of pathogens in clinical specimens without amplification of the target strand of DNA or RNA. federal law in the United States restricts the use of such probes to research. Nucleic Acid Amplification Test Strategies In theory. the care with which the assays are performed is important. including PCR.. However. The sensitivity of NAATs is far greater than that of traditional assay methods such as culture. called hybrid capture.Intact cell (as DNA/RNA) Lysis Extraction Debris Heat ss DNA/RNA Direct Detection ssDNA/RNA Probe and reporter Heat Hybridize Complementary strand extension Detection 20–30 cycles Reporter Antibody and reporter Hybridize DNA/RNA hybrid Solid support Antibody capture Probe Target Amplification ssDNA/RNA Hybridize Signal Amplification ssDNA/RNA Probe (bDNA) Hybrid Capture ssRNA DNA probe Hybridize DNA/RNA e103 CHAPTER e14 Laboratory Diagnosis of Infectious Diseases Detection Detection Detection FIGURE e14-3 Strategies for amplification and/or detection of a target-probe complex. and Staphylococcus aureus). requires repeated heating of the DNA to separate the two complementary strands of the double helix. or the original target-probe signal may be amplified via hybridization with an additional probe containing multiple copies of a secondary reporter target sequence (branched-chain DNA. with antibody directed at the DNA/RNA hybrids used to concentrate them and a second antibody coupled to a reporter molecule attached to the captured hybrid. PCR. Trichomonas vaginalis. including EIA and culture. gonorrhoeae. The sensitivity and specificity of probe assays for direct detection are comparable to those of more traditional assays. Mycobacterium spp.g. DNA or RNA extracted from microorganisms is heated to create single-stranded (ss) DNA/RNA containing appropriate target sequences. and signal detection via a labeled probe. and human papillomavirus. DNA/RNA hybrids can also be “captured” on a solid support (hybrid capture). and the resulting DNA/RNA hybrid is captured on a solid support by antibody specific for DNA/RNA hybrids (concentration/amplification) and detected by chemiluminescentlabeled antibody specific for DNA/RNA hybrids. and group A Streptococcus. because Copyright © 2008 The McGraw-Hill Companies.. and other bacteria (e. trachomatis. including Chlamydia trachomatis. Nucleic acid probes are available commercially for direct detection of various bacterial and parasitic pathogens. however. and self-sustaining sequence replication. N. An assortment of probes are available for confirming the identity of cultured pathogens. unless a method-validation protocol for diagnostic testing has been performed.. says are available for C. There are several strategies for nucleic acid amplification tests (NAATs). N. including some dimorphic molds. LCR. All rights reserved. Methods for the monitoring of PCR after each amplification cycle—via either incorporation of fluorescent dyes into the DNA during primer extension or use of fluorescent probes capable of fluorescence resonance energy transfer—have now decreased the period required to detect a specific target. Probes for the direct detection of bacterial pathogens are often aimed at highly conserved 16S ribosomal RNA sequences. . gonorrhoeae. exponential amplification of a pathogen-specific DNA or RNA sequence depends on primers that anneal to the target sequence. These target sequences may be hybridized directly (direct detection) with probes attached to reporter molecules. a single target nucleic acid sequence can be amplified to detectable levels. The amplified nucleic acid can be detected after the reaction is complete or (in real-time detection) as amplification proceeds. strand displacement amplification. the first and still most common NAAT. A combined assay to detect and differentiate agents of vaginitis/vaginosis (Gardnerella vaginalis. an RNA probe anneals to a DNA target. In each case.

An alternative NAAT employs transcription-mediated amplification. Application of Nucleic Acid Tests In addition to the applications already discussed. ANTIVIRAL TESTING See Chap. and hepatitis B and C virus infections. Branched-chain DNA (bDNA) testing is an alternative to NAATs for quantitative nucleic acid testing. and most clinical laboratories refer requests for such testing to reference laboratories. aureus or vancomycin-resistant Enterococcus faecium. or epsilometer (E-test). or intermediate. or clonal. such as Mycobacterium. cytomegalovirus (PCR). or MBC). or TMA).9% of the starting inoculum can also be determined (minimum bactericidal concentration. Automated sequencing of several hundred bases is then performed. resistant. DE LENCASTRE H: Bridges from hospitals to the laboratory: Genetic portraits of methicillin-resistant Staphylococcus aureus clones. For some organisms. a miniaturized version of the broth dilution technique using microwell plates. interpretation of results. amplification assays for Mycobacterium tuberculosis. N. in which an RNA target sequence is converted to DNA. bDNA attaches to a site different from the target-binding sequence of the original probe. Two approaches are useful. The lowest concentration of antibiotic that inhibits visual microbial growth in this test system is known as the minimum inhibitory concentration (MIC). Such testing is used to screen for infection control problems. The amplified bDNA signal is detected by chemiluminescence. cytomegalovirus infection. have been developed. the minimum concentration of antibiotic required to kill 99. These methods have been carefully calibrated against quantitative methods and clinical experience with each antibiotic. PART 7 Infectious Diseases FURTHER READINGS AIRES DE SOUSA M. lends itself to automation and is commonly used in larger clinical laboratories. are similar to the broth microdilution methods used to determine the MIC for bacteria. which is then exponentially transcribed into RNA target. probe sequences. such as Bacillus anthracis. it is becoming the definitive method for identification of unusual or difficult-to-cultivate organisms. Ehrlichia. group B Streptococcus. and the sequence information is compared with large databases containing sequence information for thousands of different organisms. differences in ≤3 bands) suggest that different bacterial isolates are closely related. The first is a qualitative assessment of susceptibility. are technically difficult. Methods for determining the MFC against fungal agents such as Aspergillus spp. and methicillin-resistant S. Identification of otherwise difficult-to-identify bacteria involves an initial amplification of a highly conserved region of 16S rDNA by PCR. . hepatitis B virus. Chemiluminescent-labeled oligonucleotides can then bind to multiple repeating sequences on the bDNA. resistant. and analyte-specific reagents (ASRs) to develop “in-house” assays for diagnostic use. The advantage of this method is that only a single heating/annealing step is required for amplification. Quantitative NAATs are available for HIV (PCR). Simpler methods of strain typing include sequencing of single or multiple genes and PCR-based amplification of repetitive DNA sequences in the bacterial chromosome. and hepatitis C (PCR and transcription-mediated amplification. In the past. Mycoplasma hominis. aureus are on the market. Legionella. such as obligate anaerobes. The advantage of bDNA over PCR is that only a single heating/annealing step is required to hybridize the target-binding probe to the target sequence for amplification. Borrelia. sample processing. and hepatitis C virus have been approved by the FDA. Many laboratories have validated and perform quantitative assays for these and other pathogens (e. in which thousands of unique nucleic acid sequences can be detected on a single silicon chip. The demonstration that bacteria of a single clone have infected multiple patients in the context of a possible means of transmission (e. to fluconazole and voriconazole. The MIC value can be given a categorical interpretation of susceptible.. C. the need for testing of individual isolates for susceptibility to specific antifungal agents has increased. In such testing. These methods. Babesia. 170.e104 cross-contamination of clinical material with DNA or RNA from other sources (even at low levels) can cause false-positive results. FEMS Immunol Med Microbiol 40:101. If tubes in which no growth is seen are subcultured.g. The E-test method is approved for testing the susceptibility of yeasts to fluconazole. using ASRs for NAATs. Again. a health care provider) offers confirmatory evidence for an outbreak. This approach can involve either the placement of paper disks containing antibiotics on an agar surface inoculated with the bacterial strain to be tested (Kirby-Bauer or disk/agar diffusion method).e. SUSCEPTIBILITY TESTING OF BACTERIA A principal responsibility of the clinical microbiology laboratory is to determine which antimicrobial agents inhibit a specific bacterial isolate. When the strip is placed on the surface of an agar plate seeded with a bacterial strain to be tested. Nucleic acid tests are also used to determine how close the relationship is among different isolates of the same species of pathogen. such as methicillin-resistant S. many laboratories have used commercially available taq polymerase. Quantitative Nucleic Acid Test Strategies With the advent of newer therapeutic regimens for HIV-associated disease. bDNA assays for viral load of HIV. These fragments are separated by gel electrophoresis with variable polarity of the electrophoretic current and then are visualized. Future applications of nucleic acid testing will likely include the replacement of culture for identification of many pathogens with solid- state DNA/RNA chip technology. Issues related to quality control. 2004 Copyright © 2008 The McGraw-Hill Companies. The MIC is estimated as the lowest concentration that inhibits visible growth.. All rights reserved. Rickettsia. and disk diffusion can be used to test the susceptibility of Candida spp. and zones of inhibition and breakpoints have been calculated on a species-by-species basis. A novel version of the disk/agar diffusion method employs a quantitative diffusion gradient. SUSCEPTIBILITY TESTING OF FUNGAL AGENTS With the advent of many new agents for treating yeasts and systemic fungal agents. and bacterial growth is inhibited. with responses categorized as susceptible. Similar band patterns (i. and flucytosine. gonorrhoeae.g. Quantitative susceptibility testing by the microbroth dilution technique. few laboratories participated in such testing because of a lack of standard methods like those available for testing bacterial agents. However. which determine the minimal fungicidal concentration (MFC). or intermediate and so is more widely used than the MBC. and Tropheryma whippelii. Pulse-field gel electrophoresis remains the usual gold standard for bacterial strain analysis. nucleic acid tests are used to detect and identify difficult-to-grow or noncultivable bacterial pathogens. with measurement of the zones of growth inhibition following incubation. and regulatory requirements have slowed the commercial development of many diagnostic assay kits. The second approach is to inoculate the test strain of bacteria into a series of broth cultures (or agar plates) with increasing concentrations of antibiotic. resulting in large DNA fragments. or the use of broth cultures containing a set concentration of antibiotic (breakpoint method). antibiotic diffuses into the medium. At present. In addition.. itraconazole. Epstein-Barr virus). several systems have now been approved for antifungal susceptibility testing. smallpox virus. While 16S sequencing is not as rapid as other methods and is still relatively expensive for routine use in the clinical microbiology laboratory. methods for rapid detection of agents of public health concern. and Yersinia pestis. hepatitis B (PCR). routine susceptibility testing generally is not performed because of the difficulty of growing the organisms and the predictable sensitivity of most isolates to specific antibiotics. and uses an absorbent strip with a known gradient of antibiotic concentrations along its length. the response to therapy has been monitored by determining both genotype and “viral load” at various times after treatment initiation. This method involves the use of restriction enzymes that recognize rare sequences of nucleotides to digest the bacterial DNA. trachomatis.

SCHEUERMANN RH: Nucleic acid testing for viral burden and viral genotyping. J Clin Microbiol 36:2096. . FRIEDMAN LS: Serologic and molecular diagnosis of hepatitis B virus. Clin Infect Dis 38:1724. 2004 PANCHOLI P et al: Rapid detection of cytomegalovirus infection in e105 transplant patients. 2004 PFALLER MA et al: Clinical evaluation of a frozen commercially prepared microdilution panel for antifungal susceptibility testing of seven antifungal agents. J Clin Microbiol 40:1581. 2002 SERVOSS JC. 2005 MAGIORAKOS AP. 2005 CALIENDO AM et al: Distinguishing cytomegalovirus (CMV) infection and disease with CMV nucleic acid assays. 1998 CHAPTER e14 Laboratory Diagnosis of Infectious Diseases Copyright © 2008 The McGraw-Hill Companies. J Clin Microbiol 40:1694. 2004 YEGHIAZARIAN T et al: Quantitation of human immunodeficiency virus type 1 RNA levels in plasma by using small-volume-format branched-DNA assays. HADLEY S: Impact of real-time fungal susceptibility on clinical practices. All rights reserved. Clin Infect Dis 41:1677. Curr Opin Infect Dis 17:511. including the new triazoles posaconazole. 2004 DOMIATI-SAAD R.BARON EJ et al: Prolonged incubation and extensive subculturing do not increase recovery of clinically significant microorganisms from standard automated blood cultures. 2002 COCKERHILL FR et al: Optimal testing parameters for blood cultures. Clin Liver Dis 8:267. Clin Chim Acta 363:197. ravuconazole and voriconazole. Expert Rev Mol Diagn 4:231.

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Another contributor to secondary immunosuppression after burn injuries is the endocrine system. chemical. accompanied by positive cultures). Pseudomonas aeruginosa became a major problem in burn-wound management. Burns predispose to infection by damaging the protective barrier function of the skin. tachycardia and hyperventilation accompany the metabolic changes induced by extensive burn injury and are not necessarily indicative of bacterial sepsis. decreases in production and release of monocytes and macrophages. susceptible host tissues. Invasive infection—localized and/or systemic—occurs when these bacteria penetrate viable tissue. BURNS EPIDEMIOLOGY Over the past decade. Neutrophil and complement functions have also been shown to be impaired after burns. Madoff. and by inducing systemic immunosuppression. All rights reserved. and flammable liquids and gases are the major causes of burns. Changes in body temperature.e15 Infectious Complications of Burns and Bites Lawrence C. glucagon. but the number of bacteria grows rapidly beneath the burn eschar. Florencia Pereyra The skin is an essential component of the nonspecific immune system. or a healed skin donor site). Thermal burns may cause massive destruction of the integument as well as derangements in humoral and cellular immunity. and (4) invasive infection in unexcised burn wounds (infection that is secondary to a partial. the assessment of these changes is complicated. the wound is colonized with other microbes. The substantial impact of immunocompromise on infection is due to effects on both the cellular and the humoral arms of the immune system. however. reaching ~8. and the degeneration of the wound with the appearance of a new eschar. The cascade of events that follow a severe burn injury and that lead to multiorgan system failure and death are thought to represent a two- step process: The burn injury itself. While many burn injuries are minor and require little or no intervention. Fig. tachycardia. and yeasts derived from the gastrointestinal and upper respiratory flora. The frequency of infection parallels the extent and severity of the burn injury. Breaches in this protective barrier thus represent a form of immunocompromise that predisposes the patient to infection. and other hormones that directly affect lymphocyte proliferation. a grafted burn. altered mentation. PATHOPHYSIOLOGY Loss of the cutaneous barrier facilitates entry of the patient’s own flora and of organisms from the hospital environment into the burn wound. aldosterone.. Aspergillus spp. Increased permeability of the gut wall to bacteria and their components (e. The timing of these biopsies can be guided by clinical changes. but in some centers burn wounds are rou- CHAPTER e15 Infectious Complications of Burns and Bites Copyright © 2008 The McGraw-Hill Companies. For example. the burn patient is predisposed to infection at remote sites (see below) as well as at the sites of burn injury. With the advent of antimicrobial agents. Fig.000 persons are hospitalized for these injuries.or full-thickness burn wound and is manifested by separation of the eschar or by violaceous. endotoxin) also contributes to immune dysregulation and sepsis. with ensuing hypovolemia and tis. is followed by invasive infection arising from large amounts of devitalized tissue. including gram-positive bacteria. permitting the development of infection caused by environmental opportunists and components of the host’s skin flora. However. favors further bacterial colonization and proliferation. as seen in a partialthickness burn that is allowed to close by secondary intention.g. Thus. Given the difficulty of evaluating burn wounds solely on the basis of clinical observation and laboratory data. and 20. Early surgical excision of devitalized tissue is now widely used. thus facilitating the entry of pathogenic microorganisms. CLINICAL MANIFESTATIONS Since clinical indications of wound infection are difficult to interpret. increases in suppressor T cells. the wound is colonized with gram-positive bacteria from the surrounding tissue. protecting the host from potential pathogens in the environment. and the agents of mucormycosis) have emerged as increasingly important pathogens in burn-wound patients. neutropenia or neutrophilia. for example. e15-3) or the development of ecthyma gangrenosum at a remote site points to a diagnosis of invasive P. and diminution in levels of immunoglobulin follow major burns. Herpes simplex virus (HSV) infection has also been found in burn wounds. dark brown. The appearance of a green discoloration of the wound or subcutaneous fat (Fig. catecholamines. (2) burn-related surgical wound infection (purulent infection of excised burn and donor sites that have not yet epithelialized. bacterial cell products play a potent role in inducing proinflammatory mediators that contribute to this uncontrolled systemic inflammatory response. Signs of infection include the conversion of a partial-thickness to a full-thickness burn. Less common anaerobic bacteria are typically found in infections of electrical burns or when open wound dressings are used. In addition. gram-negative bacteria. (3) burnwound cellulitis (extension of infection to surrounding healthy tissue.4 × 103 cfu/g on day 4 after the burn. secretion of proinflammatory cytokines. hypotension. and smoking-related sources are also important. It is therefore not surprising that multiorgan failure and infectious complications are the major causes of morbidity and death in serious burn injury and that as many as 10. As antibiotics more effective against Pseudomonas have become available. cortisol. the estimated incidence of burn injuries in the United States has steadily declined. e15-2). or black discoloration of the eschar. but electrical. because profound alterations in homeostasis occur as a consequence of burns per se and because inflammation without infection is a normal component of these injuries. and renal failure may result from invasive burn wounds and sepsis. growth hormone. Bites and scratches from animals and humans allow the inoculation of microorganisms past the skin’s protective barrier into deeper. e15-1). still. (Biofilms are surface-associated communities of bacteria. and burn-wound infections can be classified in relation to the excision site as (1) burn-wound impetigo (infection characterized by loss of epithelium from a previously reepithelialized surface. especially those on the face. along with the impairment of local immune responses. 50. the sudden separation of the eschar from subcutaneous tissues. are attributable to thermoregulatory dysfunction.000 patients in the United States die of burn-related infections each year. color changes (e. Severe burn injuries cause a state of immunosuppression that affects innate and adaptive immune responses. a role for biofilms has been recognized in experimental animal models of burn-wound infection. and suppressive T cells are seen. thrombocytopenia. fungi (particularly Candida albicans. The increased levels of multiple cytokines detected in burn patients are compatible with the widely held belief that the inflammatory response becomes dysregulated in these individuals.. aeruginosa infection. wounds must be monitored carefully for changes that may reflect infection. that allow the microbes to persist and to resist the effects of host immunity and antimicrobial agents. . structural fires. >1 million burn injuries are brought to medical attention each year. The avascularity of the eschar. The majority of burn patients are men. Alterations in body temperature. natural killer cell activity. the appearance of a dark brown or black discoloration of the wound). the new appearance of erythema or violaceous edema in normal tissue at the wound margins. Initially. decreases in the number and activity of circulating helper T cells. Infants account for ~10% of all reported cases. increasing levels of vasopressin. Scalds. A margin of erythema frequently surrounds the sites of burns and by itself is not usually indicative of infection. often embedded in a matrix. wound biopsies are necessary for definitive diagnosis of infection.) Streptococci and staphylococci were the predominant causes of burn-wound infection in the preantibiotic era and remain important pathogens at present.g.e107 sue hypoxia. By day 7..000 have major burns involving at least 25% of the total body surface area.

Sheridan.) Copyright © 2008 The McGraw-Hill Companies. The wound requires additional debridement. a topical antimicrobial agent used to eradicate nasal colonization with MRSA. its interaction with structural proteins causes keratinocyte and fibroblast toxicity that can delay wound healing if silver-based compounds are used indiscriminately. Boston. A blood culture positive for the same organism seen in large quantities in biopsied tissue is a reliable indicator of burn sepsis. Boston. eyes. In recent years. Early surgical excision of burned tissue. Septic pulmonary emboli may also occur. The cream penetrates eschars and thus can prevent or treat infection beneath them. a number of other infections due to the immunosuppression caused by extensive burns and the manipulations necessary for clinical care put burn patients at risk. nystatin may be mixed with silver sulfadiazine or mafenide acetate as topical therapy. Sheridan. In addition to infection of the burn wound itself. PART 7 Infectious Diseases BURN-WOUND INFECTIONS The ultimate goal of burn-wound management is closure and healing of the wound. Histopathologic evidence of invasion of viable tissue by microorganisms is a more definitive indicator of infection. Silver sulfadiazine is often used initially. The presence of >105 viable bacteria per gram of tissue is highly suggestive of invasive infection and of a dramatically increased risk of sepsis. or toxicity (leukopenia). the four widely used topical antimicrobial agents—silver sulfadiazine cream. Note the dark brown to black discoloration of the eschar. its use without dressings allows regular examination of the wound area. over the ears. Boston. The biopsy specimen is examined for histologic evidence of bacterial invasion. (Courtesy of Dr. The activity of mafenide acetate against gram-positive bacteria is limited. full-thickness chest wall burns. now the most common infectious complication among hospitalized burn patients. greatly decreases mortality rates associated with severe burns. mafenide acetate cream. or digits). this approach provides controlled and prolonged release of nanocrystalline silver into the wound. urinary tract infection. with permission. immobility. bacterial chondritis (particularly in patients with burned ears). Mafenide acetate has broader activity against gram-negative bacteria. rates of fungal infection have increased in burn patients.) tinely biopsied at regular intervals. A small study found FIGURE e15-2 A severe upper-extremity burn infected with Pseudomonas aeruginosa.e108 FIGURE e15-1 Cellulitis complicating a burn wound of the arm and demonstrating extension of the infection to adjacent healthy tissue. Pneumonia. This agent is most often used when gram-negative bacteria invade the burn wound and when treatment with silver sulfadiazine fails. poor wound penetration. with permission. The efficacy of mupirocin in reducing burn-wound bacterial counts and preventing systemic infections is comparable to that of silver sulfadiazine. Robert L. All rights reserved. Endocarditis. and limited toxicity. Robert L.g. with permission. In addition. among the risk factors associated with secondary pneumonia are inhalation injury. Nanocrystalline silver dressings provide broader antimicrobial coverage than any other available topical preparation. This noninvasive technique might be of use in determining the flora present in excised burn areas or in areas where the skin is too thin for biopsy (e. exhibiting activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). . with extensive debridement of necrotic tissue and grafting of skin or skin substitutes. and intraabdominal infection also complicate serious burn injury. and that it elicits hypersensitivity reactions in up to 7% of patients. with liquefaction of tissue. Mupirocin.and full-thickness burns. is most often nosocomially acquired via the respiratory route. and quantitative microbiologic cultures are performed. resulting in metabolic acidosis. Suppurative thrombophlebitis may complicate the vascular catheterization necessary for fluid and nutritional support in burns.) FIGURE e15-3 A burn wound infected with Pseudomonas aeruginosa. Robert L. Massachusetts General Hospital. is increasingly being used in burn units where MRSA is prevalent. The bactericidal properties of silver are related to its effect on respiratory enzymes on bacterial cell walls. (Courtesy of Dr. moderate ability to penetrate eschars. Surface cultures may provide some indication of the microorganisms present in the hospital environment but are not indicative of the etiology of infection.. which is suggestive of Pseudomonas infection. but its value can be limited by bacterial resistance. The foremost disadvantages of mafenide acetate are that it can inhibit carbonic anhydrase. All four agents are broadly active against many bacteria and some fungi and are useful before bacterial colonization is established. When superficial fungal infection occurs. and uncontrolled wound sepsis with hematogenous spread. Massachusetts General Hospital. limiting the number of dressing changes and therefore reducing the risk of nosocomial infections as well as the cost of treatment. intubation. Note the green discoloration at the wound margins. Sheridan. silver nitrate cream. these agents are routinely applied to partial. Massachusetts General Hospital. In addition. (Courtesy of Dr. and nanocrystalline silver dressings—dramatically decrease the bacterial burden of burn wounds and reduce the incidence of burn-wound infection.

and Enterobacteriaceae producing extended-spectrum β-lactamases have been associated with burn-wound infections and identified in burn-unit outbreaks.000 population. or grafting frequently result in bacteremia.000 Americans seek medical e109 attention for dog bites. Other microorganisms causing infection after cat bites are similar to those causing dog-bite wound infections. Pasteurella infections tend to advance rapidly. Pasteurella multocida. a normal component of the feline oral flora. An exception involves cases requiring burn-wound manipulation. Like dog-bite wounds. topical therapy should be changed to mafenide acetate. doubleblind. oxacillin.. and Capnocytophaga canimorsus (formerly designated DF-2).. 800. and Porphyromonas spp. sharp feline incisors penetrate deeply into tissue. is a small gram-negative coccobacillus implicated in the majority of cat-bite wound infections.. resulting in pneumonia or bacteremia. Infection with Bartonella henselae causes cat-scratch disease (Chap. All rights reserved. however. Subeschar clysis (the direct instillation of an antibiotic. the skin of the animal and victim. Children are more likely than adults to sustain canine bites. Both bites and scratches from cats are prone to infection from organisms in the cat’s oropharynx. These bites most often involve the hands and arms. Like that of dog-bite wound infections. Patients without prior immunization should receive tetanus immune globulin and undergo primary immunization. Strict infection-control practices (including microbiologic surveillance in burn units) and appropriate antimicrobial therapy remain important measures in reducing rates of infection due to resistant organisms. endocarditis. sometimes foul-smelling discharge. excision. often within hours. dogs bite >4. The use of oral antibiotics for selective digestive decontamination (SDD) to decrease bacterial colonization and the risk of burn-wound infection is controversial and has not been widely adopted. The same risk factors for systemic infection following dog-bite wounds apply to cat-bite wounds. DOG BITES In the United States. and chorioamnionitis.g.g. glucocorticoid use. millions of animal-bite wounds are sustained. or who are immunosuppressed. with >1000 emergency department visits each day and about a dozen deaths per year. which may be lifethreatening. the microflora of cat-bite wound infections is usually mixed. Each year. who have undergone splenectomy. In the absence of culture data. Patients with burn wounds frequently have alterations in metabolism and renal clearance mechanisms that mandate the monitoring of serum antibiotic levels. vancomycin (1 g IV every 12 h) may be substituted for oxacillin (and is efficacious against MRSA). Since procedures such as debridement. mezlocillin. debridement. Systemic treatment with antibiotics active against the pathogens present in the wound should be instituted. 153) and is an important late consequence of cat bites and scratches. prophylactic systemic antibiotics have no role in the management of burn wounds and can in fact lead to colonization with resistant microorganisms. Tularemia (Chap. multidrug-resistant gram-negative rods. Tularemia (Chap.that nystatin powder (6 million units/g) was effective for treatment of superficial and deep burn-wound infections caused by Aspergillus or Fusarium spp. Most dog bites are provoked and are inflicted by the victim’s pet or by a dog known to the victim. Such coverage is usually achieved with an antibiotic active against gram-positive pathogens (e. 386. This organism is a thin gram-negative rod that is difficult to culture on most solid media but grows in a variety of liquid media.g. an estimated 15–20% Copyright © 2008 The McGraw-Hill Companies. many of the microorganisms involved are capable of causing systemic infection. The microbiology of dog-bite wound infections is usually mixed and includes β-hemolytic streptococci. Many wounds also include anaerobic bacteria such as Actinomyces. with the highest incidence of 6 bites per 1000 population among boys 5–9 years old. placebo-controlled trial in patients with burns involving >20% of the total body surface area. and moist healing of partial-thickness wounds. The effects of SDD on the normal anaerobic bowel flora must be taken into consideration before this approach is used. fever. aeruginosa and other gram-negative rods (e. lymphadenopathy. covering organisms commonly encountered in that particular burn unit. The vast majority are inflicted by pet dogs and cats. Other bite wounds are a consequence of encounters with animals in the wild or in occupational settings. When invasive wound infection is diagnosed. moisture-retention ointments with antimicrobial properties can promote rapid autolysis. acute leukemia. treatment should be broad in spectrum. These infections are particularly likely in hosts with edema or compromised lymphatic drainage in the involved extremity (e. Victims are more often male than female.. meningitis. although organisms from the soil. antibiotic prophylaxis has been associated with increased secondary infections of the upper and lower respiratory tract and the urinary tract as well as with prolonged hospitalization. . These bites frequently occur during efforts to break up a dogfight. Staphylococcus spp. CHAPTER e15 Infectious Complications of Burns and Bites BITES AND SCRATCHES Each year in the United States.. prophylactic systemic antibiotics are administered at the time of wound manipulation. Women sustain cat bites more frequently than do men. systemic lupus erythematosus. Pasteurella spp. Eikenella corrodens. cat-bite wounds may result in the transmission of rabies or in the development of tetanus. In addition. Fusobacterium.7 million people each year and are responsible for 80% of all animal-bite wounds. Prevotella. the specific agents used should be chosen on the basis of data obtained by wound culture or data on the hospital’s resident flora. In some studies. and ciprofloxacin (400 mg IV every 12 h) may be substituted for mezlocillin.g. The microbiology of bite-wound infections in general reflects the oropharyngeal flora of the biting animal. after a bite on the arm in a woman who has undergone radical or modified radical mastectomy) and in patients who are immunocompromised by medication or disease (e.g. 3 g IV every 4 h. resistant enterococci. of which become infected. and bites most often involve an upper extremity. All burn-injury patients should undergo tetanus booster immunization if they have completed primary immunization but have not received a booster dose in the past 5 years. While many of these wounds require minimal or no therapy. the levels achieved with standard doses are often subtherapeutic. dog bites and scratches may result in systemic illnesses such as rabies (Chap. Because the narrow. cat bites are more likely than dog bites to cause septic arthritis and osteomyelitis. Among children <4 years old.000 require treatment in an emergency department. a significant number result in infection. Treatment of infections caused by emerging resistant pathogens remains a challenge in the care of burn patients.. The bacteria are occasionally seen within polymorphonuclear leukocytes on Wrightstained smears of peripheral blood from septic patients. In addition to these products. In penicillin-allergic patients. into wound tissues under the eschar) is a useful adjunct to surgical and systemic antimicrobial therapy. causing severe inflammation accompanied by purulent drainage. In general. and renal failure. cat bites and scratches result in infection in more than half of all cases. Systemic manifestations (e. MRSA. Infection typically manifests 8–24 h after the bite as pain at the site of injury with cellulitis accompanied by purulent. Septic arthritis and osteomyelitis may develop if a canine tooth penetrates synovium or bone. which number >100 million. SDD was associated with reduced mortality rates in the burn intensive care unit and in the hospital and also with a reduced incidence of pneumonia. and lymphangitis) may also occur. the annual incidence of dog and cat bites has been reported as 300 bites per 100. In a randomized. and the animal’s feces may also be involved. 151) has also been reported to follow cat bites. of those injured. canimorsus following dog-bite wounds may result in fulminant sepsis. 2 g IV every 4 h) and with a drug active against P. disseminated intravascular coagulation. Pasteurella may also be spread by respiratory droplets from animals. 151) has also been reported to follow dog bites. brain abscess. twothirds of all these injuries involve the head or neck. or hepatic cirrhosis). often piperacillin.. the development of these conditions is particularly likely when punctures are located over or near a joint. While most infections resulting from dog-bite injuries are localized to the area of injury. 5 mg/kg IV per day). CAT BITES Although less common than dog bites. including bacteremia. 188) and tetanus (Chap. Infection with C. particularly in hosts who have impaired hepatic function. 133). especially in the hand. and gentamicin.

joints. and headache. are isolated from 50% of human-bite wound infections. quinolones. The oral flora of hospitalized and debilitated patients often includes Enterobacteriaceae in addition to the usual organisms. nerves. BITE-WOUND INFECTIONS WOUND MANAGEMENT Wound closure is controversial in bite injuries. Staphylococcus epidermidis. Hepatitis B. and tendons. causing traumatic laceration of the hand. and tetanus have been reported to be transmitted by human bites. βlactam antibiotics. corrodens (which is particularly common in clenched-fist injury. All rights reserved. the microflora of bite wounds reflects the oral flora of the biting animal. and foul odor. aeruginosa.e110 OTHER ANIMAL BITES Infections have been attributed to bites from many animal species. or foul-smelling exudate is present. after an incubation period of 1–4 weeks. owners of exotic pets). The differential diagnosis includes Rocky Mountain spotted fever. Moreover. A small-tipped swab may be used to culture deep punctures or small lacerations. and secondary syphilis. which are inflicted by actual biting.and cat-bite wounds. For several reasons. which cause a clinical illness known as rat-bite fever. Small uninfected wounds may be allowed to close by sec- Copyright © 2008 The McGraw-Hill Companies. The snake’s oral flora includes many species of aerobes and anaerobes. or may take place during fights. and severe migratory arthralgias are usually followed by a maculopapular rash. tetracyclines.e. E. Streptobacillary rat-bite fever was frequently fatal in the preantibiotic era. and the possible involvement of joints. and approximate the wound edges. including Fusobacterium nucleatum and Prevotella. as abscess and cellulitis). Porphyromonas. laboratory workers. Common aerobic isolates include viridans streptococci. result in particularly serious infections. The clenched position of the fist during injury. laceration. by culture of the organisms on enriched media. The diagnosis is made by direct observation of the causative organisms in tissue or blood. HSV infection. and the amount of time elapsed since injury. chills. Staphylococcus aureus. including feral cats. multocida. Bite wounds from aquatic animals such as alligators or piranhas may contain Aeromonas hydrophila. chills. Venomous snakebites (Chap. which includes multiple species of aerobic and anaerobic bacteria. may further promote the introduction of bacteria as contaminated tendons retract beneath the skin’s surface. tuberculosis. and abscesses in many organs. immunosuppression. and functional limitations. The phenotypic characteristics of NO-1 are similar to those of asaccharolytic Acinetobacter species. The wound should be inspected carefully for evidence of infection. In the United States. dermatologic lesions. and Clostridium spp. and “clenched-fist” injuries. and Peptostreptococcus spp. or scratch). 188). the type of attack (provoked or unprovoked). and Haemophilus influenzae. The deep spaces of the hand.e. The original lesion may eventually progress to an eschar. nerve. Bites from Old World monkeys (Macaca) may also result in the transmission of B virus (Herpesvirus simiae. Local and regional authorities should be contacted to determine whether an individual species could be rabid and/or to locate and observe the biting animal when rabies prophylaxis may be indicated (Chap. myocarditis. many of these isolates produce β-lactamases. wilderness campers.. medical attention is often sought only after frank infection develops. Injuries to the hand warrant consultation with a hand surgeon for the assessment of tendon. indole-. cercopithecine herpesvirus). anaerobic cultures should be undertaken if abscesses. Bites from nonhuman primates are highly susceptible to infection with pathogens similar to those isolated from human bites (see below). Many authorities prefer not to attempt primary closure of wounds that are or may become infected. walruses. pneumonia. including the type of biting animal. and urease-negative. Culture and Gram’s staining of all infected wounds are essential. . such as P. Complications include endocarditis. liver disease. NO-1 is oxidase-. It is often useful to include a diagram or photograph of the wound in the medical record. all strains identified have been shown to be susceptible to aminoglycosides. Human-bite wounds become infected more frequently (~10–15% of the time) than do bites inflicted by other animals. Proteus spp. pleomorphic gram-negative rod) or Spirillum minor (a spirochete). including redness. mice. which are sustained when the fist of one individual strikes the teeth of another. headache. Rat-bite fever is distinguished from acute bitewound infection by its typical manifestation after the initial wound has healed. and gerbils. a cause of serious infection of the human central nervous system. syphilis. it is biologically possible to transmit HIV through human bites. the risk of rodent bites is usually greatest among laboratory workers or inhabitants of rodent-infested dwellings (particularly children). Most members of the cat family.. with associated lymphangitis and regional lymphadenopathy. Lyme disease. NO-1 (CDC nonoxidizer group 1) is a recently identified bacterium associated with dog. including the bones. a general physical examination should be conducted and should include an assessment of vital signs as well as an evaluation for evidence of lymphangitis. The vast majority of cases in the United States are streptobacillary. Anaerobic species. HUMAN BITES Human bites may be self-inflicted. mastectomy. clenched-fist injuries. remove foreign bodies. These infections have occurred in healthy persons with no underlying illness and in some instances have progressed from localized to systemic illnesses. which is probably due to one or more species of Mycoplasma colonizing these animals. The white blood cell count should be determined and blood cultured if systemic infection is suspected. debride devitalized tissue. may be sustained by medical personnel caring for patients. exudate. tendons. since the microorganisms causing disease are less predictable in these cases. and muscular damage. including rats. followed by extension of the hand. and sulfonamides. and immunization history should be obtained. These infections reflect the diverse oral microflora of humans. Delayed primary closure may be undertaken after the risk of infection is over. hepatitis C. Generally. see below). which characteristically involves the palms and soles and may become confluent or purpuric. To date. myalgias. lymphadenopathy. or sexual activity. Bacteroides fragilis. Infections in which NO-1 has been isolated have tended to manifest locally (i. The systemic illness includes fever. preferring to irrigate these wounds copiously. Finally. which are more common than occlusional injuries. Suspicious human-bite wounds should provoke careful questioning regarding domestic or child abuse. The infection is diagnosed by direct visualization of the spirochetes in blood or tissue or by animal inoculation. Small rodents. domestic abuse. or by serologic testing with specific agglutinins. The type of wound (puncture. Bites of seals. Fever.. i. 391) result in severe inflammatory responses and tissue necrosis—conditions that render these injuries prone to infection. veterinarians) or recreational exposure (hunters and trappers. Often these bites are sustained as a consequence of occupational exposure (farmers. although this event is quite unlikely. the depth of penetration. PART 7 Infectious Diseases APPROACH TO THE PATIENT: Animal or Human Bites A careful history should be elicited. actinomycosis. Streptobacillary disease follows an incubation period of 3– 10 days. and bones should be assessed. are frequently inoculated with organisms in the course of such injuries. Haverhill fever is an S. leptospirosis. moniliformis infection acquired from contaminated milk or drinking water and has similar manifestations. In addition. Details on antibiotic allergies. devitalized tissue. Human bites are categorized as “occlusional” injuries. splenectomy.. whereas Spirillum infection occurs mainly in Asia. harbor P. meningitis. Spirillum infection (referred to in Japan as sodoku) causes pain and purple swelling at the site of the initial bite. Radiographs should be obtained when the bone may have been penetrated or a tooth fragment may be present. as well as animals that prey on rodents may transmit Streptobacillus moniliformis (a microaerophilic. and polar bears may cause a chronic suppurative infection known as seal finger. It is also reasonable to culture samples from uninfected wounds due to bites inflicted by animals other than dogs and cats.

aureus. and crush injuries. involvement of the hands or genital region. aureus. Cat Usually Consider rabies prophylaxis. influenzae. or meningitis) should also be treated with IV penicillin G. Failure to respond should prompt a consideration of diagnostic alternatives and surgical evaluation for possible drainage or debridement. cMay be hazardous in patients with immediate-type hypersensitivity reaction to penicillin. For macaque monkeys. canimorsus. Leptospira spp. should be treated. Second-generation cephalosporins (cefuroxime.and monkey-bite wounds should be treated presumptively because of the high rate of infection. but the response to therapy must be carefully monitored. and β-lactamasepositive oral anaerobes should be used. Antibiotics are generally given for 10–14 days. anaerobes. Human. when bone or joint may be involved. S.. Serious infection with P. double-strength. particularly those involving the hand. Pasteurella spp. Because it is often difficult to distinguish signs of infection from tissue damage caused by the envenomation. anaerobes As for occlusional plus Eikenella corrodens Erythromycin (500 mg PO qid) or a fluoroquinolone Cefoxitinc Always Always Examine for tendon. Although symptomatic infection frequently will not yet have manifested at this point. clenchedfist Monkey Viridans streptococci. the location. streptococci. pneumonia. All rights reserved. . These are suggestions for empirical therapy and need to be tailored to individual circumstances and local conditions. C. including that due to liver disease or splenectomy. and extent of the bite wound. nerve. and when comorbidity is present (see text). aureus. as indicated by the biting species and by Gram’s stain and culture results (Table e15-1).0 g IV every 6 h). facial wounds. canimorsus sepsis requires a 2-week course of IV penicillin G (2 million units IV every 4 h) and supportive measures. severity. as above Ampicillin/sulbactam as above or imipenem (500 mg q6h) As for human bite Alternative in Penicillin-Allergic Patient Clindamycin (150–300 mg PO qid) plus either TMP-SMX (1 DS tablet PO bid) or ciprofloxacin (500 mg PO bid) Clindamycin plus TMP-SMX as above or a fluoroquinolone Other Considerations Consider rabies prophylaxis. Alternative agents include second. Antivenin for venomous snake bite As for human bite As for human bite Always CHAPTER e15 Infectious Complications of Burns and Bites Snake Rodent Pseudomonas aeruginosa. would appear reasonable. 391) may not require antibiotic treatment. agents with activity against S. many clinicians base the decision to treat bite wounds with empirical antibiotics on the species of the biting animal. The choice of antibiotics for penicillin-allergic patients (particularly those in whom immediate-type hypersensitivity makes the use of cephalosporins hazardous) is more difficult and is based primarily on in vitro sensitivity since data on clinical efficacy are inadequate.. antibiotics should be effective against S. For dog and cat bites. and prior mastectomy on the side of an involved upper extremity. Carefully evaluate for joint/ bone penetration. and many will become infected. The combination of an extendedspectrum penicillin with a β-lactamase inhibitor (amoxicillin/clavulanic acid. Other factors favoring treatment for bite wounds include severe injury. Established Infection Antibiotics should be administered in all established bite-wound infections and should be chosen in light of the most likely potential pathogens. ondary intention. H. many early wounds will harbor pathogens.0 g IV q6h) Amoxicillin/clavulanate or ampicillin/ sulbactam. trimethoprim-sulfamethoxazole. Studies of antibiotic prophylaxis for wound infections are limited and have often included only small numbers of cases in which various types of wounds have been managed according to various protocols. Capnocytophaga canimorsus P. Puncture wounds due to cat bites should be left unsutured because of the high rate at which they become infected. potential bone or joint involvement. Seal finger appears to respond to doxycycline (100 mg twice daily for an interval guided by the response to therapy). Streptobacillus moniliformis.. In vitro data suggest that azithromycin alone provides coverage against most commonly isolated bite-wound pathogens.or third-generation cephalosporins or ciprofloxacin. multocida. A meta-analysis of eight randomized trials of prophylactic antibiotics in patients with dog-bite wounds demonstrated a reduction in the rate of infection by 50% with prophylaxis. consider B virus prophylaxis with acyclovir. Presumptive or Prophylactic Therapy The use of antibiotics in patients presenting early after bite injury (within 8 h) is controversial. DS.g. occlusional Human. Management of C. as above Amoxicillin/clavulanate or ampicillin/ sulbactam... cefoxitin) also offer substantial coverage. many authorities continue to recommend treatment directed against the snake’s oral flora—i. Proteus spp. A single IV dose of antibiotics may be given to patients who will be discharged after initial management. and oral anaerobes. For human bites. ampicillin/sulbactam) appears to offer the most reliable coverage for these pathogens.5–3.e. anaerobes Preferred Antibiotic(s)a Amoxicillin/clavulanate (250–500 mg PO tid) or ampicillin/ sulbactam (1. especially with venomous snakes Sometimes aAntibiotic choices should be based on culture data when available. multocida (e. ticarcillin/clavulanic acid. as in crush wounds. Facial wounds are usually sutured after thorough cleaning and irrigation because of the importance of a good cosmetic result in this area and because anatomic factors such as an excellent blood supply and the absence of dependent edema lessen the risk of infection. Clostridium spp. aureus. The combination of an antibiotic active against gram-positive cocci and anaerobes (such as clindamycin) with trimethoprim-sulfamethoxazole or a fluoroquinolone.5–3. P. canimorsus infection include cephalosporins and fluoroquinolones. they are usually given for 3–5 days. Bacteroides fragilis. Bites by venomous snakes (Chap. Most cat-bite wounds. However. the administration of broadly active agents such as ceftriaxone (1–2 g IV every 12–24 h) or ampicillin/sulbactam (1. When prophylactic antibiotics are administered. or joint involvement. Pasteurella multocida. Alternative ANTIBIOTIC THERAPY agents for the treatment of C. S.TABLE e15-1 MANAGEMENT OF WOUND INFECTIONS FOLLOWING ANIMAL AND HUMAN BITES Prophylaxis Advised for Early Uninfected Wounds Sometimesb e111 Biting Species Dog Commonly Isolated Pathogens Staphylococcus aureus. sepsis. Complications such as osteomyelitis or septic arthritis mandate a longer duration of therapy. All human. Note: TMP-SMX. multocida Ampicillin/sulbactam as above Penicillin VK (500 mg PO qid) Clindamycin plus TMP-SMX as above or a fluoroquinolone Doxycycline (100 mg PO bid) Sometimes. IV regimens should be used for hospitalized patients. which is active against many of the other potential pathogens. Copyright © 2008 The McGraw-Hill Companies. and the existence of comorbid conditions in the host. Haemophilus influenzae. host immunocompromise. in the absence of sound clinical trials. bProphylactic antibiotics are suggested for severe or extensive wounds.

Br J Surg 77:100. Churchill Livingstone. MMWR 52:605. J Trauma 20:1021. 1991 MCMANUS WF et al: Subeschar antibiotic infusion in the treatment of burn wound infection. . 2001. Arch Intern Med 157:1933. All rights reserved. N Engl J Med 340:85. Correlation between quantitative and qualitative burn wound biopsy culture and surface alginate swab culture. Clin Infect Dis 20:421. FURTHER READINGS BAKER AS et al: Isolation of Mycoplasma species from a patient with seal finger. 5th ed. Medicine (Baltimore) 70:287. World J Surg 16:30. G Mandell et al (eds). 2000 KULLBERG BJ et al: Purpura fulminans and symmetrical peripheral gangrene caused by Capnocytophaga canimorsus (formerly DF-2) septicemia—a complication of dog bite. pp 3198–3206 PART 7 Infectious Diseases Copyright © 2008 The McGraw-Hill Companies. JAMA 279:51. 1999 GOLDSTEIN EJ: Bite wounds and infection. 1994 DE LA CAL M et al: Survival benefit in critically ill burned patients receiving selective decontamination of the digestive tract: A randomized. 1990 FLEISHER GR: The management of bite wounds. 1980 PRUITT BJ et al: The changing epidemiology of infection in burn patients. double-blind trial. Clin Infect Dis 14:633. Ann Emerg Med 23:535. especially the hand. including dogs and cats in many areas of the world. 1998 YOUN YK et al: The role of mediators in the response to thermal injury. Infect Dis Clin North Am 5:663. 1991 WEISS HB et al: Incidence of dog bite injuries treated in emergency departments. Immobilization of the infected area. 1996 ——— et al: Quantitative microbiology in the management of burn patients. Rabies is endemic in a variety of animals. Ann Surg 241:424. World J Surg 16:57. Burns 22:173. New York. Infect Dis Clin North Am 14:321. 188). 1996 TALAN DA et al: Bacteriological analysis of infected dog and cat bites. Elevation of the site of injury is an important adjunct to antimicrobial therapy. 1977 WEBER DJ et al: Infections resulting from animal bites. consisting of both passive administration of rabies immune globulin (with as much of the dose as possible infiltrated into and around the wound) and active immunization with rabies vaccine. Burns 22:177. 2003 CUMMINGS P: Antibiotics to prevent infection in patients with dog bite wounds: A meta-analysis of randomized trials. II.e112 Rabies and Tetanus Prophylaxis Rabies prophylaxis. with clinical outcome following burn surgery and change of dressings. 2000 STEER JA et al: Quantitative microbiology in the management of burn patients. N Engl J Med 340:138. 1992 SHERIDAN RL et al: Cutaneous herpetic infections complicating burns. 1992 YURT RW: Burns. Clin Infect Dis 27:1168. 1998 CENTERS FOR DISEASE CONTROL AND PREVENTION: Nonfatal dog bite– related injuries treated in hospital emergency departments— United States. should be given in consultation with local and regional public health authorities for many wild-animal (and some domestic-animal) bites and scratches as well as for certain nonbite exposures (Chap. Burns 26:621. 2005 FALLOUJI MA: Traumatic love bites. is also beneficial. I. The B Virus Working Group. 1992 HOLMES GP et al: Guidelines for the prevention and treatment of Bvirus infections in exposed persons. 2000. A tetanus booster immunization should be given if the patient has undergone primary immunization but has not received a booster dose in the past 5 years. in Principles and Practice of Infectious Diseases. 1999 TAN JS: Human zoonotic infections transmitted by dogs and cats. Patients who have not previously completed primary immunization should be immunized and should also receive tetanus immune globulin. Many local health authorities require the reporting of all animal bites. Relationship between bacterial counts obtained by burn wound biopsy culture and surface alginate swab culture. 1995 KAYE ET: Topical antibacterial agents. placebo-controlled.

Africa. Without a basic knowledge of the epidemiology and life cycles of the major parasites. EIA EIA. or travel to areas of high endemicity. Central and Snails South America. and e16-3 summarize the geographic distributions. cats Humans Lung. soliumb (pork tapeworm) Somatic tapeworms Echinococcus granulosus (hydatid disease) E. and e16-3 are available commercially or from the Centers for Disease Control and Prevention. and the methods employed for the diagnosis of flatworm. micea Humans. MRI May resemble cholangiocellular carcinoma CT. Central and South America. Note: WB. Continuing interaction with the laboratory staff and the surgical pathologists increases the likelihood that parasites in body fluids or biopsy specimens will be examined carefully by the most capable individuals. WB WB WB — — — Recurrent bacterial cholangitis Cirrhosis. other mammals Humans Ova. liver Liver Muscles.e16 Laboratory Diagnosis of Parasitic Infections Sharon L. MRI. multilocularis (hydatid disease) T. and protozoal infections. Reed. sheep Humans. Diagnosis CHAPTER e16 Laboratory Diagnosis of Parasitic Infections Geographic Distribution Intermediate (Transmission) Definitive Parasite Stage Body Fluid or Tissue Serologic Tests Other Worldwide Worldwide Worldwide Worldwide Beef Grain beetles Copepods–fishc Swine Humans Humans. when the nocturnal microfilariae are active. liver biopsy Liver. other mammals Humans Humans Humans Ova Ova Ova Ova Ova Adults. camels. EIA — WB China. ed to serve as a guide to the correct diagnostic procedures for the ma. the medical classification of important human parasites in this chapter emphasizes their geographic distribution. dOva seldom reach the fecal stream during acute disease. adults Ova. respectively. feces Feces Urine Feces — — — — EIA WB. Its ova are identical to those of T. CT. CT. ova Ova. japonicum bT. India Far East. central nervous system. it is difficult to approach the diagnosis of parasitic infections systematically. India Far East. humans Dogs Foxes. enzyme immunoassay. . Charles E. urine. roundworm. humans Swine. Southeast Asia Sheep-raising areas Orient. segments Ova Ova. their transmission. Africa Chest radiography. physicians must counsel their patients to ensure that specimens are collected properly and arrive at the laboratory promptly. cWhen there are two intermediate hosts. haematobium S. the diagnosis of bancroftian filariasis is unlikely to be confirmed by the laboratory unless blood is drawn near midnight. West Indies Snails Africa Far East Snails aLarvae also can mature in intestinal villi of humans and mice. the first is separated from the second by a dash. western blot. Definitive hosts are infected by the second intermediate host. Serologic tests listed in Tables e16-1. e16-2. Davis The cornerstone for the diagnosis of parasitic infections is a thorough history of the patient’s illness. dogs. radiography Sheep-raising and hunting areas Subarctic areas Worldwide Sheep. saginata. GA. Blood flukes Schistosoma mansoni S. In addition to selecting the correct diagnostic procedures. Atlanta. Copyright © 2008 The McGraw-Hill Companies. Tables e16-1. North Africa China. recreation. For example. segments Hydatid Hydatid Cysticercus Feces Feces Feces Feces — — — WB Motile segments — Megaloblastic anemia in 1% Especially Mexico.d bile Lung. Epidemiologic aspects of the illness are especially important because the risks of acquiring many parasites are closely related to occupation. soliumb (pork tapeworm) Flukes (Trematodes) Intestinal flukes Fasciolopsis buski Heterophyes heterophyes Metagonimus yokogawai Liver flukes Clonorchis sinensis Fasciola hepatica Lung flukes Paragonimus spp. scolices and segments of the two species differ. Balkans. adults Ova. and the anatomic location and stages of their life cycle in humans. EIA. portal hypertension Chest radiography. others Rodents. CNS WB. Accordingly. humans. South America Snails–water chestnuts Snails–fish Snails–fish Snails–fish Snails–watercress Snails–crabs/ crayfish Humans Humans Humans Humans Humans. Laboratory personnel and surgical pathologists should be notified in advance when a parasitic infection is suspected. adults Feces Feces Feces Feces. segments Ova. the anatomic locations. solium can cause either intestinal infections or cysticercosis. CNS. All rights reserved. or bladder biopsy Liver biopsy Africa.e113 jor parasitic infections and to direct the reader to other chapters that contain more comprehensive information about each infection. e16-2. sputum. The text and tables are intendTABLE e16-1 FLATWORM INFECTIONS Life-Cycle Hosts Parasite Tapeworms (Cestodes) Intestinal tapeworms Taenia saginata (beef tapeworm) Hymenolepis nana (dwarf tapeworm) Diphyllobothrium latum (fish tapeworm) T. MRI Rectal snips. bile Feces.

rapid immunographic assay [available at the National Institutes of Health (301496-5398)]. Before accepting a report of negativity for ova and parasites as final. a minimum of three samples collected on alternate days should be examined. anemia Dissemination in immunodeficiency Malabsorption/autoinfection. saginata are morphologically indistinguishable from those of Taenia solium. signs/symptoms. Because of the cyclic shedding of most parasites in the feces.S. eye — EIAb Dog and cat hookworm Also caused by roundworms of other species aBlood should be drawn at midnight. humans Larvae Larvae Skin Viscera. Mexico.. which patients sometimes bring to the physician. the beef tapeworm. biopsy Diagnosis Parasite Stage Body Fluid or Tissue Serologic Tests Other Geographic Distribution Intermediate (Transmission) Definitive PART 7 Infectious Diseases Tissue Roundworms Trichinella spiralis (trichinellosis) Wuchereria bancrofti (filariasis) Brugia malayi (filariasis) Loa loa (African eye worm) Onchocerca volvulus (river blindness) Dracunculus medinensis (guinea worm) Angiostrongylus cantonensis Worldwide Coastal areas in tropics and subtropics Asia. except for infection acquired in the South Pacific. fecal-oral Soil. sputum. Analysis of fecal samples entails both macroscopic and microscopic examination. diurnal Examine nodules or skin snips May be visible in lesion Eosinophilic meningitis Larva Migrans Syndromes Ancylostoma braziliense (creeping eruption) Toxocara canis and cati (visceral larva migrans) Tropical and temperate zones Tropical and temperate zones Soil→skin Soil. CNS. fecal-oral Soil→skin Soil→skin Soil→skin Raw fish Humans Humans Humans Humans Humans Humans Birds Ova Ova Ova Ova/larvae Ova/larvae Larvae Ova. CNS. Note: Sx. All rights reserved. enzyme immunoassay. Egypt Fecal-oral Soil. Some intestinal parasites are more readily detected in material other than feces. Motility is an important distinguishing characteristic. . larvae. anemia Sx of pulmonary migration. Africa. When delays in transport to the laboratory are unavoidable. Africa. Watery or loose stools are more likely to contain protozoal trophozoites. duodenal fluid Feces — — — — — EIA — “Cellophane tape” test Rectal prolapse Sx of pulmonary migration Sx of pulmonary migration. humans Dogs/cats. Refrigeration will also preserve trophozoites for a few hours and protozoal cysts and helminthic ova for several days. The only tapeworm with motile segments is Taenia saginata. the physician should insist that the laboratory undertake each of these procedures. Taiwan. Central and South America Africa Southeast Asia. Pacific U. Caribbean Swine/humans Mosquitoes Mosquitoes Mango flies (Chrysops) Blackflies Cyclops Snails/slugs. worldwide Moist tropics and subtropics Southeast Asia. central nervous system. they should be transported promptly to the laboratory or washed and preserved in fixative for later examination. If adult worms or tapeworm segments are observed. The patient should be instructed to collect feces in a clean waxed or cardboard container and to record the time of collection on the container. New collection kits with instructions for the patient to transfer portions of the sample directly into fixative and bacterial carrier medium may enhance the recovery of trophozoites. RAPID. For ex- Copyright © 2008 The McGraw-Hill Companies. Microscopic examination of feces is not complete until direct wet mounts have been evaluated and concentration techniques as well as permanent stains have been applied. adults Perianal skin Feces Feces Feces Feces Feces. RAPID — — — — Muscle biopsy Nocturnal periodicitya Nocturnal May be visible in eye. Fecal samples should be collected before ingestion of barium or other contrast agents for radiologic procedures and before treatment with antidiarrheal agents and antacids. Indian subcontinent West and Central Africa Africa.e114 TABLE e16-2 ROUNDWORM INFECTIONS Life-Cycle Hosts Parasite Intestinal Roundworms Enterobius vermicularis (pinworm) Trichuris trichiura (whipworm) Ascaris lumbricoides (roundworm of humans) Ancylostoma duodenale (Old World hookworm) Necator americanus (New World hookworm) Strongyloides stercoralis (strongyloidiasis) Capillaria philippinensis Temperate and tropical zones Temperate and tropical zones Temperate and tropical zones Eurasia. shrimp/fish Swine/ humans Humans Humans Humans Humans Humans Rats Larvae Microfilariae Microfilariae Microfilariae Adults/larvae Adults/larvae Larvae Muscle Blood. RAPID EIA. fecal samples should be kept in polyvinyl alcohol or another fixative to preserve protozoal trophozoites. because the ova of T. Examination of a single sample can be up to 50% less sensitive. Pacific. bThe presence of hemagglutinins is a useful clue. fecal-oral Dogs/cats. but protozoal cysts and all stages of helminths may be found in formed feces. EIA. INTESTINAL PARASITES Most helminths and protozoa exit the body in the fecal stream. Contamination with water (which could contain free-living protozoa) or with urine (which can damage trophozoites) should be avoided. because these substances change the consistency of the feces and interfere with microscopic detection of parasites. the cause of cysticercosis. lymph nodes Blood Blood Skin/eye Skin CSF (rarely found) EIA EIA.

Two routine solutions are used to make wet mounts for the identification of the various life stages of helminths and protozoa: physiologic saline for trophozoites. The iron-hematoxylin stain is excellent for critical work. mucous membranes RE system CNS. humans Humans. RE. cyst Troph. All rights reserved. wild animals Cats Asexual Asexual Tryp Tryp Amastigote. nasal swab. culture Biopsy. other animals? Animals. Encephalitozoon spp. Iodine solution must never be used to examine specimens for trophozoites because it kills the parasites and thus eliminates their characteristic motility. rodents Humans. dogs. most sensitive for L. skin. dogs.. PCR Also chancre. scrapings. donovani (kala-azar) Toxoplasma gondii (toxoplasmosis) Subtropics and tropics U. Use of the “cellophane-tape” technique to detect pinworm ova on the perianal skin sometimes also reveals ova of T. Permanently stained smears allow study of the cellular detail necessary for definitive identification. ample. IFA. liver CT. enzyme immunoassay. biopsy. L. liver Feces Feces Feces Feces Feces EIA. cyst Oocyst Oocyst Oocyst Spore Feces. especially in the differentiation of Entamoeba histolytica from other amebas. IIF. indirect fluorescent antibody. braziliensis (mucocutaneous) L. c IIF. other Limited use IIF IIFb Card agglutination. saginata deposited perianally when the motile segments disintegrate (Table e16-4). gambiense (African sleeping sickness) T. eye. reticuloendothelial. cCard agglutination is provided to endemic countries by the World Health Organization. EIA IFA. cornea DFA DFA Biopsy. culture Worldwide.) (microsporidiosis) Free-Living Amebas Naegleria Acanthamoeba Worldwide Worldwide Warm water Soil. Slides permanently stained for trophozoites should be prepared before concentration. Modified acid-fast staining and fluorescent auramine microscopy are useful adjuncts for detection and identifica- Copyright © 2008 The McGraw-Hill Companies. dogs. but trichrome staining. The formalin-ether technique is preferable. cysts. dLimited specificity. Additional slides stained for cysts and ova may be made from the concentrate. cyst CNS. cyst Troph. humans Troph. which can be completed in 1 h.S. DFA. In many instances. etc. especially tropics Worldwide Worldwide Worldwide Worldwide? Worldwide? Fecal-oral Fecal-oral Fecal-oral Fecal-oral Fecal-oral ? Humans Humans Humans Humans. PCR Modified trichrome. lymph nodes Reactivation in immunosuppression Biopsy. muscles. identification of parasites from wet mounts or concentrates must be considered tentative. culture Biopsy. trophozoite. . and Strongyloides larvae. lymph nodes Also chancre. and larvae and dilute iodine solution for protozoal cysts and ova. CNS.a modified safranin. other mammals Humans Rodents. in asplenia. DFA. antigen detection Antigen detection — Antigen detection — — Ultrasound. water Humans Humans Troph. ova. troph Blood Blood Blood. because all parasites sediment but not all float. herbivores Humans. CSF Multiple organs/ blood Skin Skin. biopsy. indirect immunofluorescence. EIA EIA. cruzi (Chagas’ disease) Leishmania tropica. swine Humans. especially New England Sub-Saharan East Africa Sub-Saharan West Africa Mexico→ South America Widespread in tropics and subtropics Mexico→ South America Widespread in tropics and subtropics Worldwide Mosquitoes Ticks Tsetse flies Tsetse flies Reduviid bugs (triatomes) Sandflies (Phlebotomus) Sandflies (Lutzomyia) Sandflies (Phlebotomus) Humans. The two most common concentration procedures for detecting small numbers of cysts and ova are formalin-ether sedimentation and zinc sulfate flotation. nares CNS.a DFA. PCR e115 Diagnosis Parasite Stage Body Fluid or Tissue Serologic Tests Other Intermediate (Transmission) Geographic Distribution Definitive CHAPTER e16 Laboratory Diagnosis of Parasitic Infections Blood and Tissue Protozoans Plasmodium spp. polymerase chain reaction. wild animals Humans. IIFb.a biopsy. EIA IFAb. (malaria) Babesia microti (babesiosis) Trypanosoma rhodesiense (African sleeping sickness) T. CSF. tryp. is a satisfactory alternative that also reveals parasites in specimens preserved in polyvinyl alcohol fixative. acid-fast. Note: troph. PCR PCR aAcid-fastness is best demonstrated by auramine fluorescence or modified acid-fast stain. CSF Blood. autofluorescence. bContact the CDC at 770-488-7760. rodents Humans. EIAd IFAb. trypomastigote form. examination of duodenal contents is sometimes necessary to detect Giardia lamblia. PCR Acid-fast. dogs. tryp Amastigote Amastigote Amastigote Cyst. donovani. EIA. PCR. culture. scrapings.TABLE e16-3 PROTOZOAL INFECTIONS Life-Cycle Hosts Parasite Intestinal Protozoans Entamoeba histolytica (amebiasis) Giardia lamblia (giardiasis) Isospora belli Cryptosporidium Cyclospora cayetanensis Microsporidium (Enterocytozoon bieneusi. IIF PCR Animal spp. PCR Acid-fasta Acid-fast. culture Biopsy. central nervous system. cerebrospinal fluid. PCR String test. Cryptosporidium. direct fluorescent antibody. scrapings. other animals Humans.

anion column/wet mount and Giemsa croscopic examination. ova Serology.5 mL for rats).2 mL of whole heparinized blood (0. bInject mice intraperitoneally with 0. Isospora belli oocysts Duodenal aspirate or jejunal biopsyb Although most tissue parasites stain b Cryptosporidium oocysts Duodenal aspirate or jejunal biopsy with the traditional hematoxylin and b Microsporidium spores Duodenal aspirate or jejunal biopsy eosin. The clinician should also be able to advise the surgeon Invasion of tissue by protozoa and helminths renders the choice of diag. cruzi can sometimes be visualized in stained smears of peripheral Roundworms blood.and pathologist about optimal techniques for the identification of parnostic techniques more difficult. Clonorchis (Opisthorchis) sinensis ova Examination of bile for ova and adults in cholangitis Nuclepore filtration of blood facilitates Fasciola hepatica ova Examination of bile for ova and adults in cholangitis the detection of microfilariae. liver biopsy and liver ultrasound spp. The physician should insist on wet Spinal Fluid mounts. All rights reserved. propriate body fluid or biopsy site for miAfrican trypanosomesa Mouse or rat inoculationb Buffy coat. sputum. urine (S. Enterobius vermicularis ova and adults Perianal “cellophane tape” test for ova and adults liver. Tables e16-5 and As above and xenodiagnosis Trypanosoma cruzic As for African species e16-6 provide additional information Fibroblast cell lines Toxoplasma gondii Buffy coat/Giemsa about the identification of parasites in Microfilariaed None Nuclepore filtration/wet mount and Giemsa samples from specific anatomic locations. and punch biopsy of skin lesions for the identification detect Schistosoma haematobium in the young Ethiopian immigrant or the AmerTABLE e16-5 IDENTIFICATION OF PARASITES IN BLOOD AND OTHER BODY FLUIDS ican traveler who returns from Africa with hematuria. The Centrifugation. cDetectable in blood by conventional techniques only during acute disease. also be stained with appropriate special bCommercial string test is satisfactory. concentration techniques. cellular amastigote forms of Leishmania haematobium). rectal snips (especially for S. For example. microfilariae. Most paCopyright © 2008 The McGraw-Hill Companies. After 5 days. and T. but microfilarial worms and blood protozoa are aTrypanosoma rhodesiense and T. sputum or lung of malaria and the critical distinction biopsy for filariform larvae in disseminated disease among the various Plasmodium species Protozoans are made by microscopic examination of Entamoeba histolytica trophozoites and cysts Serology. They of onchocerciasis. including Cryptosporidium and Cy. checked daily for trypanosomes as described above. brain biopsy for neurocysticercosis rican trypanosomes because these active Flukes (Trematodes) parasites cause noticeable movement of the erythrocytes in the microscopic field. Plasmodium spp. biopsy of lung or brain for larvae Schistosoma ova Serology for all. and Loa loa (diurnal). Thick and thin smears/Giemsa or Wright’s Not useful for diagnosis should help the physician to select the apBuffy coat/Giemsa Media available from CDC Leishmania spp. the collection of rectal snips for the diagnosis of must remember that the urine sediment offers the best opportunity to schistosomiasis. need to be reminded to examine wet mounts and iron-hematoxylin– stained preparations of pulmonary specimens for helminthic ova and BLOOD AND TISSUE PARASITES E. and Body Fluid. mansoni). and spleen are the best sources for Trichuris trichiura ova None microscopic detection and culture of Ascaris lumbricoides ova and adults Examination of sputum for larvae in lung disease Leishmania in kala-azar and of T. stains. 203). in Giemsa-stained blood smears are the dDay (1000–1400 h) and night (2200–0200 h) blood should be drawn to maximize the chance of detecting Wuchereria (nocplasmodia. Wet mounts are sometimes more sensitive than stained smears Taenia saginata ova and segments Perianal “cellophane tape” test for ova for the detection of microfilariae and AfT. when Trypanosoma cruzi Parasites and Fecal Stages Alternative Diagnostic Procedures is no longer microscopically detectable Tapeworms (Cestodes) in blood smears. the excision of skin snips for the diagnosis because the trophozoites are located primarily in the abscess wall. and African turnal except for Pacific strains). Brugia (nocturnal). The surgical pathologist who is accustomed to applying silver stains for tion of several intestinal protozoa. Call the CDC (770-488-7775) for information on diagnosis and treatment. Urine The laboratory procedures for detection of parasites in other body fluids are simiNone Schistosoma haematobium Centrifugation/wet mount lar to those used in the examination of feMicrofilariae (in chyluria) As for blood None ces. cruzi in Hookworm ova and occasional larvae Examination of sputum for larvae in lung disease chronic Chagas’ disease. solium ova and segments Serology. anion column/wet mount As for blood African trypanosomes trichrome or iron-hematoxylin stain is and Giemsa Nonnutrient agar overlaid with Naegleria fowleri Centrifugation/wet mount and Giemsa satisfactory for all tissue helminths in Escherichia coli or trichrome body fluids other than blood. Isospora and Cryptosporidium are acid-fast. e16-2. Xenodiagnosis is successful in ∼50% of patients The most common parasites detected with chronic Chagas’ disease.e116 TABLE e16-4 ALTERNATIVE PROCEDURES FOR LABORATORY DIAGNOSIS OF PARASITES FOUND IN FECES a tients with Chagas’ disease present in the chronic phase. Parasite Enrichment/Stain Culture Technique e16-3. physicians must under. trypanosomes (Table e16-5). but aspirates of the bone marrow. serology. histolytica. tail blood should be more easily visualized when stained with Giemsa or Wright’s stain. surgical biopsy specimens should aStains and concentration techniques are discussed in the text. and permanent stains for all body fluids. For example. which offer a quick guide to the Blood geographic distribution and anatomic locations of the major tissue parasites.Pneumocystis to induced sputum and transbronchial biopsies may clospora (Table e16-3). Tables e16-1. liver biopsy for trophozoites stained thick and thin blood films Giardia lamblia trophozoites and cysts Duodenal aspirate or jejunal biopsyb (Chap. The diagnosis Strongyloides larvae Duodenal aspirate or jejunal biopsy. gambiense. The intraParagonimus spp. PART 7 Infectious Diseases . histolytica (Table e16-6).asites in specimens obtained by certain specialized minor procedures stand that aspiration of an amebic liver abscess rarely reveals E.

EIA IIF. mens are improperly obtained or processed. Rectal snips: From four areas of mucosa. EIAb EIA. costaricensis EOSINOPHILIA a Comment When hydatid cyst leaks During muscle encystation and in CSF with neurocysticercosis RAPIDc During larval migration During larval migration Profound during migration and early years of infection Up to 7000/μL Varies but can reach 5000–8000/μL >3000/μL With extensive cutaneous eruption In visceral larva migrans and eosinophilic meningitis In eosinophilic meningitis During larval migration in mesenteric vessels aUnless otherwise noted. volvulus adults and microfilariae Trichinella spiralis larvae (and perhaps Taenia solium cysticerci) Schistosoma ova of all species.TABLE e16-6 MINOR PROCEDURES FOR DIAGNOSIS OF PARASITIC INFECTIONS Parasite(s) and Stage Onchocerca volvulus and Mansonella streptocerca microfilariae Procedure Skin snips: Lift skin with a needle and excise ∼1 mg to a depth of 0. bResearch or commercial laboratories only. place a drop on a slide. other nonspecific laboratory abnormalities may suggest parasitic infection in patients with appropriate geographic and/ or environmental exposures. Contact Dr. Corneal scrapings: Obtain sample from ophthalmologist for immediate Giemsa staining and culture on nutrient agar overlaid with Escherichia coli. enzyme immunoassay. indirect immunofluorescence. Swabs. trophozoites or cysts Cutaneous and mucocutaneous Leishmania spp. cAvailable at the NIH (301-496-5398) and commercially. and Onchocerca volvulus. japonicum Roundworms Ascaris lumbricoides Hookworm species Strongyloides stercoralis Trichinella spiralis Filarial speciesb Toxocara spp. TABLE e16-8 SEROLOGIC AND MOLECULAR TESTS FOR NONSPECIFIC TESTS PARASITIC INFECTIONS a Eosinophilia (>500/μL) is a common accompaniment of infections with Parasite. bWuchereria bancrofti. and examine wet mounts and Giemsa stains of the saline either directly or after filtration. be obtained from the Centers for Disease Control and Prevention (CDC) in and culture of cutaneous and mucocutaneous species of Leishmania Atlanta. take 2-mg snips. Loa loa. EIA (IgM)e EIA. all tests are available at the CDC.5 mL of saline for 4 h. An otherwise insufficient volume of material may be stained with Giemsa. EIA IIF. polymerase chain reaction. Fasciola hepatica Clonorchis (Opisthorchis) sinensis Schistosoma mansoni S. rhodesiense trypomastigotes Acanthamoeba spp. The results of serologic tests not listed in the tables should be are simple procedures. absolute numbers of eosinophils may be high in trichinellosis and the migratory phases of filariasis (Table e16-7). PCR EIA. but especially S. Brugia spp. Loa loa adults and O. This table includes both common and uncommon parasites that frequently elicit eosinophilia during infection. mansoni Trypanosoma gambiense and T. WB EIAb CHAPTER e16 Laboratory Diagnosis of Parasitic Infections TABLE e16-7 PARASITES FREQUENTLY ASSOCIATED WITH Parasite Tapeworms (Cestodes) Echinococcus granulosus Taenia solium Flukes (Trematodes) Paragonimus spp. and anemia and thrombocytopenia in a febrile traveler or immigrant are among the hallmarks of malaria. aspirates.interpreted with caution. CT and MRI also contribute to the diagnosis of infections with many tissue parasites and have become invaluable adjuncts in the diagnosis of neurocysticercosis and cerebral toxoplasmosis. microcytic e117 anemia of heavy hookworm infections. PCR DFA. IIF. haematobium S. Infection Antibody Antigen or DNA/RNA most of the tissue helminths. Ancylostoma braziliense Gnathostoma spinigerum Angiostrongylus cantonensis A. Eosinophilia is not a manifestation of protoCysticercosis WB zoal infections. aCounts of >100/mg are associated with significant risk of complications. Muscle biopsies: Excise ~1.a Biopsies of subcutaneous nodules: Stain routine histopathologic sections and impression smears with Giemsa. or punch biopsies of skin lesions: Obtain specimen from margin of lesion for Giemsa staining of impression smears.b RAPID.b PCR PCR PCR PCR PCRb PCRb PCR PCR DFA. Biochemical evidence of cirrhosis or an abnormal urine sediment in an African immigrant certainly raises the possibility of schistosomiasis. PCR. Like the hypochromic. direct fluorescent antibody. rapid immunographic assay. Alexandre da Silva at the CDC (770-488-4072). . western blot. tease onto a glass slide.b DFA. Note: EIA. EIA gration of the larval stages. Count microfilariae. eDetermination of infection within the last 3 months may require additional tests by a research laboratory. Tapeworms Intestinal helminths provoke eosinophilia only during pulmonary miEchinococcosis WB. Weigh each sample.5 mm from several sites. with the possible exceptions of those due to Isospora and Flukes Dientamoeba fragilis. Paragonimiasis Schistosomiasis Fascioliasis Roundworms Strongyloidiasis Trichinellosis Toxocariasis Filariasis Protozoans Uniformly high in acute stage May be high in acute stage Variable 50% of infected travelers 25% of infected travelers Up to 6000/μL in acute infection Amebiasis Giardiasis Cryptosporidiosis Malaria (all species) Babesiosis Chagas’ disease Leishmaniasis Toxoplasmosis Microsporidiosis Cyclosporiasis Acanthamoebiasis Naegleriasis Balmuthiasis EIA IIFd IIF IIF. but the diagnosis can be missed if the speci. Most PCRs listed are now available at the CDC and in commercial or research laboratories..b DFA. ANTIBODY AND ANTIGEN DETECTION Useful antibody assays for many of the important tissue parasites are available.0 g of deltoid or gastrocnemius muscle and squash between two glass slides for direct microscopic examination. most of those listed in Table e16-8 can bLymph node aspiration is contraindicated in some infections and should be used judiciously. Aspirate of chancre or lymph node:b Aspirate center with 18-gauge needle. PCR DFA EIA EIA EIA EIAc WB. a Virtually every helminth has been associated with eosinophilia. Copyright © 2008 The McGraw-Hill Companies.b PCR EIA. RAPID. and flatten with a second slide before examining directly at 10×. WB. Preparations may be fixed in alcohol or stained. and section and culture on special media from CDC. place it in 0. dOf limited use for management of acute disease. All rights reserved. Most antigen and antibody parasite detection kits are available commercially. DFA. RAPID.b RAPID. and examine for motile forms.

MOLECULAR TECHNIQUES DNA hybridization with probes that are repeated many times in the genome of a specific parasite and amplification of a specific DNA fragment by the polymerase chain reaction (PCR) have now been established as useful techniques for the diagnosis of several protozoan infections (Table e16-8). and the presence of IgG antibody to T. In addition to PCR of anticoagulated blood. in Manual of Clinical Microbiology. only multiple negative blood smears or the failure to identify the infecting species justifies PCR for the diagnosis or proper management of malaria. 7th ed. Washington. DC. DC. N Engl J Med 354:119. Although PCRs are now used primarily for the detection of protozoans. 2007. In contrast. ASM Press. the preparation of thick and thin blood smears remains the procedure of choice for the diagnosis of malaria in individual patients because diagnostic titers to plasmodia develop slowly and do not differentiate species—a critical step in patient management. Washington. 2003 WALKER M et al: Parasitic central nervous system infections in immunocompromised hosts: Malaria. histolytica is the major exception. ASM Press. as in assays for antibody to most parasites. 2006 WILSON M et al: Toxoplasma. vol 2. All rights reserved. MOODY AH: Diagnostic Techniques in Medical Parasitology. in Manual of Clinical Microbiology. J Clin Microbiol 40:1892. 1988 FREEDMAN DO et al: Spectrum of disease and relation to place of exposure among ill returned travelers. E. pp 2070–2081 ——— et al: Molecular immunological approaches to the diagnosis of parasitic infection. 9th ed. Clin Infect Dis 42:115. Filarial antigens cross-react with those from other nematodes. . gondii does not constitute proof of active disease. leishmaniasis. 2006 GARCIA LS: Laboratory identification of the microsporidia. DC. Despite these specific limitations. a large proportion of the world’s population has been exposed to Toxoplasma gondii. vol 2. 2000 SEYBOLT LM et al: Diagnostic evaluation of newly arrived asymptomatic refugees with eosinophilia. Sensitive. biopsy specimens. pp 557–568 PART 7 Infectious Diseases Copyright © 2008 The McGraw-Hill Companies. Washington. Clin Microbiol Rev 16:713. 2006. 2002 ——— et al: Algorithms for detection and identification of parasites. Wright. 9th ed. 2007. 770-488-4072. microsporidiosis. PR Murray et al (eds). it is an adjunct to conventional techniques for parasite detection and should be requested only when microscopic and immunodiagnostic procedures fail to establish the probable diagnosis. pp 2020–2039 HERWALDT BL: Cyclospora cayetanensis: A review. the presence of antibody in the filarial assay fails to distinguish between past and current infection. B Detrick et al (eds). the CDC (contact Dr. ASM Press. For example. in Manual of Molecular and Clinical Laboratory Immunology. For example. and bronchoalveolar lavage fluid (Table e16-8). Commercial kits for the detection of antigen by enzyme-linked immunosorbent assay or of whole organisms by fluorescent antibody assay are now available for several protozoan parasites (Table e16-8). the restricted geographic distribution of many tropical parasites increases the diagnostic usefulness of both the presence and the absence of antibody in travelers from industrialized countries. FURTHER READINGS FLECK SL. Fewer antibody assays are available for the diagnosis of infection with intestinal parasites. 2006 TANYUKSEL M et al: Laboratory diagnosis of amebiasis. and African trypanosomiasis. focusing on the outbreaks of cyclosporiasis in the 1990s. London. specific serologic tests are invaluable in the diagnosis of amebiasis. Clin Infect Dis 31:1040. active research efforts are likely to establish their feasibility for the detection of several helminths.e118 The value of antibody assays is limited by several factors. Although PCR is very sensitive. Clin Infect Dis 42:363. Alexandre da Silva. for details) and several commercial lab- oratories now perform PCRs for detection of certain specific parasites in stool samples. PR Murray et al (eds).

Long treatment courses are required. albendazole acts by selectively binding to free β-tubulin in nematodes. they have become first-line agents for the treatment of severe falciparum malaria in some areas where multidrug resistance is a major problem. www. therefore. Thus. generating free radicals and other metabolites that damage parasite proteins. Although they have been used for almost 100 years. Artemisinin Derivatives Artesunate. with amodiaquine administration. Agranulocytosis and hepatotoxicity can develop with repeated use. Like chloroquine (the other major 4-aminoquinoline). Foremost among the many factors that have probably contributed to this failure is the provision of suboptimal treatment for years. Antimonials* Despite associated adverse reactions and the need for prolonged parenteral treatment. The fact that Leishmania spp.cdc. Poor absorption may be advantageous for the treatment of intestinal helminths. their mechanism of action against Leishmania spp. which led to the development of drug resistance among parasites. this fundamental disruption of cellular metabolism also offers treatment for a wide range of parasitic diseases. and their activity against Leishmania spp. the pentavalent antimonial compounds (designated Sbv) have remained the first-line therapy for all forms of leishmaniasis throughout the world. Albendazole Like all benzimidazoles. ≤1%).to sixfold. the mean half-life of the terminal elimination phase is nearly 36 h. These agents are at least 10-fold more potent in vivo than other antimalarial drugs and presently show no cross-resistance with known antimalarial drugs. Moore Amphotericin B See Table 201-1 and Chap. meglumine antimonate is principally used in francophone countries. spectrum of activity. Specific treatment recommendations for the parasitic diseases of humans are listed in the chapters on those diseases. as administered for cystic and alveolar echinococcal disease) have been associated with liver function abnormalities and bone marrow toxicity. The antimalarial effect of these agents results primarily from dihydroartemisinin. Artemether appears to be effective for the treatment of schistosomiasis and is being evaluated for community-based treatment programs. More prolonged courses (e. However. Co-infection with HIV impairs the treatment response. . this drug should not be used for prophylaxis. 191.gov/ncidod/dpd/professional/drug_service. and have survived the test of time. Amodiaquine interferes with hemozoin formation through complexation with heme.S. 201. Artemisinin and its derivatives are cleared rapidly from the circulation. One factor that explains the drugs’ highly selective toxicity against malaria is that parasitized erythrocytes concentrate artemisinin and its derivatives to concentrations 100-fold higher than those in uninfected erythrocytes. Food and Drug Administration (FDA) but are considered investigational for the treatment of certain infections (see Table 201-1). has only recently come to light.htm). Their short half-lives limit their value for prophylaxis and monotherapy. the World Health Organization (WHO) has recommended that artemisinin and its derivatives be used only in areas where there is proven multidrug resistance. CHAPTER e17 Pharmacology of Agents Used to Treat Parasitic Infections Copyright © 2008 The McGraw-Hill Companies. and expulsion by the host. death. and the parent compound artemisinin are sesquiterpene lactones derived from the wormwood plant Artemisia annua. use trypanothione rather than glutathione (which is used by mammalian cells) may explain the parasite-specific activity of antimonials. contact information for these manufacturers may be available from the CDC. albeit rarely (1 case in 2000 treatment courses).. when prolonged use is anticipated.. reaching a level significantly higher than that achieved in plasma. The metabolite albendazole sulfoxide is responsible for the drug’s therapeutic effect outside the gut lumen.e17 Pharmacology of Agents Used to Treat Parasitic Infections Thomas A. artemether. a compound to which artemether and artesunate are both converted. incremental increases in both the recommended daily dosage (to 20 mg/kg) and the duration of treatment (to 28 days) satisfactorily compensated for the growing resistance until around 1990. Artemisinin and its derivatives are highly lipid soluble and readily cross both host and parasite cell membranes. but successful treatment of tissue helminth infections (e. Sodium stibogluconate is available in aqueous solution and is administered parenterally. the endoperoxide moiety of dihydroartemisinin decomposes. There has since been a steady erosion in the capacity of Sbv to induce long-term cure in patients with kala-azar who live in eastern India. Although low-level unresponsiveness to Sbv was identified in India in the 1970s. but are not active against intrahepatic forms. and safety for use during pregnancy and lactation is presented in Chap. but there are few data regarding the drug’s use in patients with hepatic disease. Drugs marked with a dagger (†) are available only through their manufacturers. Albendazole is extensively metabolized in the liver. amodiaquine is now of limited use because of the spread of resistance. the mean half-life of the first phase is <2 h. are effective.g. the drug should be administered in treatment cycles of 28 days interrupted by 14 days off therapy. Although rapidly absorbed. Albendazole is poorly absorbed from the GI tract. thus. Severe adverse events can occur. Pentavalent antimonials are active only after bioreduction to the trivalent Sb(III) form. A combined formulation of artemether and lumefantrine has been de- e119 This chapter deals exclusively with the pharmacologic properties of the agents used to treat infections due to parasites. rectal. recrudescence may occur. but there are no recommendations concerning dosage adjustment in patients with impaired renal function. The artemisinin compounds are rapidly effective against the asexual blood forms of Plasmodium spp.g. All rights reserved. or IM administration. IV. resulting in starvation. with the principal plasma metabolite monodesethylamodiaquine as the predominant antimalarial agent. Amodiaquine Amodiaquine has been widely used in the treatment of malaria for >40 years. In the presence of heme or molecular iron. hydatid disease and neurocysticercosis) requires that a sufficient amount of active drug reach the site of infection. primarily because they are affordable. depending on the derivative. The drugs are taken up by the reticuloendothelial system. When administered IV. The compounds are available for oral. Irreversible damage occurs in gastrointestinal (GI) cells of the nematodes. Many of the agents discussed herein are approved by the U. The high concentrations of albendazole sulfoxide attained in cerebrospinal fluid (CSF) probably explain the efficacy of albendazole in the treatment of neurocysticercosis. a critical enzyme involved in the oxidative stress management of Leishmania spp. While highly injurious to nematodes. Singledose albendazole therapy in humans is largely without side effects (overall frequency. Prolonged therapy with full-dose albendazole (800 mg/d) should be approached cautiously in patients also receiving drugs with known effects on the cytochrome P450 system. Amodiaquine and its metabolites are all excreted in urine. inhibiting the polymerization of tubulin and the microtubule-dependent uptake of glucose. This slower phase may be due to conversion of pentavalent antimony to a trivalent form that is the likely cause of the side effects often seen with prolonged therapy. Drugs marked in the text with an asterisk (*) are available only through the Centers for Disease Control and Prevention (CDC) Drug Service (telephone: 404-639-3670 or 404-639-2888. When these agents are used alone. Albendazole sulfoxide crosses the blood-brain barrier. Information on these agents’ major toxicities. amodiaquine behaves as a prodrug after oral administration. arteether. This form inhibits trypanothione reductase. to limit the development of resistance. Sodium stibogluconate is the only pentavalent antimonial available in the United States. Resistance is a major problem in some areas. Administration with a fatty meal increases its absorption by two. may be enhanced by this localization. Antimony appears to have two elimination phases.

While piperazine itself has no antifilarial activity. because it does not eradicate hypnozoites from the liver. and arthralgias. However. Ciprofloxacin See Table 201-1 and Chap. respectively. rapid schizontocidal and gametocidal activity against blood forms of P. Both agents are active against Entamoeba histolytica and appear to work by blocking peptide elongation and thus inhibiting protein synthesis. Because of the potential for drug accumulation. 127. Dehydroemetine Emetine is an alkaloid derived from ipecac. DEC is active against Ascaris spp. The bioavailability of atovaquone varies considerably. Bithionol is readily absorbed from the GI tract. and slowly excreted in the urine in unchanged form. with cure rates of 80–90% recorded in acute infections. Malarone is a fixed-dose combination of atovaquone and proguanil used for malaria prophylaxis as well as for the treatment of acute. Compared with susceptible strains. interleukin (IL) 6. (2) The rhodoquinone respiratory chain link is unique to the parasite. because it exhibits extensive tissue binding. Benznidazole is believed to exert its trypanocidal effects by generating oxygen radicals to which the parasites are more sensitive than mammalian cells because of a relative deficiency in antioxidant enzymes. Clindamycin See Table 201-1 and Chap. 191. Benznidazole is highly lipophilic and readily absorbed. with pruritus. however. Continued accumulation of chloroquine in the parasite’s acidic food vacuoles results in drug levels that are 600-fold higher at this site than in plasma. The drug is active against both the erythrocytic and the exoerythrocytic stages of Plasmodium spp. About half of the parent drug is excreted in urine. Azoles See Table 201-1 and Chap. In the mammalian respiratory chain. All rights reserved. DEC is well absorbed after oral administration. The drug is eliminated largely by renal excretion. but the rate of excretion decreases as plasma levels decline. only 5% of the dose is excreted unchanged in the urine. 161. This agent exhibits potent activity against toxoplasmosis and babesiosis when used with pyrimethamine and azithromycin. falciparum. a progressive decrease in efficacy when the drug is used widely in human populations) has not been observed. Chloroquine. If more than one dose is to be administered to an individual with renal dysfunction. Absorption after a single oral dose is slow.e. inhibiting the electron transport system at the level of the cytochrome bc1 complex. Chloroquine can be administered IV. the dose should be reduced commensurate with the reduction in creatinine clearance rate. Benznidazole also appears to alter the balance between proand anti-inflammatory mediators by downregulating the synthesis of nitrite. chloroquine-resistant plasmodia transport chloroquine out of intraparasitic compartments more rapidly and maintain lower chloroquine concentrations in their acid vesicles. concentrates in the food vacuoles of intraerythrocytic parasites because of a relative pH gradient between the extracellular space and the acidic food vacuole. The development of resistance under drug pressure (i. a loading dose is required to yield effective plasma concentrations. a weak base. Alkalinization of the urine prevents renal excretion and increases the half-life of DEC. chloroquine is rapidly converted to a membrane-impermeable protonated form and is trapped. although DEC’s effect is variable when administered to persons with filariasis. its mechanism of action remains to be fully defined. Emetine is rapidly absorbed after parenteral administration. the parasite is effectively killed with its own metabolic waste. Patients co-infected with this nematode may expel live but paralyzed worms after treatment. Atovaquone Atovaquone is a hydroxynaphthoquinone that exerts broad-spectrum antiprotozoal activity via selective inhibition of parasite mitochondrial electron transport. making once-weekly administration possible for prophylaxis in areas with sensitive strains. diethylcarbamazine (DEC) remains the treatment of choice for lymphatic filariasis and loiasis and has also been used for visceral larva migrans. Malarone has been shown to be effective in regions with multidrug-resistant P. It is not active against intrahepatic forms (P. DEC enhances adherence properties of eosinophils. Bithionol Bithionol is a chlorinated bisphenol with activity against trematodes. Bithionol competitively inhibits electron transfer to fumarate by rhodoquinone. vivax and P. Use in patients with onchocerciasis can precipitate a Mazzotti reaction. disruption of microtubule formation. . Dapsone See Table 201-1 and Chap. No dosage adjustments are needed in patients with mild to moderate renal impairment. The elimination half-life is increased in patients with moderate hepatic impairment. Bithionol is parasite specific for two reasons: (1) Fumarate reductase catalyzes the reverse of the reaction of mammalian succinic dehydrogenase in the Krebs cycle. and alteration of helminthic surface membranes resulting in enhanced killing by the host’s immune system.. dehydroemetine is synthetically derived from emetine and is considered less toxic. ovale and Plasmodium malariae and against susceptible strains of P. Benznidazole This oral nitroimidazole derivative is used to treat Chagas’ disease. but excessively rapid parenteral administration can result in seizures and death from cardiovascular collapse. PART 7 Infectious Diseases Copyright © 2008 The McGraw-Hill Companies. falciparum malaria.. Like other piperazines. fever. 127. the piperazine ring of DEC is essential for the drug’s activity. Parasitized erythrocytes accumulate chloroquine in significantly greater concentrations than do normal erythrocytes. Proposed mechanisms include immobilization due to inhibition of parasite cholinergic muscle receptors. Hydroxychloroquine. It is no longer produced. vivax and P. In addition. The mean half-life of chloroquine is 4 days. as a result. Azithromycin See Table 201-1 and Chap. is equivalent to chloroquine in its antimalarial efficacy but is preferred to chloroquine for the treatment of autoimmune disorders because it produces less ocular toxicity when used in high doses. patients with Plasmodium vivax or Plasmodium ovale infections must be given radical prophylaxis. Once it enters the acidic food vacuole. inhibiting parasite heme polymerase. but the dose should not be reduced for persons with acute malaria and renal insufficiency. The high accumulation of chloroquine results in an increase in pH within the food vacuole to a level above that required for the acid proteases’ optimal activity. increases two. Resistance to atovaquone has yet to be reported. a congener of chloroquine. Although DEC was shown to be an effective agent for treatment of lymphatic filariasis in 1947.to threefold with a fatty meal. Chloroquine is well absorbed. rapidly distributed throughout the body. but limited supplies are available from the CDC. ovale). with peak plasma concentrations reached within 1–2 h. uncomplicated P. the quinone electron carrier is ubiquinone. The drug is extensively metabolized. A therapeutic drug level in plasma is reached 2–3 h after oral administration (the preferred route). and IL-10 in macrophages. Fasciola hepatica uses fumarate reduction coupled to rhodoquinone for anaerobic energy metabolism. Atovaquone possesses a novel mode of action against Plasmodium spp.e120 veloped for the treatment of acute uncomplicated falciparum malaria in areas where Plasmodium falciparum is resistant to chloroquine and antifolates. It is unknown if atovaquone is dialyzable. the result is impaired anaerobic energy metabolism and trematode death. and is dose-limited above 750 mg. with <5% found in feces. the use of atovaquone is contraindicated in persons with severe renal impairment (creatinine clearance rate < 30 mL/min).. Monthly administration provides effective prophylaxis against both bancroftian filariasis and loiasis. Both agents are contraindicated in patients with renal disease. No parenteral form is available. Diethylcarbamazine* A derivative of the antihelminthic agent piperazine with a long history of successful use. 127. Chloroquine This 4-aminoquinoline has marked. falciparum.

This difference results in a lower turnover of ornithine decarboxylase and a more rapid decrease of polyamines in trypanosomes than in the mammalian host. The mechanisms by which fumagillin inhibits microsporidial replication are poorly understood. Iodoquinol is contraindicated in patients with liver disease. . Diloxanide furoate is given alone to asymptomatic cyst passers. Widespread use of ivermectin for treatment of intestinal nematode infections in sheep and goats has led to the emergence of drug resistance in veterinary practice. Eflornithine readily crosses the blood-brain barrier. Although originally designed as an antineoplastic agent. and scabies. b. This drug is effective when used topically to treat ocular infections due to Encephalitozoon spp. histolytica. Eflornithine is less toxic but more costly than conventional therapy. releasing furoic acid and the ester diloxanide. Grapefruit juice should be avoided during treatment because it increases both halofantrine’s bioavailability and halofantrine-induced QT interval prolongation by inhibiting CYP3A4 at the enterocyte level. production resumed after eflornithine was discovered to be an effective cosmetic depilatory agent. Eflornithine HCl can be administered IV or PO. the production of this effective agent ceased despite the increasing incidence of human African trypanosomiasis. its bioavailability after oral administration is only 54%. The diminished effectiveness of eflornithine against T. Furazolidone is a monoamine oxidase (MAO) inhibitor. only diloxanide appears in the systemic circulation. When given systemically. which damage important cellular compo- nents. Furazolidone This nitrofuran derivative is an effective alternative agent for the treatment of giardiasis and also exhibits activity against Isospora belli. and infection with Dientamoeba fragilis. the dosage should be reduced in patients with renal failure. For patients with active amebic infections. The selective antiparasitic activity of eflornithine is partly explained by the structure of the trypanosomal enzyme. thus caution should be used in its concomitant administration with other drugs (especially indirectly acting sympathomimetic amines) and in the consumption of food and drink containing tyramine during treatment. a substituted acetanilide. including DNA. is an effective luminal agent for the treatment of amebiasis. a hydroxyquinoline. however. Since it is the only agent active against Giardia that is available in liquid form. rhodesiense. It is poorly absorbed. involves an NADH oxidase. balantidiasis. glutamate-dependent chloride channels. Fumagillin Fumagillin is a water-insoluble antibiotic that is derived from the fungus Aspergillus fumigatus and is active against microsporidia. the first enzyme in the biosynthesis of the polyamines putrescine and spermidine. However. While active against the intestinal helminths Ascaris lumbricoides and Enterobius vermicularis. chiefly as the glucuronide metabolite. Iodine dermatitis occurs occasionally during iodoquinol treatment. therefore. Ivermectin is highly active against microfilariae of the lymphatic filariases but has no macrofilaricidal activity. this side effect was readily reversed when administration of the drug was stopped. All rights reserved. b. Although the mechanism of action is poorly understood. an enzyme required for the maintenance of intracellular thiols in the correct redox state and in the removal of reactive oxygen metabolites. The elimination half-life of halofantrine is 1–2 days. eflornithine has proven effective against some trypanosomatids. Most serious are the reactions related to prolonged high-dose therapy (optic neuritis. b. synergistic activity is seen. Polyamines are essential for the synthesis of trypanothione. it should be used with caution in patients with thyroid disease. forming a complex with ferriprotoporphyrin IX and interfering with the degradation of hemoglobin. strongyloidiasis. however. Protein-bound serum iodine levels may be increased during treatment and can interfere with certain tests of thyroid function. or DFMO) is a fluorinated analogue of the amino acid ornithine. Omeprazole reduces the oral bioavailability of furazolidone. levels peak within 1 h and disappear within 6 h. The kidney excretes >80% of the drug dose. These effects may persist for as long as 6 months after discontinuation of therapy. is a luminally active agent used to eradicate the cysts of E. However. which lacks a 36-amino-acid C-terminal sequence found on mammalian ornithine decarboxylase. Diloxanide furoate is rapidly absorbed after oral administration. diloxanide is generally administered in combination with a 5-nitroimidazole such as metronidazole or tinidazole. Diloxanide furoate is contraindicated in pregnant and breast-feeding women and in children <2 years of age. When coadministered with a 5-nitroimidazole. furazolidone treatment is contraindicated in mothers who are breast-feeding and in neonates. gambiense. After ingestion. although it is an oral alternative for the treatment of malaria due to chloroquine-resistant P. Recent data suggest that ivermectin acts by opening the neuromuscular membrane-associated. hypertensive crises have not been reported in patients receiving furazolidone. The drug acts as an irreversible suicide inhibitor of ornithine decarboxylase. More than 65% of the drug dose can be recovered from the urine as colored metabolites. The killing effect correlates with the toxicity of reduced products. Eflornithine has specific activity against all stages of infection with Trypanosoma brucei gambiense. At one point. which should not occur if the recommended dosage regimens are followed. CSF levels are highest in persons with the most severe central nervous system (CNS) involvement. fumagillin was effective but caused thrombocytopenia in all recipients in the second week of treatment. Its activity is believed to be similar to that of chloroquine. peripheral neuropathy). Halofantrine exhibits erratic bioavailability. rhodesiense appears to be due to the parasite’s ability to replace the inhibited enzyme more rapidly than T. the occurrence of systemic adverse reactions indicates that this is not the case. the latter acts directly as an amebicide. and ornithine decarboxylase is similar in trypanosomes and mammals. Because hemolytic anemia can occur in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency and glutathione instability. Iodoquinol Iodoquinol (diiodohydroxyquin). it is excreted mainly in feces. however. Although furazolidone had been thought to be e121 largely unabsorbed when administered orally. this development may portend problems in human medical use. It is the drug of choice for the treatment of onchocerciasis. Ivermectin is active at low doses against a wide range of helminths and ectoparasites. Halofantrine This 9-phenanthrenemethanol is one of three classes of arylaminoalcohols first identified as potential antimalarial agents by the World War II Malaria Chemotherapy Program. falciparum. unlike the reductive activation of metronidazole. Eflornithine† Eflornithine (difluoromethylornithine. cutaneous larva migrans. When ivermectin is used in combination with other agents such as DEC or albendazole for treatment of lymphatic filariasis. Furazolidone undergoes reductive activation in Giardia lamblia trophozoites—an event that. diloxanide furoate is hydrolyzed by enzymes in the lumen or mucosa of the intestine. but its absorption is significantly enhanced when it is taken with a fatty meal. and it has been suggested that—since furazolidone inhibits MAO gradually over several days—the risks are small if treatment is limited to a 5-day course. The influx of chloride ions results in hyperpolarization and muscle pa- CHAPTER e17 Pharmacology of Agents Used to Treat Parasitic Infections Copyright © 2008 The McGraw-Hill Companies. although the drug may inhibit methionine aminopeptidase 2 by irreversibly blocking the active site. ivermectin is only variably effective in trichuriasis and is ineffective against hookworms. it is often used to treat young children. it is inactive against T.23-dihydroavermectin) is a derivative of the macrocyclic lactone avermectin produced by the soil-dwelling actinomycete Streptomyces avermitilis. About 90% of an oral dose is excreted in the urine within 48 h. Its mechanism of action is unknown. Halofantrine is metabolized into N-debutyl-halofantrine by the cytochrome P450 enzyme CYP3A4. Ivermectin Ivermectin (22. polyamines are also essential for cell division in eukaryotes. Because the drug contains 64% organically bound iodine.Diloxanide Furoate Diloxanide furoate. halofantrine is thought to share mechanism(s) with the 4-aminoquinolines.

The drug and its main metabolite are not appreciably removed by hemodialysis. and the drug should be discontinued. falciparum in parts of Africa and Southeast Asia. no dose adjustment is needed in persons with renal insufficiency. This agent conforms structurally and in mode of action to the arylaminoalcohol group of antimalarial drugs. mefloquine should not be prescribed to patients with neuropsychiatric conditions.g. All rights reserved. Mebendazole This benzimidazole is a broad-spectrum antiparasitic agent widely used to treat intestinal helminthiases. Pharmacokinetic differences have been detected among various ethnic populations. Lumefantrine exerts its antimalarial effect as a consequence of its interaction with heme. does not inhibit the synthesis of parasitic nucleic acids and proteins. No special chemoprophylactic dosage adjustments are indicated for the achievement of plasma concentrations in dialysis patients that are similar to those in healthy persons. and seizure disorder. In patients with impaired liver function. However. and mild eye irritation may also occur. Concomitant use of quinine. Levamisole Levamisole is the levo-isomer of tetramisole and is used to treat ascariasis and hookworm infection. skin edema. falciparum is resistant to chloroquine and antifolates. Ivermectin is available only as an oral formulation. and a terminal elimination half-life of ~4–5 days in patients with malaria. Vaccinations with attenuated live bacteria should be completed at least 3 days before the first dose of mefloquine. No data exist on mefloquine use after halofantrine use. Artemether and lumefantrine have synergistic activity. levamisole is well tolerated. usually in persons with massive parasite burdens. The pharmacokinetic properties of lumefantrine are reminiscent of those of halofantrine. Mefloquine may lower plasma levels of anticonvulsants. Although its antimalarial activity is slower than that of the artemisinin-based drugs. When used for the treatment of helminthic infections. malaise. the metabolites are excreted in the urine. depression. however. and halofantrine. this quinoline is active only against the asexual erythrocytic stages of malarial parasites. it is almost completely excreted in feces. Unlike quinine. or confusion develops during prophylaxis. psychosis. Adverse effects in patients with filarial infections include fever.e122 ralysis—particularly of the nematode pharynx. with variable oral bioavailability. thus it is available only in tablet form. Lumefantrine Lumefantrine (benflumetol). Mefloquine Mefloquine is the preferred drug for prophylaxis of chloroquine-resistant malaria. including liver function tests and ophthalmic examinations. About 98% of the drug binds to protein. lightheadedness. however. The use of this drug is contraindicated in patients with preexisting blood disorders (e. has marked blood schizontocidal activity against a wide range of plasmodia. No dose reduction is warranted in patients with renal function impairment. In practice. The drug is highly protein bound. leading to higher plasma levels. with more symptoms in individuals with a heavy parasite burden. since mefloquine has been shown to exert variable effects on ritonavir pharmacokinetics that are not explained by hepatic CYP3A4 activity or ritonavir protein binding. only 5–10% of a standard dose is measurable in plasma. Mefloquine should be used with caution by individuals participating in activities requiring alertness and fine-motor coordination. including depression. a fluorene (benzindene) derivative synthesized in the 1970s by the Chinese Academy of Military Medical Sciences (Beijing). The combined formulation of artemether and lumefantrine has been developed for the treatment of falciparum malaria in areas where P. . Sleep abnormalities (insomnia. or drugs producing β-adrenergic blockade may cause significant electrocardiographic abnormalities or cardiac arrest. The proportion absorbed from the GI tract is extensively metabolized in the liver. with side effects usually limited to GI disturbances. Levamisole is rapidly absorbed from the GI tract and is extensively metabolized in the liver. Administration of mefloquine with quinine or chloroquine may increase the risk of convulsions. This event causes sustained depolarization of the muscle membrane and results in paralysis of the worm. high doses can be used for treatment. animal studies indicate that it accumulates at the highest concentration in adipose tissue and liver. The effect of food on bioavailability is unknown. In onchocerciasis. Despite the development of drug-resistant strains of P. Psychosis and seizures occur rarely. the recrudescence rate with the recommended lumefantrine regimen is lower. with consequent blockage of the oral ingestion of nutrients. Like quinine and chloroquine. Transient abdominal pain and diarrhea sometimes occur. mefloquine is an effective drug throughout most of the world. Ivermectin is distributed widely throughout the body. agranulocytosis) or Sjögren’s syndrome. periodic evaluations are recommended. Ivermectin is generally administered as a single dose of 150–200 μg/ kg. generalized anxiety disorder. Levamisole appears to act by binding to a distinctive ion channel that forms a nicotinic acetylcholine receptor on nematode muscle. Although both mefloquine and chloroquine inhibit hemozoin formation and heme degradation. and clinical studies in China on several hundred patients show the combination to be safe and well tolerated. including quinine. Halofantrine must not be given simultaneously with or <3 weeks after mefloquine because a potentially fatal prolongation of the QTc interval on electrocardiography may occur. Cross-resistance of mefloquine with halofantrine and with quinine has been documented in limited areas. quinidine. the paralysis is seen only in the parasite. impaired liver or biliary function results in higher plasma mebendazole levels in treated patients. these distinctions are of minor importance compared with host immune status and parasite sensitivity. these psychiatric symptoms may be considered prodromal to a more serious event. Mebendazole is available only in oral form but is poorly absorbed from the GI tract. mefloquine differs in that it forms a complex with heme that may be toxic to the parasite. myalgia. with little accumulation in the brain. Its absorption is adversely affected by vomiting and diarrhea but is significantly enhanced when the drug is administered with or after food. Because mebendazole is poorly absorbed. use of mefloquine is not considered an indication for pregnancy termination. Its mechanism of action is similar to that of albendazole. Women of childbearing age who are traveling to areas where malaria is endemic should be warned against becoming pregnant and encouraged to practice contraception during malaria prophylaxis with mefloquine and for up to 3 months thereafter. therefore. PART 7 Infectious Diseases Copyright © 2008 The McGraw-Hill Companies. Metabolites appear in the urine and bile. restlessness. Mefloquine is excreted mainly in the bile and feces. the elimination of mefloquine may be prolonged. considerable augmentation of oral bioavailability by concomitant fat intake. however. mefloquine has a relatively poor affinity for DNA and. Because these chloride channels are present only in invertebrates. it is a more potent inhibitor of parasite malic dehydrogenase and exhibits a more specific and selective effect against intestinal nematodes than the other benzimidazoles. Few data exist to guide therapy in hosts with conditions that may influence drug pharmacokinetics. If the drug is to be administered for a prolonged period. in the case of unplanned pregnancy. Mefloquine HCl is poorly water soluble and intensely irritating when given parenterally. and (occasionally) postural hypotension. the adverse effects of ivermectin in therapeutic doses are minimal.. pruritus. a degradation product of hemoglobin metabolism. schizophrenia. mefloquine. abnormal dreams) have occasionally been reported. Caution should be exercised with regard to concomitant antiretroviral therapy. as a result. More severe complications of ivermectin therapy for onchocerciasis include encephalopathy in patients heavily infected with Loa loa. its incidence of side effects is low. If acute anxiety. This reaction has led to the suspension of ivermectin distribution for this indication in regions where the two filarial infections are coendemic. The severity of such side effects is related to the intensity of parasite infection. The adverse effects are generally self-limiting and only occasionally require symptom-based treatment with antipyretics or antihistamines. In the absence of parasitic infection.

General recommendations for the use of miltefosine are limited by the exclusion of specific groups from the published clinical trials: persons <12 or >65 years of age. It is also a molluscacide and is used in snail-control programs. Resistance to miltefosine has not been observed clinical- ly. However. is widely distribut.5 months are required for erythrocyte cholinesterase levels to return to normal. peroxidases. Metrifonate Metrifonate has selective activity against Schistosoma haematobium. Although fears of the development of cysticercosis in patients with Taenia solium infections have proved unfounded. and other highly reactive and cytotoxic molecules. Tablets are given on an empty stomach in the morning after a liquid meal the night before. the recommended use of purgatives. Miltefosine is the first oral drug that has proved to be highly effective and comparable to amphotericin B against visceral leishmaniasis in India. Nifurtimox* This nitrofuran compound is a cheap and effective oral agent for the treatment of acute Chagas’ disease. Melarsoprol enters the parasite via an adenosine transporter. the necessarily long duration of therapy. Melarsoprol. drug-resistant strains lack this transport system. originally developed as an antineoplastic agent. primarily by glucuronidation. the drug is administered for 7 days. as a result. a nitro anion radical is formed and undergoes autooxidation.5% of the original drug is excreted in urine. The drug is approved for use in children 1–11 years of age. which theoretically can result in autoinfection. a program sponsored by the WHO and other international groups. however. The efficacy of a 28-day treatment course in Indian visceral leishmaniasis is equivalent to that of amphotericin B therapy. A second course is often prescribed. When nifurtimox is reduced in the trypanosome.2-dichlorovinyl dimethylphosphate. lamblia directly reduces nitazoxanide by transfer of electrons in the absence of ferredoxin. <0. Melarsoprol is always administered IV. 127. This trivalent arsenical compound is indicated for the treatment of HAT with neurologic involvement and for the treatment of early HAT that is resistant to suramin or pentamidine. it is still recommended that a brisk purgative be given 2 h after the first dose. The most serious adverse reaction is reactive encephalopathy. It is recommended that nitazoxanide be taken with food. This organophosphorous compound is a prodrug that is converted nonenzymatically to dichlorvos (2. miltefosine (hexadecylphosphocholine). a highly active chemical that irreversibly inhibits the acetylcholinesterase enzyme.. like other drugs containing heavy metals. All rights reserved. however. but the drug is believed to inhibit tegumental acetylcholine receptors that mediate glucose transport. nitazoxanide is rapidly hydrolyzed to an active metabolite. Niclosamide Niclosamide is active against a wide variety of adult tapeworms but not against tissue cestodes. it appears that a shortened course of 21 days may be equally efficacious. metrifonate produces a 95% decrease in plasma cholinesterase activity within 6 h.. Trypanosoma cruzi. it is active against other intestinal protozoa as well. Studies have shown that the PFOR enzyme from G.e123 ed.e. HIV-infected patients. Metronidazole and Other Nitroimidazoles See Table 201-1 and Chap. but the course may have to be interrupted because of drug toxicity. Miltefosine In the early 1990s. was discovered to have significant antiproliferative activity against Leishmania spp. Despite the abundance of catalases. depriving the parasite of its main sulfhydryl antioxidant. resulting in the generation of the superoxide anion O2–. In 1995. where antimonial-resistant cases are prevalent. they are very vulnerable to by-products of oxygen reduction.. persons with the most advanced disease. Nitazoxanide Nitazoxanide is a 5-nitrothiazole compound used for the treatment of cryptosporidiosis and giardiasis. Because melarsoprol is intensely irritating. Tizoxanide then undergoes conjugation. After oral administration.Melarsoprol* Melarsoprol has been used since 1949 for the treatment of human African trypanosomiasis (HAT). lamblia. However. The drug uncouples oxidative phosphorylation in parasite mitochondria. brucei parasites in vitro and in experimental animal models. thereby blocking the uptake of glucose by the intestinal tapeworm and resulting in the parasite’s death. its antiparasitic effects appear to be more specific. Melarsoprol sequesters dihydrotrypanothione. A small but therapeutically significant amount of the drug enters the CSF. tizoxanide (desacetyl-nitazoxanide). Nifurtimox is well absorbed and undergoes rapid and extensive biotransformation. Treated persons should not be exposed to neuromuscular blocking agents or organophosphate insecticides for at least 48 h after treatment. no studies have been conducted to determine whether the pharmacokinetics of CHAPTER e17 Pharmacology of Agents Used to Treat Parasitic Infections Copyright © 2008 The McGraw-Hill Companies. and— most important—limited availability (i. . After a single oral dose. Cure rates in cutaneous leishmaniasis are comparable to those obtained with antimony. disintegration of the adult tapeworm results in the release of viable ova. 2. Miltefosine is also effective in previously untreated visceral infections. DDVP). with ~80% of the arsenic found in feces. The DNA-derived PFOR protein sequence of Cryptosporidium parvum appears to be similar to that of G. Schistosomal cholinesterase is more susceptible to dichlorvos than is the corresponding human enzyme. and T. Metrifonate is administered in a series of three doses at 2-week intervals. The exact mechanism of action of metrifonate is uncertain. with an average case-fatality rate of 50%. These effects are synergistic. helping to maintain an intracellular reducing environment by reduction of disulfide trypanothione to its dithiol derivative dihydrotrypanothione. and this dose is followed by another 1 h later. interacts with thiol groups of several different proteins. Prolonged use is required. which affects 6% of treated individuals and usually develops within 4 days of the start of therapy. care must be taken to avoid infiltration of the drug. breast-feeding women. which develops in 40– 70% of recipients. hydroperoxyl radical (HO2). Trypanosomes lack catalase and have very low levels of peroxidase. entered into an agreement with the company now known as ASTA Medica/Zentaris to develop miltefosine for the treatment of visceral leishmaniasis in India. The activity of miltefosine is attributed to interaction with cell signal transduction pathways and inhibition of phospholipid and sterol biosynthesis. The compound is excreted rapidly. and individuals with significant renal or hepatic insufficiency. depriving the parasite of the essential enzyme system that is responsible for keeping trypanothione reduced. Its use is limited by its side effects. nifurtimox has a poor therapeutic index. Niclosamide is poorly absorbed. Tropical Disease Research. Melarsoprol is highly toxic. on a named-patient basis from the manufacturer). For treatment of hymenolepiasis. hydrogen peroxide (H2O2).g. Glucocorticoids are administered with melarsoprol to prevent this development. The scolex and proximal segments of the tapeworms are killed on contact with niclosamide and may be digested in the gut. The drug is readily absorbed from the GI tract. and inhibits trypanothione reductase.. and accumulates in several tissues. Trypanothione reductase is a key enzyme involved in the oxidative stress management of both Trypanosoma and Leishmania spp. Interference with the PFOR enzyme–dependent electron transfer reaction may not be the only pathway by which nitazoxanide exerts antiprotozoal activity. Niclosamide rapidly causes spastic paralysis of intestinal cestodes in vitro. and superoxide dismutases that neutralize these destructive radicals in mammalian cells. with a fairly rapid return to normal. however. cysteine) on which the mammalian host depends for maintenance of high thiol levels. The antiprotozoal activity of nitazoxanide is believed to be due to interference with the pyruvate-ferredoxin oxidoreductase (PFOR) enzyme–dependent electron transfer reaction that is essential to anaerobic energy metabolism. The selectivity of arsenical action against trypanosomes is due at least in part to the greater melarsoprol affinity of reduced trypanothione than of other monothiols (e. The changing view on the mode of action of arsenicals is well documented.

rapidly metabolized. It is the mainstay of treatment for schistosomiasis and is a critical part of community-based control programs. Praziquantel induces changes in the antigenicity of the parasite by causing the exposure of concealed antigens. Pyrantel pamoate is usually effective in a single dose. whose inhibition of dihydrofolate reductase in the parasite disrupts deoxythymidylate synthesis. It is well absorbed but undergoes extensive first-pass hepatic clearance. leading to the expulsion of live but mostly paralyzed worms. headache. Although the exact mechanism of action remains unclear. Primaquine must be metabolized by the host to be effective. Therefore. Although the parasiticidal activity of the three oxidative metabolites remains unclear.9%). Proguanil exerts its effect primarily by means of the metabolite cycloguanil. All rights reserved. paromomycin is poorly absorbed from the intestinal lumen. they are believed to affect both pyrimidine synthesis and the mitochondrial electron transport chain. systemic absorption is very limited. as competition for binding sites may occur. Patients should be warned that their urine might have an intense orange-red color. Tizoxanide is excreted in urine. including decreases in glucose uptake. paromomycin can cause ototoxicity and nephrotoxicity. oxamniquine produces marked tegumental alterations that are similar to those seen with praziquantel but that develop less rapidly. including DNA. Despite its toxicity. Primaquine is otherwise well tolerated. Proguanil (Chloroguanide) Proguanil inhibits plasmodial dihydrofolate reductase and is used with atovaquone for oral treatment of uncomplicated malaria or with chloroquine for malaria prophylaxis in parts of Africa without widespread chloroquine-resistant P. falciparum. bile. It is available for parenteral and aerosolized administration. primarily the liver. thus interfering with a key pathway involved in the biosynthesis of pyrimidines required for nucleic acid replication. In treated adult schistosomes. only a small fraction of the dose of the parent drug is excreted unchanged. This safe. lamblia than standard agents. Praziquantel This heterocyclic pyrazinoisoquinoline derivative is highly active against a broad spectrum of trematodes and cestodes. Like levami- PART 7 Infectious Diseases Copyright © 2008 The McGraw-Hill Companies. Tizoxanide is highly bound to plasma protein (>99. Symptoms begin 30 min after ingestion. Side effects are uncommon and usually mild. although hallucinations and seizures have been reported. Praziquantel is completely metabolized in humans. may require spasmolytics for relief. it is known to exert a wide range of effects. this aminoglycoside is an effective oral agent for the treatment of infections due to intestinal protozoa. The drug is 75% protein-bound. Pentamidine Isethionate This diamidine is an effective alternative agent for some forms of leishmaniasis and trypanosomiasis. Serum levels are reduced by glucocorticoids. or with cimetidine. including interaction with trypanosomal kinetoplast DNA. Oxamniquine is administered orally as a single dose and is well absorbed. Primaquine Phosphate Primaquine. Piperazine The antihelminthic activity of piperazine is confined to ascariasis and enterobiasis. 40–60% of the proguanil dose is excreted by the kidneys. and spleen. and feces. and the synthesis of nucleic acids and proteins. inexpensive drug is used to treat a variety of intestinal nematode infections but is ineffective in trichuriasis. and ATP levels. Primaquine causes marked hypotension after parenteral administration and therefore is given only by the oral route. particularly carbohydrates. women of childbearing age for whom atovaquone/proguanil is prescribed should continue taking folate supplements to prevent neural-tube birth defects. with an elimination half-life of 12 days. in fact. Oxamniquine exhibits anticholinergic properties. Pyrantel Pamoate Pyrantel is a tetrahydropyrimidine formulated as pamoate. vivax infections. lactate release. and the high levels of drug in the gut compensate for this relatively weak activity. well-tolerated. The metabolites appear to have significantly less antimalarial activity than primaquine. it remains the drug of choice for radical cure of P. . but its primary mode of action seems to rely on ATP-dependent enzymatic drug activation generating an intermediate that alkylates essential macromolecules. Patients should be warned. causing an influx of chloride ions in the nematode somatic musculature. as this occurrence can be unsettling. carbamazepine. becoming evident 4–8 days after treatment. and phenytoin. kidney. and toxicity should not be a concern in persons with normal kidneys. Drug levels are increased and elimination is impaired in patients with hepatic insufficiency. causing misreading of mRNA codons. irrespective of the G6PD status of the patient. Levels of the drug are increased when it is taken with food. Food retards absorption and reduces bioavailability. and is excreted slowly over several weeks. and usually disappear spontaneously after a few hours. however. dizziness. The main routes of elimination are hepatic biotransformation and renal excretion. adrenal. The ultimate effect is flaccid paralysis of the muscle fibers. however. and tizoxanide glucuronide is excreted in urine and bile. Topical formulations are not generally available. nausea. Proguanil is extensively absorbed regardless of food intake. glycogen content. Paromomycin inhibits protozoan protein synthesis by binding to the 30S ribosomal RNA in the aminoacyl-tRNA site. the major mechanism is disruption of the parasite tegument. If absorbed or administered systemically. and inhibition of RNA polymerase. All of the effects of praziquantel can be attributed either directly or indirectly to an alteration of intracellular calcium concentrations. like other aminoglycosides. Pentamidine does not penetrate well into the CNS. with 80% of the dose recovered as metabolites in urine within 4 days. Parenteral paromomycin appears to be effective against visceral leishmaniasis in India. causing tetanic contractures with loss of adherence to host tissues and. Paromomycin (Aminosidine) First isolated in 1956. Pulmonary concentrations of pentamidine are increased when the drug is delivered in aerosolized form. disintegration or expulsion. No steady-state plasma concentration is attained in persons given daily injections. although susceptibility to this drug exhibits regional variation. It is rapidly and almost completely absorbed from the GI tract. and drowsiness. has a broad spectrum of activity against all stages of plasmodial development in humans but has been used most effectively for eradication of the hepatic stage of these parasites. interference with polyamine synthesis by a decrease in the activity of ornithine decarboxylase. Oxamniquine This tetrahydroquinoline derivative is an effective alternative agent for the treatment of Schistosoma mansoni. About 70% of an administered dose is excreted in urine as a mixture of pharmacologically inactive metabolites. However. The drug may induce the oxidation of hemoglobin into methemoglobin. Pentamidine isethionate is well absorbed. ribosomal function. the result is extensive accumulation of pentamidine in tissues. While its mechanism of action remains undefined. Patients should be tested for G6PD deficiency before they receive primaquine. their hemolytic activity is greater than that of the parent drug. Paromomycin is less active against G.e124 tizoxanide and tizoxanide glucuronide differ in fasted versus fed subjects. Praziquantel exerts its parasitic effects directly and does not need to be metabolized to be effective. Patients with schistosomiasis who have heavy parasite burdens may develop abdominal discomfort. Piperazine acts as an agonist at extrasynaptic γ-aminobutyric acid (GABA) receptors. ultimately. an 8-aminoquinoline. Praziquantel also produces alterations in schistosomal glucose metabolism. It is not known to what extent praziquantel crosses the placenta. The pharmacokinetics of nitazoxanide in patients with impaired hepatic and/or renal function have not been studied. It is. There are no clinical data indicating that folate supplementation diminishes drug efficacy. chloroquine. is highly tissue bound. caution should be used when administering this agent concurrently with other highly plasma protein–bound drugs with narrow therapeutic indices.

Pyrimethamine When combined with short-acting sulfonamides. equally effective agents. Pyrantel pamoate is poorly absorbed from the intestine. Suramin is parenterally administered. the parasites that cause these infections cannot utilize preformed pyrimidines obtained through salvage pathways but rather rely completely on de novo pyrimidine synthesis. in humans. more rarely. The differing relative quinacrine uptake rate between human cells and G. The drug’s metabolites are also excreted in urine and may be responsible for toxicity in patients with renal failure. which may explain its usefulness in dracunculiasis and trichinosis. serum levels of theophylline should be monitored closely in this situation. this diaminopyrimidine is effective in malaria. only cautious use is advised. Quinacrine is rapidly absorbed from the intestinal tract and is widely distributed in body tissues. which produces hyperpolarization of muscle cells in intestinal helminths. When tafenoquine is taken with food. It binds to plasma proteins and persists at low levels for several weeks after infusion. At the usual dosage. it is likely to be similar to that of other benzimidazole drugs: namely. spiramycin appears to have the lowest risk of drug interactions. particularly by CYP3A4. the drug is 87% bound to human plasma proteins. blood dyscrasias. Like primaquine. However. inhibition of polymerization of parasite β-tubulin. It is not recommended for pregnant women or for children <12 months old. Quinine and Quinidine When combined with another agent. pyrimethamine alone causes little toxicity except for occasional skin rashes and. tafenoquine is a potent oxidizing agent. causing hemolysis in patients with G6PD deficiency as well as methemoglobinemia. quinacrine can be obtained from alternative sources through the CDC Drug Service. resulting in its irreversible paralysis and allowing the natural expulsion of the worm. Its production was discontinued in 1992. This drug does not penetrate the CNS. Thiabendazole also suppresses egg and/ or larval production by some nematodes and may inhibit the subsequent development of eggs or larvae passed in feces. the drug should be administered with folinic acid. Indeed. drug concentrations remain at therapeutic levels for up to 2 weeks. No particular adjustments are recommended in patients with renal or hepatic failure. can include life-threatening ventricular arrhythmias that disappear with drug discontinuation. Pyrimethamine is well absorbed. Its prolonged half-life (2–3 weeks) allows longer dosing intervals when the drug is used for prophylaxis. The drug inhibits the nonenzymatic polymerization of the highly reactive. the urinary excretion of active compounds represents only 20% of the administered dose. The cinchona alkaloids are extensively metabolized. The usual dose of thiabendazole is determined by the patient’s weight. Tafenoquine has been well tolerated in clinical trials. The drug is rapidly absorbed from the GI tract but can also be absorbed through the skin. Suramin appears to inhibit all trypanosome glycolytic enzymes more effectively than it inhibits the corresponding host enzymes. and analgesic effects. 127. vivax. Quinidine is both more potent as an antimalarial and more toxic than quinine. While the mechanism of action is similar to that of other macrolides. Serious reactions to spiramycin are rare. Tetracyclines See Table 201-1 and Chap. The drug also inhibits the helminth-specific enzyme fumarate reductase. there have been no reports of drug resistance in humans. Resistance correlates with decreased drug uptake. Quinine acts rapidly against the asexual blood stages of all forms of human malaria. This agent is extensively metabolized in the liver before ultimately being excreted. Quinine concentrates in the acidic food vacuoles of Plasmodium spp. >85% of the dose is passed unaltered in feces. in neonates. the drug has as its target the nicotinic acetylcholine receptor on the surface of nematode somatic muscle. Suramin* This derivative of urea is the drug of choice for the early stage of African trypanosomiasis. 127. thus inhibiting multiple enzymes essential to parasite energy metabolism. toxicity is avoided by an increase in the concentration of plasma glycoproteins. The absorbed portion is metabolized and excreted in urine. Coadministration of thiabendazole in patients taking theophylline can result in an increase in theophylline levels by >50%. However. but some treatment regimens are parasite specific. Of the available macrolides. For severe malaria. Pyrantel pamoate has minimal toxicity at the oral doses used to treat intestinal helminthic infection. Although not commercially available. The drug inhibits NADH oxidase—the same enzyme that activates furazolidone. . the efficacy of spiramycin in toxoplasmosis appears to stem from its rapid and extensive intracellular penetration. Unlike mammalian cells. Piperazine. Renal excretion of quinine is decreased when cimetidine is taken and increased when the urine is acidic. Quinacrine* First introduced as an antimalarial agent in 1930. thiabendazole remains one of the most potent of the numerous benzimidazole derivatives. falciparum and P. Therefore. Thiabendazole Discovered in 1961. chloroquine-resistant malaria and babesiosis. only quinidine (the dextroisomer of quinine) is available in the United States. drug levels are lower in patients with malaria.sole. thiabendazole has anti-inflammatory. the cinchona alkaloid quinine is effective for the oral treatment of both uncomplicated. Despite the emergence and global spread of thiabendazole-resistant trichostrongyliasis among sheep. Quinine is readily absorbed when given orally. The efficacy of pyrimethamine is increasingly limited by the development of resistant strains of P. In patients with malaria. Dose reduction is necessary in persons with severe renal impairment. at these doses. Thiabendazole is active against most intestinal nematodes that infect humans. lamblia may explain the selective toxicity of the drug. The drug readily crosses the placenta. quinacrine is the only drug approved by the FDA for the treatment of giardiasis. its absorption is increased by 50% and the most commonly reported adverse event—mild GI upset—is diminished. antipyretic. Single amino acid substitutions to parasite dihydrofolate reductase confer resistance to pyrimethamine by decreasing the enzyme’s binding affinity for the drug. Pyrantel depolarizes the neuromuscular junction of the nematode. All rights reserved. toxoplasmosis. Its use requires cardiac monitoring. CHAPTER e17 Pharmacology of Agents Used to Treat Parasitic Infections Copyright © 2008 The McGraw-Hill Companies. and isosporiasis. Spiramycin is rapidly and widely distributed throughout the body and reaches concentrations in the placenta up to five times those in serum. Tafenoquine Tafenoquine is an 8-aminoquinoline with causal prophylactic activity. The drug is polyanionic and acts by forming stable complexes with proteins. which results in macrophage drug concentrations 10– 20 times greater than serum concentrations. the elimination half-life of quinine increases according to the severity of the infection. Sulfonamides See Table 201-1 and Chap. Bone marrow suppression sometimes occurs at the higher doses used for toxoplasmosis. Spiramycin† This macrolide is used to treat acute toxoplasmosis in e125 pregnancy and congenital toxoplasmosis. The antiprotozoal mechanism of quinacrine has not been fully elucidated. In animals. is antagonistic to pyrantel pamoate and should not be used concomitantly. Its metabolism is negligible. Alcohol is best avoided due to a disulfiram-like effect. In healthy volunteers. for which folate derivatives are essential cofactors. its use has declined significantly because of a higher frequency of adverse effects than is seen with other. Thiabendazole is available in tablet form and as an oral suspension. This agent is excreted mainly in bile. Thiabendazole should be taken after meals. most of the dose is excreted within the first 24 h. only 20% of the dose is excreted unchanged in urine. Complications of treatment are rare but. Although the exact mechanism of its antihelminthic activity has not been fully elucidated. toxic heme molecule into the nontoxic polymer pigment hemozoin.

McGraw-Hill. and trichomoniasis. 2005. . MCCARTHY JS: Benzimidazoles (albendazole. L Brunton et al (eds). All rights reserved. mebendazole. cestodes. Trimethoprim-Sulfamethoxazole See Table 201-1 and Chap. Pittsburgh. 2d ed. 2d ed. administration with food enhances its absorption and shortens the elimination half-life of the active metabolite. 1995 PART 7 Infectious Diseases Copyright © 2008 The McGraw-Hill Companies. Both the sulfoxide and the sulfone metabolites are highly protein bound (>99%). pp 1021–1036 SHAPIRO TA.e126 Tinidazole This nitroimidazole is effective for the treatment of amebiasis. however. tinidazole must undergo reductive activation by the parasite’s metabolic system before it can act on protozoal targets. WHO. VL Yu et al (eds). 127. triclabendazole). however. FURTHER READINGS ABRAMOWICZ M (ed): Drugs for parasitic infections. 2004 MOORE TA. Tinidazole inhibits the synthesis of new DNA in the parasite and causes degradation of existing DNA. In contrast. 11th ed. Adv Parasitol 61:47. Triclabendazole is effective against all stages of Fasciola spp. In addition. and pharmacovigilance. in Goodman and Gilman’s The Pharmacological Basis of Therapeutics. New York. giardiasis. No information exists on drug interactions. ESun Technologies. Treatment with triclabendazole is typically given in one or two doses.. the significantly longer half-life of tinidazole (>12 h) offers potential cure with a single dose. No clinical data are available regarding dose adjustment in renal or hepatic insufficiency. Triclabendazole While most benzimidazoles have broad-spectrum antihelminthic activity. with little activity against nematodes. pharmacokinetics. resulting in helix destabilization and strain breakage of DNA. dose adjustment is unlikely to be necessary. the antihelminthic activity of triclabendazole is highly specific for Fasciola spp. they exhibit minimal or no activity against F. pp 1021–1048 WARD SA et al: Antimalarial drugs and pregnancy: Safety. Lancet Infect Dis 7:136. 2007 WINSTANLEY P. and Paragonimus spp. Med Lett Drugs Ther 46:1. The mechanism of action and side effects of tinidazole are similar to those of metronidazole. This damage appears to be produced by short-lived reduction intermediates. given the short course of therapy and extensive hepatic metabolism of triclabendazole. The reduced free-radical derivatives alkylate DNA. 2005. Triclabendazole is rapidly absorbed after oral ingestion. 2006 WORLD HEALTH ORGANIZATION: Model Prescribing Information: Drugs Used in Parasitic Diseases. with consequent cytotoxic damage to the parasite. Geneva. Like metronidazole. GOLDBERG DE: Drugs used in the chemotherapy of protozoal infections: Malaria. The active sulfoxide metabolite of triclabendazole binds to fluke tubulin by assuming a unique nonplanar configuration and disrupts microtubule-based processes. thiabendazole. WARD S: Malaria chemotherapy. Resistance to triclabendazole in veterinary use has been reported in Australia and Europe. hepatica. in Antimicrobial Therapy and Vaccines. and other trematodes. no resistance has been documented in humans. but adverse events appear to be less frequent and severe with tinidazole.

and a few small red dots may appear over the cytoplasm (Maurer’s clefts). dark brown-black pigment Banana-shaped. Pale red Schüffner’s dots increase in number as the parasite matures. lysis of red blood cells by water leaves the stained white cells and parasites. the relapsing parasites P. P. 2d ed.e18 Atlas of Blood Smears of Malaria and Babesiosis Nicholas J. orange-brown pigment Round or oval. triangular nucleus. Wright’s. Male gametocytes. 12–18 merozoites. Giemsa’s.) Copyright © 2008 The McGraw-Hill Companies. All rights reserved. Red James’s dots are prominent. D. The malaria parasites are readily seen under the microscope (×1000 magnification) in thick and thin blood smears stained with supravital dyes (e. Pigment in polymorphonuclear cells and trophozoites. Mature schizonts. falciparum Asexual parasites Usually only fine blue ring forms (some resembling stereo headsets) are seen. White. Rare in peripheral blood. Parasitemia level is low. Babesia does not cause the production of pigment in parasites.. a few orange pigment granules RBCs are enlarged. knowlesi. in which the red cells are fixed and the malaria parasites are seen inside the cells. P. B. which can persist at low densities for years. P. red blood cell. male: round. F. In the thick film. round. The e127 morphologic characteristics of the parasites are summarized in Table e18-1. fairly thick rings become highly pleomorphic as the parasite grows. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections. 8–10 merozoites. Breman Four species of blood protozoan parasites cause human malaria: the potentially lethal and often drug-resistant Plasmodium falciparum. malariae Dense. oval. This degree of sensitivity is up to 100 times greater than that of the thin film. and phagocytosed malaria pigment in >5% of neutrophils. large. P. Unlike Plasmodium. A. round trophozoites. male: light blue. nor are schizonts or gametocytes formed. Occasional infections in individuals who have been in tropical forests may be caused by monkey parasites—notably. vivax and P. dense. malariae. thick rings mature to dense. As the parasite matures. Field’s. vivax Irregular. brown or black pigment Large. 8–32 merozoites. Joel G. 8–14 merozoites. and blue (like P. C. Leishman’s). brown pigment RBCs become oval with tufted ends. ovale Regular. Young trophozoites. ovale. Parasitemia level is low. TABLE e18-1 MORPHOLOGIC CHARACTERISTICS OF HUMAN MALARIA PARASITES P. dark brown or black pigment Large. the RBC cytoplasm becomes pale. the cells become crenated. dark blue. falciparum. Old trophozoites. CHAPTER e18 Atlas of Blood Smears of Malaria and Babesiosis Schizonts Gametocytes RBC changes Note: RBC.g. No red dots are seen. male: pale blue. . The thin film is better for speciation and provides useful prognostic information in severe falciparum malaria. Parasitemia level may exceed 2%. mature trophozoite (rectangular or band-form). Several findings are associated with increased mortality risk: high parasite counts. but prominent James’s dots. and P. female: oval. malariae). with the permission of the World Health Organization. a few scattered blue-black pigment granules in cytoplasm RBCs are normal in size. Parasitemia level is low. blue. more mature parasites (>20% containing visible malaria pigment). female: darker blue. Female gametocytes. Common. E. Babesia microti appears as a small ring form resembling P. female: dense blue. allowing detection of densities as low as 50 parasites/μL. FIGURE e18-1 Thin blood films of Plasmodium falciparum. dense ring enlarges to compact. large black pigment granules RBCs are normal in size and shape. pale blue.

A. Old trophozoites. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections. Mature schizonts. Old trophozoites. with the permission of the World Health Organization. Female gametocytes. with the permission of the World Health Organization. A. C. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections. B. Female gametocytes. A. Old trophozoites. Mature schizonts. D.) FIGURE e18-4 Thin blood films of Plasmodium malariae. D. Young trophozoites. E. Male gametocytes. with the permission of the World Health Organization. D. C. Male gametocytes. . All rights reserved. Mature schizonts.e128 PART 7 FIGURE e18-2 Thin blood films of Plasmodium vivax.) Infectious Diseases FIGURE e18-3 Thin blood films of Plasmodium ovale. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections. 2d ed. B. 2d ed. C. Female gametocytes.) Copyright © 2008 The McGraw-Hill Companies. B. 2d ed. Male gametocytes.

B.) FIGURE e18-7 Thick blood films of Plasmodium ovale. B. B. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections. Gametocytes. A. Gametocytes. Schizonts. 2d ed. Gametocytes. A. . with the permission of the World Health Organization. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections. A.) Copyright © 2008 The McGraw-Hill Companies. 2d ed.e129 FIGURE e18-5 Thick blood films of Plasmodium falciparum. Trophozoites. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections. All rights reserved.) CHAPTER e18 Atlas of Blood Smears of Malaria and Babesiosis FIGURE e18-6 Thick blood films of Plasmodium vivax. 2d ed. C. with the permission of the World Health Organization. C. Trophozoites. Schizonts. with the permission of the World Health Organization. Trophozoites.

2004 PART 7 FIGURE e18-9 Thin blood film showing trophozoites of Babesia. 2d ed. SL Hoffman (eds): Tropical Medicine: Science and Practice. Imperial College Press. A.e130 FIGURE e18-8 Thick blood films of Plasmodium malariae.) FURTHER READINGS WARHURST C. Schizonts. All rights reserved. 2d ed. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections. vol 4. G Pasvol. London. with the permission of the World Health Organization. Trophozoites. . C. B. Gametocytes. Pasvol G (series eds): Malaria: A Hematological Perspective. WILLIAMS JE: Laboratory procedures for diagnosis of malaria. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections.) Infectious Diseases Copyright © 2008 The McGraw-Hill Companies. in Abdalla SH. with the permission of the World Health Organization.

harvard. aVL. .e19 Atlas of Electrocardiography Ary L. Goldberger e131 CHAPTER e19 Atlas of Electrocardiography The electrocardiograms (ECGs) in this Atlas supplement those illustrated in Chap.edu. The abbreviations used in this chapter are as follows: AF—atrial fibrillation HCM—hypertrophic cardiomyopathy LVH—left ventricular hypertrophy MI—myocardial infarction NSR—normal sinus rhythm RBBB—right bundle branch block RV—right ventricular RVH—right ventricular hypertrophy MYOCARDIAL ISCHEMIA AND INFARCTION I aVR V1 V4 II aVL V2 V5 III aVF V3 V6 II FIGURE e19-1 Anterior wall ischemia (deep T-wave inversions and ST-segment depressions in I. http://ecg. Copyright © 2008 The McGraw-Hill Companies. All of the figures are from ECG Wave-Maven. The interpretations emphasize findings of specific teaching value. Copyright 2003. 221.bidmc. All rights reserved. Beth Israel Deaconess Medical Center. V3–V6) in a patient with LVH (increased voltage in V2–V5).

e132 I aVR V1 V4 PART 9 Disorders of the Cardiovascular System II aVL V2 V5 III aVF V3 V6 II FIGURE e19-2 Acute anterolateral wall ischemia with ST elevations in V4–V6. All rights reserved. Ischemic ST depressions also in V3 and V4. I aVR V1 V4 II aVL V2 V5 III aVF V3 V6 II FIGURE e19-3 Acute lateral ischemia with ST elevations in I and aVL with probable reciprocal ST depressions inferiorly (II. and aVF). III and aVF. Left atrial abnormality. . Probable old inferior MI with Q waves in leads II. Copyright © 2008 The McGraw-Hill Companies. III.

V1 V4 II aVL V2 V5 III aVF V3 V6 II FIGURE e19-5 Acute MI with marked ST elevations in I. V1–V6 and small pathologic Q waves in V3–V6. Copyright © 2008 The McGraw-Hill Companies. . All rights reserved. III. and prominent ST-segment depressions with upright T waves in V1–V4 consistent with acute posterior MI. aVF) and laterally (V6) suggestive of I aVR acute inferolateral MI. Marked ischemic ST-segment elevations in inferior limb leads (II. Marked reciprocal ST-segment depressions in III and aVF. aVL.I aVR V1 V4 e133 CHAPTER e19 Atlas of Electrocardiography II aVL V2 V5 III aVF V3 V6 II FIGURE e19-4 Sinus tachycardia.

All rights reserved. Copyright © 2008 The McGraw-Hill Companies. .e134 I aVR V1 V4 PART 9 Disorders of the Cardiovascular System II aVL V2 V5 III aVF V3 V6 II FIGURE e19-6 Acute anterior wall MI with ST elevations and Q waves in V1–V4 and aVL and reciprocal inferior ST depressions. I aVR V1 V4 II aVL V2 V5 III aVF V3 V6 II FIGURE e19-7 NSR with premature atrial complexes. pathologic Q waves and ST elevation due to acute anterior/septal MI in V1–V3. RBBB.

V6). I aVR V1 V4 II aVL V2 V5 III aVF V3 V6 II FIGURE e19-9 Extensive old MI involving inferior-posterior-lateral wall (Q waves in leads II. and V6. and Q waves in V5. tall R waves in V1.V2. V1). . aVF. T-wave abnormalities in leads I and aVL. All rights reserved.I aVR V1 V4 e135 CHAPTER e19 Atlas of Electrocardiography II aVL V2 V5 III aVF V3 V6 II FIGURE e19-8 Acute anteroseptal MI (Q waves and ST elevations in V1–V4) with RBBB (see I. Copyright © 2008 The McGraw-Hill Companies. III. V5.

LVH. Absence of right-axis deviation and the presence of upright T waves in V1–V2 are also against RVH.04 s) Q waves in the inferior leads (II. Findings compatible with old anterolateral MI and LV aneurysm. V1 V4 II aVL V2 V5 III aVF V3 V6 II FIGURE e19-11 Old inferior-posterior MI. Pathologic Q waves in V1–V5 and I aVR aVL with ST elevations (a chronic finding in this patient).e136 I aVR V1 V4 PART 9 Disorders of the Cardiovascular System II aVL V2 V5 III aVF V3 V6 II FIGURE e19-10 NSR with PR prolongation (“1st degree AV block”). broad R wave in V1 (a Q wave equivalent). and RBBB. III. Copyright © 2008 The McGraw-Hill Companies. . Wide (0. aVF). left atrial abnormality. All rights reserved.

I aVR V1 V4 e137 CHAPTER e19 Atlas of Electrocardiography II aVL V2 V5 III aVF V3 V6 II FIGURE e19-12 NSR with RBBB (broad terminal R wave in V1) and left anterior hemiblock. . pathologic anterior Q waves in V1–V3 with slow R wave progression. Copyright © 2008 The McGraw-Hill Companies. Patient had severe multivessel coronary artery disease with echocardiogram showing septal dyskinesis and apical akinesis. All rights reserved.

I aVR V1 V4 II aVL V2 V5 III aVF V3 V6 II FIGURE e19-14 Sinus tachycardia. borderline low voltage. aVF. aVL.e138 PERICARDITIS I aVR V1 V4 PART 9 II aVL V2 V5 Disorders of the Cardiovascular System III aVF V3 V6 II FIGURE e19-13 Acute pericarditis with diffuse ST elevations in I. . Diagnosis is acute pericarditis with inferior Q wave MI. and aVF. aVF. III. depressed in V4–V6). II. Also PR-segment elevation in aVR and PR depression in the inferolateral leads. Q-wave and T-wave inversions in II. without T-wave inversions. V3–V6. All rights reserved. II. diffuse ST elevations (I. Copyright © 2008 The McGraw-Hill Companies. III. V2–V6) with associated PR deviations (elevated PR in aVR.

II. Copyright © 2008 The McGraw-Hill Companies. . right-axis deviation and RVH (Rr' in V1) in a patient with mitral stenosis. left atrial abnormality (see l.VALVULAR HEART DISEASE AND HYPERTROPHIC CARDIOMYOPATHY I aVR V1 V4 e139 CHAPTER e19 Atlas of Electrocardiography II aVL V2 V5 III aVF V3 V6 II FIGURE e19-15 NSR. and LVH by voltage criteria with borderline right-axis deviation in a patient with mixed mitral stenosis (left atrial abnormality and right-axis deviation) and mitral regurgitation (LVH). I aVR V1 V4 II aVL V2 V5 III aVF V3 V6 II FIGURE e19-16 NSR. left atrial abnormality. V1). Prominent precordial T-wave inversions and QT prolongation also present. All rights reserved.

LVH (tall R in aVL). Copyright © 2008 The McGraw-Hill Companies. I aVR V1 V4 II aVL V2 V5 III aVF V3 V6 II FIGURE e19-18 NSR. . Tall R in V4 may be due to concomitant LVH. All rights reserved. tall R in V2 with vertical QRS axis (positive R in aVF) indicating RVH.e140 I aVR V1 V4 PART 9 Disorders of the Cardiovascular System II aVL V2 V5 III aVF V3 V6 II FIGURE e19-17 Coarse AF. first-degree A-V block (P-R prolongation). Patient had severe mitral stenosis with moderate mitral regurgitation. RBBB (Rr') and left anterior fascicular block in a patient with HCM. Deep Q waves in I and aVL consistent with septal hypertrophy.

e141 CHAPTER e19 Atlas of Electrocardiography I aVR V1 V4 II aVL V2 V5 III aVF V3 V6 II FIGURE e19-19 LVH with deep T-wave inversions in limb leads and precordial leads. Striking T-wave inversions in mid-precordial leads suggest apical HCM. Copyright © 2008 The McGraw-Hill Companies. All rights reserved. .

right-axis deviation. . aVF. III. All rights reserved. V1 V4 II aVL V2 V5 III aVF V3 V6 II FIGURE e19-21 Sinus tachycardia. and V1–V5 in a patient with atrial septal defect and severe pulmonary hypertension. incomplete RBBB. RVH with tall R in V1 and deep S in V6 and inverted T waves in II. and right precordial T-wave inversions I aVR consistent with acute RV overload in a patient with pulmonary emboli. Copyright © 2008 The McGraw-Hill Companies.e142 PULMONARY EMBOLISM AND CHRONIC PULMONARY HYPERTENSION I aVR V1 V4 PART 9 II aVL V2 V5 Disorders of the Cardiovascular System III aVF V3 V6 II FIGURE e19-20 Sinus tachycardia with S1Q3T3 pattern (T-wave inversion in III).

(3) borderline peaked P waves in lead II with vertical P-wave axis (probable right atrial overload). This combination is seen typically in severe chronic obstructive lung disease. (3) delayed precordial transition. (2) incomplete RBBB (rsr' in V1–V3). V1 V4 II aVL V2 V5 III aVF V3 V6 II FIGURE e19-23 (1) Low voltage. Copyright © 2008 The McGraw-Hill Companies. (4) slow R-wave progression in V1– V3. (2) QR in I aVR V1 with narrow QRS. All rights reserved.I aVR V1 V4 e143 CHAPTER e19 Atlas of Electrocardiography II aVL V2 V5 III aVF V3 V6 II FIGURE e19-22 Signs of right atrial/RV overload in a patient with chronic obstructive lung disease: (1) peaked P waves in II. (4) superior axis deviation with an S1-S2-S3 pattern. (5) prominent S waves in V6. . and (6) atrial premature beats. with terminal S waves in V5/V6.

V4–V6) with Q-TU prolongation in a patient with severe hypokalemia. and V5) in a patient with hypercalcemia. III. Copyright © 2008 The McGraw-Hill Companies. All rights reserved. aVL. High take-off of ST segment in V2/V3. V4.e144 ELECTROLYTE DISORDERS I aVR V1 V4 PART 9 II aVL V2 V5 Disorders of the Cardiovascular System III aVF V3 V6 II FIGURE e19-24 Prominent U waves (II. . I aVR V1 V4 II aVL V2 V5 III aVF V3 V6 II FIGURE e19-25 Abbreviated ST segment such that the T wave looks like it takes off directly from QRS in some leads (I.

I aVR V1 V4 e145 CHAPTER e19 Atlas of Electrocardiography II aVL V2 V5 III aVF V3 V6 II FIGURE e19-26 NSR with LVH. Copyright © 2008 The McGraw-Hill Companies. All rights reserved. and hyperkalemia. and tall peaked T waves in the precordial leads with inferolateral ST depressions (II. . prolonged QT is secondary to associated hypocalcemia. hypertension. III. left anterior fascicular block and borderline prolonged QT interval in a patient with renal failure. left atrial abnormality. aVF. and V6).

.e146 MISCELLANEOUS I aVR V1 V4 PART 9 II aVL V2 V5 Disorders of the Cardiovascular System III aVF V3 V6 II FIGURE e19-27 Normal ECG in an 11-year-old male. T-wave inversions in V1–V2. Copyright © 2008 The McGraw-Hill Companies. Vertical QRS axis (+90°) and early precordial transition between V2 and V3 are normal findings in children. All rights reserved. I aVR V1 V4 II aVL V2 V5 III aVF V3 V6 II FIGURE e19-28 Left atrial abnormality and LVH in a patient with long-standing hypertension.

and complete left bundle branch block. Copyright © 2008 The McGraw-Hill Companies. ST elevations exhibit upward concavity and are most apparent in V3 and I aVR V4.24 s).I aVR V1 V4 e147 CHAPTER e19 Atlas of Electrocardiography II aVL V2 V5 III aVF V3 V6 II FIGURE e19-29 Normal variant ST-segment elevations in a healthy 21year-old male (commonly referred to as early repolarization pattern). All rights reserved. but within normal limits for a young adult. . Precordial QRS voltages are prominent. V1 V4 II aVL V2 V5 III aVF V3 V6 II FIGURE e19-30 NSR with first-degree AV block (PR interval = 0. No evidence of left atrial abnormality or ST depression/ T wave inversions to go along with LVH.

. The triad of sinus tachycardia. All rights reserved.e148 I aVR V1 V4 PART 9 Disorders of the Cardiovascular System I II III II II aVL V2 V5 III aVF V3 V6 II FIGURE e19-31 Dextrocardia with: (1) inverted P waves in I and aVL. QT interval is prolonged for the rate. and (3) progressively decreasing voltage across the precordium. a wide QRS complex. intraventricular conduction delay with a rightward QRS axis. and a long QT suggest tricyclic antidepressant overdose. (2) negative QRS complex and T wave in I. aVR V1 V4 aVL V2 V5 aVF V3 V6 FIGURE e19-32 Sinus tachycardia. Copyright © 2008 The McGraw-Hill Companies. Terminal S wave (rS) in I. and terminal R wave (qR) in aVR are also seen in this condition.

(Play video) Parasternal short axis view. Apical four-chamber view (top) and apical two-chamber view (bottom) comprise two orthogonal views. 222. as they are viewed in clinical practice. as well as additional static images. (Play video) Parasternal short axis. (Play video) Parasternal long axis. endocardial outlines of the left ventricle (LV) cavity are traced in systole and diastole and the LV cavity areas are then fitted to computer models of the LV to obtain systolic and diastolic volumes. There is symmetric contraction of the ventricles.If you have downloaded this PDF to your computer. Gibbons. . It provides “real time” image clips. although objective measurements of cardiac dimensions can be made (see Fig. B. A. Copyright © 2008 The McGraw-Hill Companies. demonstrating an increase in wall thickness during systole. B. With quantitative two-dimensional echocardiography. Jamil Tajik Noninvasive cardiac imaging is essential to the diagnosis and management of patients with known or suspected cardiovascular disease. Most information from a study is obtained from a visual analysis of the two-dimensional images. e149 e20 Atlas of Noninvasive Cardiac Imaging Rick Nishimura. A. This atlas supplements Chap. (Play video) Parasternal long axis view. (Play video) Parasternal long axis view. Raymond J. (Play video) Parasternal long axis view. All rights reserved. The endocardial area is outlined and is used for calculation of ejection fraction. e20-1). A. There is diastolic doming and restricted leaflet opening secondary to fusion of the commissures. (Play video) Parasternal short axis view. CHAPTER e20 Atlas of Noninvasive Cardiac Imaging FIGURE e20-1 Still frame images of an echocardiogram in diastole (left) and systole (right). The presence or absence of regional wall motion abnormalities can be assessed by examining endocardial motion as well as wall thickening. Glockner. Echocardiographic imaging is performed from multiple acoustic windows with different transducer rotations so that the entire heart and great vessels can be displayed in various planes. A. VIDEO e20-3 Real-time echocardiographic images of a patient with hypertrophic cardiomyopathy. (Play video) Parasternal short axis view. C. This illustrates the quantitative assessment of ejection fraction. you will not be able to view the videos using the links in the PDF. VIDEO e20-4 Real-time echocardiographic images of a patient with mitral stenosis. Chapter 222 describes the principles and clinical applications of these important techniques. B. evidenced by a decrease in cavity size and an increase in wall thickness during systole. VIDEO e20-2 Real-time echocardiographic images of a patient with a severe decrease in left ventricular systolic function. A. VIDEO e20-1 Real-time echocardiographic images of a patient with a normal heart. B. The estimated ejection fraction is 20%. James F. Please visit the Video Bank on the DVD to view the videos. (Play video) Apical four-chamber view.

(Play video) Color-flow imaging of a patient with a normal mitral valve showing no regurgitation into the left atrium. (Play video) Color-flow imaging demonstrating a late systolic blue-colored jet of mitral regurgitation. atrial contraction wave. B. Annular dilatation. LA. The velocity of flow is high in early diastole. During exercise (right). a. There is a mean gradient of 10 mmHg derived from the Doppler tracing. (Play video) Gray scale image showing a thickened redundant posterior leaflet with loss of coaptation. (Play video) Black and white images demonstrating leaflet morphology and motion. These are consistent with the diagnosis of moderate mitral stenosis. which corresponds to the simultaneous transmitral gradient of 11 mmHg derived from cardiac catheterization. Both leaflets prolapse into the left atrium during systole. the mean gradient rises to 29 mmHg. left ventricular pressure. VIDEO e20-7 Real-time echocardiographic images from the parasternal long axis view of a patient with mitral valve prolapse. VIDEO e20-5 Real-time images with color-flow Doppler imaging of a patient with mitral regurgitation due to ruptured chordae tendinae. left atrial pressure. All rights reserved. A. In the resting state (left) there is a mean gradient of 8 mmHg. indicating hemodynamically significant mitral stenosis. vegetation. (From RA Nishimura et al: J Am Coll Cardiol 24:152.) FIGURE e20-3 Continuous-wave Doppler echocardiogram across the mitral valve of a patient with mitral stenosis. and rheumatic involvement can all be diagnosed and the LV response to volume overload assessed by two-dimensional echocardiography. 1994. and a reacceleration during atrial systole (A). A. LV. The posterior mitral valve leaflet is completely unsupported and moves into the left atrium during systole.e150 PART 9 Disorders of the Cardiovascular System FIGURE e20-2 Continuous wave Doppler (DOPP) echocardiographic tracings across the mitral valve in a patient with mitral stenosis with simultaneous pressures in the left atrium (LA) and left ventricle (LV). B. (Play video) Color-flow imaging showing the regurgitation as a high-velocity turbulence (mosaic pattern) regurgitating into the left atrium during systole. C. prolapse. . Copyright © 2008 The McGraw-Hill Companies. flail leaflets. VIDEO e20-6 (Play video) Real-time transesophageal echocardiographic images of a patient with severe mitral regurgitation due to a flail posterior leaflet. followed by a prolonged deceleration of transmitral mitral flow velocity.

The mass moves across the mitral valve in diastole. VIDEO e20-11 (Play video) Real-time transesophageal echocardiographic images of a patient with a left atrial myxoma. CHAPTER e20 Atlas of Noninvasive Cardiac Imaging FIGURE e20-4 Continuous-wave Doppler tracings across the aortic valve in a patient with aortic stenosis. This corresponds to the simultaneous catheterization gradient of 24 mmHg between left ventricle (LV) and aorta (Ao). in which there is not enough force to open fully a mildly stenotic aortic valve. mobility. A. This presents a diagnostic dilemma as the reduced aortic valve area may be due to either critical aortic stenosis and secondary LV dysfunction or a low-output state. At baseline. The aortic valve is calcified with restricted opening.5 cm2.VIDEO e20-8 (Play video) Real-time two-dimensional echocardiographic images of a patient with a vegetation on the mitral valve. there is an increase in the transvalvular pressure gradient to 55 mmHg. This indicates the presence of severe aortic stenosis. There is a mobile echo density attached directly to the mitral valve apparatus. and concomitant abnormalities. During dobutamine infusion. (Play video) Gray scale image showing a questionable “drop-out” in the atrial septum. there is a mean left ventricular (LV)-aortic (Ao) gradient of 24 mmHg (by Doppler) with a calculated aortic valve area (AVA) of 0. B. with a mean transvalvular gradient calculated to be 24 mmHg. Although an echocardiographic examination cannot provide pathologic confirmation of the etiology of a mass. There is a large echo-dense mass in the left atrium that is attached to the atrial septum. Right. with normalization of the stroke volume. in many instances the diagnosis can be suspected from the appearance. (Play video) Color-flow imaging confirms flow across the atrial septum. VIDEO e20-9 (Play video) Real-time two-dimensional parasternal e151 long axis echocardiographic images from a patient with aortic stenosis. VIDEO e20-10 Real-time echocardiographic images showing a close-up view of the atrial septum in a patient with a large secundum atrial septal defect. Left. . All rights reserved. There is an increase in velocity to 3 m/s. attachments. Copyright © 2008 The McGraw-Hill Companies. FIGURE e20-5 Continuous-wave Doppler echocardiogram across the aortic valve in a patient with low output–low gradient aortic stenosis and a reduced ejection fraction.

In this patient. The opposite occurs during expiration (EXP). The deceleration time (DT) indicates the relative change in LA and LV pressures as blood begins to fill the LV. e20-8). FIGURE e20-7 Pulsed-wave Doppler tracings of the mitral valve inflow velocities superimposed on left atrial (LA) and left ventricular (LV) pressures. in which there is a high early diastolic velocity [rapid filling wave (RFW)] and low velocity of atrial contraction resulting in a high E:A ratio with a short (150 ms) deceleration time (DT).e152 VIDEO e20-12 (Play video) Real-time two-dimensional echocardiographic images of a patient with a pericardial effusion. This increases LV pressure. they are equal. This results in a fall in the transmitral flow velocity. VIDEO e20-13 (Play video) Real-time two-dimensional echocardiographic images from the parasternal long axis view of a patient with a large aneurysm of the ascending aorta. The effusion is shown as black echo-free space surrounding the heart. The initial (early diastolic) velocity of mitral inflow (E) correlates with the driving pressure across the mitral valve. There is a dissociation of intrathoracic and intracardiac pressures so that the PAWP has a larger inspiratory (INSP) fall than the LV pressure. the E velocity exceeds the A velocity. . Both ventricular diastolic pressures (*) are elevated. suggestive of mild diastolic dysfunction (see Fig. PART 9 Disorders of the Cardiovascular System FIGURE e20-6 Pulsed-wave Doppler echocardiogram of transmitral flow recorded simultaneously with pulmonary artery wedge pressure (PAWP) and left ventricular (LV) pressure in a patient with constrictive pericarditis. Normally. Copyright © 2008 The McGraw-Hill Companies. All rights reserved. which rises to meet the LA pressure. resulting in a low E:A ratio and prolonged deceleration time (DT). The LV diastolic pressure is normal at 12 mmHg. FIGURE e20-8 High-fidelity left ventricular pressure (LV) curve superimposed on a mitral inflow velocity curve obtained by Doppler echocardiography in a patient with stage I diastolic dysfunction. There is a restriction to filling. causing a decrease in the driving force across the mitral valve. There is a decrease in the early diastolic filling and an increase with filling at atrial contraction. FIGURE e20-9 High-fidelity left ventricular (LV) and right ventricular (RV) pressure tracings superimposed on a Doppler mitral inflow velocity tracing in a patient with stage III diastolic dysfunction. The A velocity on the mitral flow velocity curve is a reacceleration of flow due to atrial contraction.

A. All rights reserved. Philadelphia. with permission. A. there is contraction of all segments of the myocardium. Strain rates can be used to examine the degree of dyssynchronous contraction of the ventricle. The images during peak exercise show regional wall motion abnormalities in the anteroapical distribution indicative of myocardial ischemia. (Play video) Apical four-chamber (top) and two-chamber (bottom) views. FIGURE e20-11 Still frame images demonstrating regional wall motion abnormalities during an exercise echocardiogram in a patient with known coronary artery disease. and apical septum (red line). there are increases in contractility and in the thickening of all segments of the myocardium. mid septum (blue line). The studies at rest are shown on the left and the studies during peak exercise are on the right. left ventricle. LV. Left. (Play video) Parasternal long axis (top) and short axis (bottom) views. The systolic frames immediately after exercise show regional wall motion abnormalities in the anterior and apical segments (arrows). right ventricle (From JK Oh et al: The Echo Manual. VIDEO e20-15 Real-time two-dimensional stress echocardiogram of e153 a patient with coronary artery disease. 1999. 2d ed. Right. Shown are the different strain rates over time of the basal septum (yellow line).VIDEO e20-14 Real-time two-dimensional stress echocardiogram in a normal subject. B. The upper frame is from the apical four-chamber view and the lower frame is from the apical twochamber view. The studies at rest are shown on the left and the studies during peak exercise are on the right. During exercise. The systolic frames in the resting state show symmetric contraction of all segments of the myocardium. Lippincott Williams & Wilkins. RV. Strain rate is a measure of regional deformation (or contraction). which may help in determining patients who would benefit from biventricular pacing. . (Play video) Apical four-chamber (top) and two-chamber views (bottom). CHAPTER e20 Atlas of Noninvasive Cardiac Imaging FIGURE e20-10 Strain rate images from a patient with severe left ventricular dysfunction illustrating dyssynchronous contraction.) Copyright © 2008 The McGraw-Hill Companies. At rest. B. (Play video) Parasternal long axis (top) and short axis (bottom) views.

FIGURE e20-13 Adenosine 99mTc sestamibi scan in a 50-year-old male with a previous anterior infarct. although both 201Tl. vertical long axis. The relative advantage of 201Tl and 99mTc are detailed in Table e20-1. Lower radiopharmaceutical cost Measurement of increased pulmonary uptake Less hepatobiliary and bowel uptake Detection of resting ischemia (hibernating myocardium) Technetium Better image quality (particularly in obese patients) Ventricular function assessment (gated SPECT) Shorter imaging time Shorter imaging protocols (patient/scheduling convenience) Acute imaging in myocardial infarction and unstable angina Superior quantification SPECT. showing increased lung uptake on the left (count intensity in lung >50% of that in myocardium) and normal lung uptake on the right (count intensity in lung <50% of that in myocardium). . Increased lung uptake of thallium may be seen immediately after stress. HLA. The long axis view demonstrates a thin dyskinetic apical aneurysm with preserved systolic function of the basal anterior and basal inferior wall. and coronary angiographic variables. A “dual-isotope” protocol is employed in some centers. signifying a fixed defect without further ischemia during stress. horizontal long axis. single photon emission computed tomography. primarily for patient and scheduling convenience. It reflects increased pulmonary capillary wedge pressure and occurs in the presence of severe coronary artery disease and/or left ventricular dysfunction. All rights reserved. SA. The better image quality and assessment of ventricular function permitted by 99mTc compounds have contributed to their more common use for stress imaging. This uses 201Tl for the initial rest image and a 99mTc-labeled compound for the subsequent stress image. short axis in the middle of the left ventricle.and 99mTc-labeled compounds provide clinically useful myocardial perfusion images in the majority of patients. Disorders of the Cardiovascular System VIDEO e20-16 (Play video) MRI scan in real-time of a patient with a large left ventricular apical aneurysm. Copyright © 2008 The McGraw-Hill Companies. VLA. The stress images (left) show a large defect involving the apex and anterior walls (white arrows) with little change from the rest images (white arrows). stress. It provides important adverse prognostic information that is incremental to other clinical.e154 TABLE e20-1 Thallium RELATIVE ADVANTAGES OF THALLIUM 201 AND TECHNETIUM 99M PART 9 FIGURE e20-12 Anterior planar thallium images following stress.

. FIGURE e20-16 MR image of a patient with a right ventricular myxoma. There is a thin central jet of aortic regurgitation going into the left ventricular outflow tract. Imaging the heart 10–20 min after gadolinium injection demonstrates enhancement of the infarcted tissue (visible as dense white image). showing a severe coarctation of the descending aorta. VIDEO e20-17 (Play video) Three-dimensional reconstruction of an MR angiogram. All rights reserved. FIGURE e20-15 MR scan with delayed enhancement of a patient with an apical left ventricular infarction (top). The large collateral vessels as a result of the coarctation are shown. VIDEO e20-18 (Play video) Cine MR scan of a patient with a dilated ascending aorta (annulo-aortic ectasia). demonstrating abnormal pericardial thickening. which is shown as a bright oblong structure in the right ventricular outflow tract. Copyright © 2008 The McGraw-Hill Companies. as the tissue retains contrast by virtue of its large extracellular volume.e155 CHAPTER e20 Atlas of Noninvasive Cardiac Imaging FIGURE e20-14 MR images with contrast enhancement of a patient with constrictive pericarditis.

RCA. saphenous vein graft to the circumflex artery. saphenous vein graft to the diagonal artery. DIAG. All rights reserved. VIDEO e20-19 (Play video) CT coronary angiogram showing a normal right coronary artery. saphenous vein graft to the right coronary artery. In the upper left panel is an anteriorposterior view of the heart and grafts. Copyright © 2008 The McGraw-Hill Companies. FIGURE e20-19 Three-dimensional reconstruction of a CT angiogram demonstrating three saphenous vein coronary artery bypass grafts in different views.e156 PART 9 Disorders of the Cardiovascular System FIGURE e20-17 Noncontrast image from electron beam CT revealing two small foci of calcification in the left anterior descending artery (arrows). . The movie highlights multiple thin slices through the right coronary artery. CX. FIGURE e20-18 CT coronary angiogram showing a normal right coronary artery. The heart is sequentially rotated clockwise in the panels going from left to right to illustrate the ability of CT angiography to visualize the saphenous vein grafts.

.e157 CHAPTER e20 Atlas of Noninvasive Cardiac Imaging FIGURE e20-20 Cardiac CT images demonstrating a calcified mass in the right ventricle. which at pathologic examination was a chronic thrombus. All rights reserved. Copyright © 2008 The McGraw-Hill Companies. Calcification is seen as a bright signal in both the noncontrast (upper) and contrast-enhanced (lower) images.

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The rate of the sinus pacemaker is slow at I aVR the beginning of the strip during expiration.28 s).\ e21 Atlas of Cardiac Arrhythmias Ary L.bidmc. Goldberger The abbreviations used in this chapter are as follows: AF—atrial fibrillation AV—atrioventricular AVRT—atrioventricular reentrant tachycardia LBBB—left bundle branch block LV—left ventricular LVH—left ventricular hypertrophy MI—myocardial infarction NSR—normal sinus rhythm RBBB—right bundle branch block VT—ventricular tachycardia WPW—Wolff-Parkinson-White V1 V4 e159 CHAPTER e21 Atlas of Cardiac Arrhythmias The electrocardiograms in this Atlas supplement those illustrated in Chaps. All of the figures are from ECG Wave-Maven. Atrial tachycardia may produce a similar pattern. Beth Israel Deaconess Medical Center. I aVR II aVL V2 V5 III aVF V3 V6 II FIGURE e21-1 Respiratory sinus arrhythmias. http://ecg. a physiologic finding in a healthy young woman. . Copyright © 2008 The McGraw-Hill Companies. then accelerates during inspiration and slows again with expiration. Copyright 2003. V1 V4 II aVL V2 V5 III aVF V3 V6 II FIGURE e21-2 Sinus tachycardia (110/min) with first-degree AV block (PR interval = 0. 225 and 226. The P wave is visible after the ST-T wave in V1–V3. The interpretations emphasize findings of specific teaching value.edu.harvard. All rights reserved.

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FIGURE e21-3 Sinus rhythm (pulse rate about 62/min) with 2:1 AV block causing marked bradycardia.
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FIGURE e21-4 NSR with 2:1 AV block. Left atrial abnormality. RBBB with left anterior fascicular block. Possible inferior myocardial infarction.

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FIGURE e21-5 Marked junctional bradycardia (25 beats/min). Rate is regular, flat baseline between narrow QRS complexes without P
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FIGURE e21-6 Sinus rhythm at a rate of 64/min with third degree (complete) AV block at a rate of 40/min. The narrow QRS complex indicates an A-V junctional pacemaker. Left atrial abnormality.

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FIGURE e21-8 Multifocal atrial tachycardia with varying P-wave morphologies and P-P intervals; right atrial overload with peaked P waves in II, III, and aVF; superior axis; poor R-wave progression with de-

layed transition in precordial leads in patient with severe obstructive lung disease.

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FIGURE e21-9 NSR in a patient with Parkinson’s disease. Tremor artifact, best seen in limb leads. This tremor artifact may sometimes be confused with atrial flutter/fibrillation.
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FIGURE e21-10 Atrial tachycardia with atrial rate 200/min (note lead V1), 2:1 AV block, and one premature ventricular complex. Also

present: LVH with intraventricular conduction defect and slow precordial R-wave progression (cannot rule out old MI).

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FIGURE e21-11 Atrial tachycardia with 2:1 block. The non-conducted (“extra”) P waves just after the QRS complex are best seen in lead V1. Also, there is incomplete RBBB and borderline QT prolongation.
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FIGURE e21-12 Atrial tachycardia [180/min with 2:1 AV block (see lead V1)]. LVH by left precordial voltage. Slow R-wave progression (V1–V4) compatible with old anteroseptal MI.

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FIGURE e21-13 AV nodal reentrant tachycardia (AVNRT) at a rate of 150/min.
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FIGURE e21-14 Atrial flutter with 2:1 conduction. Extra atrial waves in the early ST segment, seen, for example, in leads II and V1.

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FIGURE e21-15 Atrial flutter with atrial rate 300/min and 2:1 or 3:1 conduction. Flutter waves best seen in lead II.
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FIGURE e21-16 Wide complex tachycardia. Atrial flutter with 2:1 conduction and LBBB, not to be mistaken for VT. Atrial activity is present in lead II at rate of 320/min.

Copyright © 2008 The McGraw-Hill Companies. All rights reserved.

. I aVR V1 V4 II aVL V2 V5 III aVF V3 V6 II FIGURE e21-18 AF with complete heart block and a junctional escape mechanism causing a slow regular ventricular response (45/ min). Q-T (U) prolongation. The ventricular rhythm is irregularly irregular. The QRS complexes show intraventricular conduction defect with left-axis deviation and LVH. Copyright © 2008 The McGraw-Hill Companies.I aVR V1 V4 e167 CHAPTER e21 Atlas of Cardiac Arrhythmias II aVL V2 V5 III aVF V3 V6 II FIGURE e21-17 AF with LBBB. All rights reserved.

Polarity of the delta waves (most positive in lead II and lateral chest leads) consistent with a right-sided bypass tract. .e168 I aVR V1 V4 PART 9 Disorders of the Cardiovascular System II aVL V2 V5 III aVF V3 V6 II FIGURE e21-19 AF with right-axis deviation and LVH. with triad of short PR. Copyright © 2008 The McGraw-Hill Companies. I aVR V1 V4 II aVL V2 V5 III aVF V3 V6 II FIGURE e21-20 WPW pre-excitation pattern. Tracing suggests biventricular hypertrophy in a patient with mitral stenosis and aortic valve disease. All rights reserved. and delta waves. wide QRS.

I aVR V1 V4 e169 CHAPTER e21 Atlas of Cardiac Arrhythmias II aVL V2 V5 III aVF V3 V6 II FIGURE e21-21 AF in patient with the WPW syndrome. and antegrade conduction down the bypass tract leading to a wide complex I aVR tachycardia. V1 V4 II aVL V2 V5 III aVF V3 V6 II FIGURE e21-22 Accelerated idioventricular rhythm (AIVR) originating from the LV and accounting for RBBB morphology. All rights reserved. Copyright © 2008 The McGraw-Hill Companies. . Not all beats are pre-excited. ST elevations in the precordial leads from underlying acute MI. Rhythm is “irregularly irregular” and rate is extremely rapid (about 230/min).

. I aVR V1 V4 II aVL V2 V5 III aVF V3 V6 II FIGURE e21-24 Monomorphic VT at rate of 170/min. The morphology of the VT is suggestive of origin from the left side of the heart. Baseline artifact is present also in leads V1–V3.60 s) QT interval in a patient with hereditary long-QT syndrome. Copyright © 2008 The McGraw-Hill Companies. All rights reserved.e170 I aVR V1 V4 PART 9 Disorders of the Cardiovascular System II aVL V2 V5 III aVF V3 V6 II FIGURE e21-23 Prolonged (0. The RBBB morphology in V1 and the R:S ratio < 1 in V6 are both suggestive of VT. near the base (RBBB with inferior/rightward axis).

low levels of high-density lipoprotein (HDL) and elevated levels of triglycerides characterize the constellation of findings denoted by some as “metabolic syndrome. This video clip explains the derivation of pulse pressure and some of the pathophysiology that determines this parameter. We now possess useful tools for modulating LDL. and portrays the role of inflammation in plaque disruption and thrombosis. Several of the animations in this collection discuss the concept of the metabolic syndrome and the role of components of the lipid profile other than LDL in atherogenesis. these features of the lipoprotein profile require renewed focus. VIDEO e22-6 (Play video) Metabolic syndrome. VIDEO e22-5 (Play video) Atherogenesis.” (From Peter Libby. Created under an unrestricted educational grant from Merck & Co. This video animation presents the rudiments of the metabolism of lipoproteins important in clinical medicine. A number of important cardiovascular risk factors tend to cluster in a pattern described by some as the “metabolic syndrome. More recent clinical information has highlighted the importance of pulse pressure. Yet. such as unstable angina or acute myocardial infarction. Thus we must add to our traditional focus on stenosis an enlarged appreciation of the pathobiology of atherosclerosis that underlies many acute coronary syn- dromes. this animation depicts the concept of stabilization of atherosclerotic plaques by intervention such as lipid lowering. We currently understand that most coronary thromboses result from a physical disruption of the atherosclerotic plaque. This video clip highlights some of the current thinking about mechanisms of atherogenesis. understanding lipoprotein metabolism provides insight into the pathophysiology of arterial disease. however. MD: Changes and Challenges in Cardiovascular Protection. VIDEO e22-1 (Play video) Pulse pressure. The video clip on pulse pressure explains the pathophysiology of this readily measured clinical variable. with new information about the risk factors for atherosclerosis expanding considerably. Our traditional approach to atherosclerosis focused on arterial stenoses as a cause of ischemia and cardiovascular events. as a prognostic indicator of cardiovascular risk. e171 e22 Atlas of Atherosclerosis Peter Libby We have learned a great deal about the biology of human atherosclerosis in recent years. We have long appreciated the importance of blood pressure as a risk factor for atherosclerosis and cardiovascular events. In particular. This animation discusses some of the metabolic derangements that underlie the “metabolic syndrome.) VIDEO e22-2 (Play video) Plaque instability. Finally. but we recognize that atherosclerotic plaques that do not cause stenoses may nonetheless precipitate clinical events. The animation on the development and complication of the atherosclerotic plaque explains some of these emerging concepts in plaque activation as they apply to the precipitation of thrombotic complications of atherosclerosis. our knowledge of the mechanism that links hypercholesterolemia to cardiovascular events has lagged the epidemiologic and observational findings.If you have downloaded this PDF to your computer. This video animation reviews current thinking about how risk factors alter the biology of the artery wall and can incite initiation and progression of atherosclerosis.” While controversy persists regarding whether cardiovascular risk due to these factors is additive or synergistic. Considerable evidence suggests that pulse pressure serves as an important risk factor for future cardiovascular events. the difference between the systolic pressure and minimum diastolic arterial pressure. you will not be able to view the videos using the links in the PDF. Cardinal Health. VIDEO e22-3 (Play video) Lipoprotein menagerie. inflammatory cells recruited from blood.. (With permission from the Academy for Health Care Education.” In the wake of increasing obesity worldwide. This video animation explains some of the current concepts of the pathophysiology of atherosclerotic plaque disruption and how it triggers arterial thrombosis. Copyright © 2002. We now possess effective revascularization modalities for addressing flow-limiting stenoses. The application of vascular biology to human atherosclerosis has revealed many new insights into the mechanisms that promote clinical events. VIDEO e22-4 (Play video) Formation and complication of atherosclerotic plaques. The series of animated video presentations presented here illustrates some of the evolving information regarding risk factors for atherosclerosis and the pathophysiology of clinical events. This presentation also discusses the importance of inflammation in these processes. . The lipid profile confers important information regarding cardiovascular risk and the effects of therapies. Low-density lipoprotein (LDL) provides an example of a well-understood cardiovascular risk factor. Inc. other aspects of dyslipidemia are on the rise and provide a growing challenge to the practitioner. Please visit the Video Bank on the DVD to view the videos. A Special CME Activity for Physicians. Several of the animations included in this series highlight the role of modified LDL as a trigger for inflammation and other aspects of the pathobiology of arterial plaques that lead to their aggravation and clinical events.) CHAPTER e22 Atlas of Atherosclerosis Copyright © 2008 The McGraw-Hill Companies. used with permission. their clinical importance is growing. All rights reserved. and risk factors such as lipoproteins. We now understand the generation of atherosclerotic plaques as a dynamic process involving an interchange between cells of the artery wall. that is. We possess a great deal of knowledge regarding the role of cholesterol in the prediction of atherosclerosis and its complications.

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and primary therapy in acute ST segment elevation myocardial infarction. 240. with prominent v waves (peaking after the ECG T wave). you will not be able to view the videos using the links in the PDF. including management of cardiogenic shock. VIDEO e23-8 (Play video) Post-stent result. VIDEO e23-3 (Play video) There is also significant stenosis in the midportion of the dominant right coronary artery. FIGURE e23-2 Cardiogenic shock is present. percutaneous coronary intervention (PCI) has assumed a major role in the management of coronary artery disease. management of distal coronary vascular disease. e173 CHAPTER e23 Atlas of Percutaneous Revascularization e23 Atlas of Percutaneous Revascularization Donald S. as is the percutaneous insertion of an experimental aortic valve. All rights reserved. e23-1 to e23-5. and stenting of a chronic totally occluded vessel. Copyright © 2008 The McGraw-Hill Companies. FIGURE e23-1 Presenting ECG—marked inferior and anterolateral ST depression. The latter has not yet been approved for clinical use but demonstrates one of the future extensions of percutaneous techniques.If you have downloaded this PDF to your computer. Arterial pressure is reduced (91/55 mmHg) despite dopamine infusion. and the respiratory rate (24/min) plus arterial desaturation (93%) on 100% O2 suggest incipient pulmonary edema. rales 2/3 way up. *At the time that Dr. Since then. Baim prepared this chapter.0-mm adjacent “kissing” balloons. VIDEO e23-2 (Play video) As seen also in this right anterior oblique projection. In addition. VIDEO e23-6 (Play video) Simultaneous kissing stent deployment in the LAD and Cx. he was a Professor of Medicine at Harvard Medical School and Senior Physician at Brigham and Women’s Hospital. unstable angina. stent thrombosis. VIDEO e23-7 (Play video) Post-stent result. The mean pulmonary capillary wedge (PCW) pressure is elevated at 23 mmHg. It is used most commonly in patients with chronic stable angina. Please visit the Video Bank on the DVD to view the videos. Baim* As indicated in Chap. CASE 1: CARDIOGENIC SHOCK WITH LEFT MAIN CORONARY ARTERY OBSTRUCTION (Figs. cool clammy extremities. he has assumed the position of Chief Medical and Scientific Officer at Boston Scientific Co. . 8 Fr guiding catheter is used to place separate wires into the left anterior descending (LAD) and circumflex (CX) arteries. Videos e23-1 to e23-10) • A 93-year-old man presented to the emergency room with 9 h of dyspnea and a sense of “dread” • Prior subendocardial MI 2 months earlier managed medically (no catheterization done) • Entry systolic pressure 70 mmHg. arterial saturation 85% on 100% oxygen rebreathing mask • Brought emergently to the catheterization laboratory—right heart catheterization performed VIDEO e23-1 (Play video) Baseline left coronary angiogram shows severe ulcerated stenosis of the distal left main coronary artery. VIDEO e23-5 (Play video) Simultaneous inflation of two 3. pressure tracings obtained at left heart catheterization in the diagnosis of obstructive hypertrophic cardiomyopathy are shown. suggestive of mitral regurgitation. This chapter illustrates some complex uses of percutaneous techniques. VIDEO e23-4 (Play video) Intraaortic balloon pump placed via contralateral groin.

and PA saturation increased from 32 to 52%. and double wire. while cardiac index (CI) rose from 1. and cardiac output normalizing over first 8 h in CCU • Patient recovered despite a peak CPK of 2300.1 (L/min)/m2. 2002. All rights reserved.4 to 2. • Coronary angio showed the cause—a critical ulcerated stenosis of the distal left main and right coronary artery (RCA) • With intraaortic balloon pump insertion via the contralateral groin. so the right coronary artery lesion was also stented. VIDEO e23-9 (Play video) Shock persists.) Copyright © 2008 The McGraw-Hill Companies. .4 (L/min)/m2. CKMB 274 • Discharged on day 7. despite a pre-procedure 85% estimated PCI mortality! Estimated PCI mortality 85% FIGURE e23-4 Estimation of risk of mortality of percutaneous coronary intervention (PCI).e174 PART 9 Disorders of the Cardiovascular System FIGURE e23-3 The aortic (Ao) pressure is reduced (78/52 mmHg). the pulmonary artery (PA) pressure is elevated (59/32 mmHg) and the PaO2 saturation (32%) corresponds to a cardiac index of 1. VIDEO e23-10 (Play video) Result. confirming the cardiogenic shock state. LEFT MAIN CORONARY ARTERY STENOSIS WITH CARDIOGENIC SHOCK • Cardiogenic shock requires emergent revascularization • Right heart catheterization is useful to assess and monitor hemodynamics. RCA stenting also performed • This stabilized hemodynamics with PCW falling to 10 mmHg. “kissing” balloon and kissing stent implantation were performed via 8 Fr guide • Because of ongoing shock. in this case showing profound shock and probable ischemic mitral regurgitation FIGURE e23-5 The PCW fell from 34 mmHg preintervention to 20 mmHg post-intervention with resolution of the tall v waves. (From M Singh et al: J Am Coll Cardiol 40:387.

with an excellent result (B) (Play video). since early discontinuation increases the risk of subacute stent thrombosis (SAT) • In this case. MYOCARDIAL INFARCTION STENTING. All rights reserved. VIDEO e23-24 The stent thrombosis was crossed with wires into the distal LAD and diagonal (A) (Play video). which was treated with thrombectomy • The LAD and diagonal were then treated with “kissing” Cypher drug-eluting stents VIDEO e23-20 Baseline angiography showing bifurcation thrombus in the LAD. Peak CPK was 337 (upper limit of normal = 200). e23-6 and e23-7. and an intraaortic balloon was placed preparatory to bypass surgery of the left system • The very early presentation and rapid intervention virtually completely aborted this life-threatening MI e175 CHAPTER e23 Atlas of Percutaneous Revascularization FIGURE e23-7 Top: Preintervention. Elapsed time since arrival in the catheterization laboratory—10 min. exposing extensive linear thrombus and stenosis in the mid-RCA. Brigham and Women’s Hospital. . WITH STENT THROMBOSIS • Coronary occlusions causing myocardial infarction usually contain some thrombus • Although routine thrombectomy has not been shown to produce benefit. VIDEO e23-13 (Play video) Guidewire passage restores antegrade flow.4 (L/min)/m2. as in most. WITH STENT THROMBOSIS (Videos e23-20 to e23-25) • A 37-year-old admitted cocaine user presented with severe chest pain and an anterior wall myocardial infarction • Baseline angiography showed LAD thrombus. blood pressure rose to 152/84 mmHg despite discontinuation of dopamine.5 × 32 mm drug-eluting stent to cover the culprit lesion. and developed recurrent pain 10 days later. VIDEO e23-18 (Play video) Post-stent in shallow RAO cranial projection shows brisk flow in a very dominant right coronary artery. VIDEO e23-15 (Play video) Positioning a 3. VIDEO e23-19 (Play video) Sheath injection shows entry into the common femoral artery just above a moderate lesion. This was again treated with thrombectomy (B) (Play video). Emergency coronary angiography shows recurrent LAD occlusion due to subacute stent thrombosis. rhythm returned to normal sinus. A. (Play video) B. VIDEO e23-14 (Play video) Some improvement in the filling defect after suction thrombectomy. A. SAT was associated with a substantial myocardial infarction This case was contributed by Dr. Boston. (Play video) B. VIDEO e23-23 (Play video) The patient self-discontinued clopidogrel at 2 months after stenting. restoring flow but showing filling defects representing thrombus. VIDEO e23-25 (Play video) The result after thrombectomy was again excellent. presumably atherosclerotic bifurcation lesion was then treated with “kissing” drug-eluting stents (DES) with a good result • It is imperative that dual antiplatelet therapy be continued for at least 6 months post DES. CASE 3: ANTERIOR MI STENT. VIDEO e23-17 (Play video) Post-stent. Bottom: Postintervention. (Play video) VIDEO e23-21 Rheolytic thrombectomy. it may reflect right ventricular involvement as might have been the case here with the very proximal right coronary occlusion • The severity of the hypotension and coexistent hypoxia here. and oxygen saturation normalized (not shown). with post-thrombectomy result. FIGURE e23-6 ECG shows sinus bradycardia. although a small filling defect remains. with permission. large thrombi respond well to thrombectomy • The underlying. James Kirshenbaum. Right heart catheterization post-stent (not shown) revealed normal hemodynamics with wedge pressure of 12 mmHg and cardiac index of 2. Elapsed time since catheterization laboratory arrival < 20 min. however. An intraaortic balloon pump was placed to stabilize the patient for bypass surgery of the left coronary artery the following day. suggest associated global ischemia due to the left main disease • The patient was clinically stable after the intervention on the right coronary artery. (Play video) VIDEO e23-22 Simultaneous drug-eluting stenting of the LAD-diagonal bifurcation (A) (Play video). INFERIOR MI WITH CARDIOGENIC SHOCK • Inferior MIs are usually more benign than anterior MIs • When there is hypotension in an inferior MI. indicating an aborted myocardial infarction with this very early reperfusion. and profound inferior ST elevation. As soon as flow was restored.CASE 2: INFERIOR MI WITH CARDIOGENIC SHOCK (Figs. Videos e23-11 to e23-19) • A 67-year-old man with no prior cardiac history has 20 min of chest pain • He is hypotensive and hypoxic (oxygen saturation 85% on 100% O2) VIDEO e23-11 (Play video) Angiography of the non-infarct left coronary shows unexpected distal left main bifurcation stenosis with possible superimposed thrombus. VIDEO e23-16 (Play video) Stent deployment. Copyright © 2008 The McGraw-Hill Companies. an accelerated idioventricular rhythm and isorhythmic dissociation. VIDEO e23-12 (Play video) The right coronary artery is occluded proximally. ST elevation resolved.

VIDEO e23-37 (Play video) After stenting. roughly 70% of these lesions can be crossed and. VIDEO e23-31 (Play video) Stent deployment. double injection. VIDEO e23-28 (Play video) Post-angioplasty result shows significant residual stenosis. VIDEO e23-35 (Play video) Stiff guidewire slightly below trajectory. poor prospects for a favorable outcome with surgery swung the balance to PCI • The availability of flexible stents for small vessels has made treatment of such vessels possible • Drug-eluting stents also reduce the incidence of restenosis (increased in patients with diabetes) to roughly 7% compared to roughly 25% with bare metal stents • Using stiff (3. • If the RCA had not been opened.5 × 24 mm drug-eluting stent in the distal posterior descending artery (PDA) (A) (Play video) and a 2. and chronic total occlusion of the circumflex (Cx) and right coronary arteries (RCA) VIDEO e23-33 (Play video) Baseline left coronary injection shows LAD disease and occluded Cx-OM. with slow flow at the apex. FIGURE e23-9 A spontaneous ventricular premature beat is followed by an augmented sinus beat marked by increased LV pressure and LVAo gradient. which was in turn stented. diffuse disease. See Chaps. the consequences of the severe LAD lesion progression might well have been more risky. and painstaking technique. VIDEO e23-30 (Play video) After documenting an excellent result in the PDA. VIDEO e23-29 Positioning a 2. and a high restenosis rate due to diabetes mellitus VIDEO e23-26 (Play video) Baseline angiogram in the shallow right anterior oblique view with cranial angulation shows the culprit lesions. STENTING DISTAL CORONARY ARTERY DISEASE IN DIABETIC PATIENTS • Diffuse distal disease in diabetics remains very challenging for both PCI and bypass surgery (due to poor distal targets) • In this patient. but this patient had a normal aortic valve on echo and asymmetric thickening of the upper left ventricular septum.5 × 16 mm stent in the proximal PDA (B) (Play video). 22. . VIDEO e23-32 (Play video) Excellent result in both vessels poststenting. small vessel diameter. VIDEO e23-38 (Play video) Poststenting view in AP cranial projection. • This patient declined to return for an attempt on the occluded Cx and did well for 10 months. which is also predilated with a 2-mm balloon. VIDEO e23-41 (Play video) Post LAD stenting. VIDEO e23-34 (Play video) Double (also known as “simultaneous”) injection of the left and right coronaries demonstrates area of distal occlusion. VIDEO e23-39 (Play video) Return of angina 10 months later—restudy shows widely patent RCA. once crossed.0–9 g) specialty guidewires. Then he returned with a patent RCA and progressive disease in the LAD. and 29. drug-eluting stenting may be an option in selected patients • They present challenges for intervention because of distal location. and the stents had not remained patent.e176 CASE 4: DISTAL CORONARY DISEASE IN A DIABETIC PATIENT (Videos e23-26 to e23-32) • This 67-year-old non-insulin dependent diabetic developed refractory angina • The culprit lesions were in the posterior descending and posterolateral branches of the dominant right coronary artery • While bypass surgery is still the standard of care in diabetic patients with multivessel coronary disease. but a decrease in femoral artery pulse pressure. This could represent aortic stenosis. and now supplies right to left collaterals to the Cx. All rights reserved. Copyright © 2008 The McGraw-Hill Companies. the guidewire is relocated to the posterolateral branch. VIDEO e23-27 (Play video) Dilation of the posterior descending artery (PDA) with a 2-mm balloon. PART 9 Disorders of the Cardiovascular System CASE 6: HYPERTROPHIC CARDIOMYOPATHY (HCM) WITH OBSTRUCTION HYPERTROPHIC CARDIOMYOPATHY (HCM) WITH OBSTRUCTION (Figs. 24. VIDEO e23-36 (Play video) Stiff guidewire now across the occlusion and in a small branch of the PDA. stented with good long-term results. consistent with HCM with obstruction (Braunwald-Brockenbrough sign). TOTAL OCCLUSION—STIFF WIRES • The presence of one or more chronic total occlusions often leads to referral to surgery FIGURE e23-8 Simultaneous recording of the left ventricular (yellow) and femoral artery (orange) pressures shows a 60 mmHg pressure gradient. VIDEO e23-40 (Play video) Progression of the proximal LAD lesion. e23-8 to e23-11) • Asymmetric hypertrophy of the upper septum can cause an intracavitary gradient within the LV due to contact of the anterior leaflet with the septum during systole CASE 5: CHRONIC TOTAL OCCLUSION STIFF GUIDEWIRE (Videos e23-33 to e23-41) • 75-year-old man with angina and inferior ischemia on exercise thallium-201 scan • Catheterization shows moderate left anterior descending (LAD) coronary artery lesion. the RCA is widely patent. plus left-to-right collaterals from AV groove Cx.

using pericardial valves mounted in an outer stent. • While the LV-Ao pressure gradient may look superficially like that seen in aortic stenosis. however. All rights reserved. the characteristic decrease in aortic or peripheral arterial pulse pressure and spike-and-dome pattern in a post-ventricular premature contraction are seen only in HCM with obstruction • An end-hole catheter positioned towards the LV apex allows recording this dynamic gradient. e177 CHAPTER e23 Atlas of Percutaneous Revascularization FIGURE e23-10 Slow pull-back of the end-hole catheter from the apex of the LV to the area just under the aortic valve shows disappearance of the pressure gradient. A pericardium tissue valve fixed to the frame in a surgical manner. is more often made by echocardiography in current practice FIGURE e23-13 CoreValve delivery by sheath withdrawal. FIGURE e23-11 Continued pull-back into the aorta shows another VPB with reduced aortic pulse pressure and a “spike and dome” central aortic pressure tracing. . again consistent with HCM with obstruction. or other comorbidities • Percutaneous balloon valvuloplasty was evaluated in the late 1980s. poor LV function. are now under investigation The case and data shown here were provided by Dr. and provided limited benefit • A new class of investigational percutaneous aortic valve replacement techniques. and intracavitary localization of the gradient during pull-back • The diagnosis and evaluation of this disease. e23-12 to e23-15) • The preferred treatment for severe aortic stenosis is surgical replacement of the aortic valve • Although the average surgical mortality for this procedure is ~4%. FIGURE e23-12 Self-expanding AV prosthesis: the CoreValve.CASE 7: PERCUTANEOUS AORTIC VALVE REPLACEMENT (Figs. with permission. Eberhard Grube of Sieburg. Copyright © 2008 The McGraw-Hill Companies. Note that the femoral artery systolic pressure is slightly higher than the central aortic pressure due to peripheral augmentation. some patients are at significantly higher risk due to advanced age. Germany.

100 80 60 40 20 0 Pre Mean 69.90 ± 22.23 ± 8.e178 140 120 p<0.96 mmHg Post Mean 22.0001 mmHg PART 9 Disorders of the Cardiovascular System FIGURE e23-14 CoreValve follow-up: Post-implant morphologic assessment by CT scan. .23 mmHg 30 Days Mean 22. Copyright © 2008 The McGraw-Hill Companies.48 ± 8. All rights reserved.40 mmHg FIGURE e23-15 CoreValve study: Peak pressure gradients.

Ascending aorta. Aortic arch. 2. Left hilum. Trachea. Descending aorta. 2. Right mainstem bronchus. Right atrium. 6. John J. 5.e24 Atlas of Chest Imaging Patricia Kritek. Main pulmonary artery. Left hemi-diaphragm (with stomach bubble). 4. e179 This atlas of chest imaging is a collection of interesting chest radiographs and computed tomograms of the chest. FIGURE e24-2 Normal chest tomogram—note anatomy. 6. EXAMPLES OF NORMAL IMAGING CHAPTER e24 Atlas of Chest Imaging FIGURE e24-1 Normal chest radiograph—review of anatomy. Right hemidiaphragm. 8. 10. 9. The readings of the films are meant to be illustrative of specific. Trachea. Esophagus. All rights reserved. Descending aorta. major findings. Retrosternal clear space. 3. 12. 8. Reilly. Carina. 11. Left hemi-diaphragm (with stomach bubble). Left ventricle. 5. 10. Left mainstem bronchus. 11. Right ventricle. Copyright © 2008 The McGraw-Hill Companies. Left upper lobe bronchus. Heart. Jr. 12. 9. 7. . 7. 4. 3. Pericardium. The associated text is not intended as a comprehensive assessment of the images. 1. 1. Aortic knob. Superior vena cava.

Findings most significant in left lung. The patient was found to have an endobronchial lesion (not visible on the CT scan) resulting in this finding. FIGURE e24-5 Left upper lobe scarring with hilar retraction with less prominent scarring in right upper lobe as well. FIGURE e24-4 CT scan revealing chronic left lower lobe collapse. All rights reserved. Copyright © 2008 The McGraw-Hill Companies.e180 VOLUME LOSS PART 10 Disorders of the Respiratory System FIGURE e24-3 CT scan demonstrating left upper lobe collapse. The superior vena cava (black arrow) is partially opacified by intravenous contrast. and decreased lung volume consistent with previous tuberculosis infection. . Note dramatic volume loss with minimal aeration. Findings consistent with previous tuberculosis infection in an immigrant from Ecuador. There is subtle mediastinal shift to the left. FIGURE e24-6 Apical scarring. traction bronchiectasis (red arrow).

and increased retrosternal clear space (red arrow). flattened diaphragms (black arrows).e181 CHAPTER e24 Atlas of Chest Imaging FIGURE e24-7 Chest x-ray (CXR) demonstrating right upper lobe collapse (yellow arrow). increased AP diameter. Copyright © 2008 The McGraw-Hill Companies. Also apparent on the film are an endotracheal tube (red arrow) and a central venous catheter (black arrow). FIGURE e24-9 CT scan of diffuse. LOSS OF PARENCHYMA FIGURE e24-8 Emphysema with increased lucency. bilateral emphysema. . All rights reserved. Note the volume loss as demonstrated by the elevated right hemi-diaphragm as well as mediastinal shift to the right.

FIGURE e24-11 Multiple. . All rights reserved. thin-walled cysts consistent with lymphangioleiomyomatosis.e182 PART 10 Disorders of the Respiratory System FIGURE e24-10 CT scan of bullous emphysema. The smaller cavity is in the right lower lobe (located below the major fissure. identified with the yellow arrow) and the larger cavity is located in the right middle lobe which is located between the minor (red arrow) and major fissures. There is an area of consolidation associated with the cavity in the right lower lobe. Cavities and air-fluid levels identified by red arrows. Copyright © 2008 The McGraw-Hill Companies. FIGURE e24-13 CT scan of parenchymal cavity. FIGURE e24-12 Two cavities on posteroanterior (PA) and lateral CXR.

While this is an anteroposterior film making cardiac size more difficult to assess. FIGURE e24-16 CXR demonstrates reticular nodular opacities bilaterally with small lung volumes consistent with usual interstitial pneumonitis (UIP) on pathology. Copyright © 2008 The McGraw-Hill Companies. FIGURE e24-17 CT scan of usual interstitial pneumonitis (UIP). also known as idiopathic pulmonary fibrosis (IPF). FIGURE e24-14 Mild congestive heart failure. Note the Kerley B lines (black arrow) and perivascular cuffing (yellow arrow) as well as the pulmonary vascular congestion (red arrow). and peripheral interstitial reticular opacities.INTERSTITIAL PROCESSES e183 CHAPTER e24 Atlas of Chest Imaging FIGURE e24-15 Pulmonary edema. Note indistinct vasculature. All rights reserved. Classic findings include traction bronchiectasis (black arrow) and honeycombing (red arrows). . Clinically. the cardiac silhouette still appears enlarged. UIP is used interchangeably with idiopathic pulmonary fibrosis (IPF). basilar predominance of the honeycombing. Note subpleural. perihilar opacities.

PART 10 Disorders of the Respiratory System FIGURE e24-19 Sarcoid—CT scan of stage I demonstrating bulky hilar and mediastinal lymphadenopathy (red arrows) without parenchymal infiltrates. . All rights reserved. FIGURE e24-21 Sarcoid—CT scan of stage II (calcified lymphadenopathy. suggesting hyperinflation. FIGURE e24-22 Sarcoid—CT scan of stage II (nodular opacities tracking along bronchovascular bundles). parenchymal infiltrates). Note apical predominance of disease.e184 FIGURE e24-18 Sarcoid—CXR of stage I (hilar lymphadenopathy without parenchymal infiltrates). The diaphragms are also flattened. FIGURE e24-20 Sarcoid—CXR of stage II (lymphadenopathy with parenchymal changes). Copyright © 2008 The McGraw-Hill Companies.

All rights reserved. . Copyright © 2008 The McGraw-Hill Companies. FIGURE e24-26 Right lower lobe pneumonia—subtle opacity on PA film (red arrow). ALVEOLAR PROCESSES FIGURE e24-25 Right middle lobe opacity illustrates major (black arrow) and minor fissures (red arrows) as well as the “silhouette sign” on the right heart border. while the lateral film illustrates the “spine sign” (black arrow) where the lower spine does not become more lucent. Also note large pulmonary artery (red arrow). Atlas of Chest Imaging FIGURE e24-23 Sarcoid—stage III with nodular parenchymal infiltrates (yellow arrows). no lymphadenopathy.e185 CHAPTER e24 FIGURE e24-24 Sarcoid—stage IV (fibrotic lung disease).

This finding is consistent with fluid density in the alveolar space.e186 PART 10 FIGURE e24-27 CT scan of diffuse. consistent with acute respiratory distress syndrome (ARDS). Disorders of the Respiratory System FIGURE e24-28 CXR reveals diffuse. FIGURE e24-29 CT scan of ARDS demonstrates ground-glass infiltrates with more consolidated areas in the dependent lung zones. Note that the patient has an endotracheal tube (red arrow) and has a central venous catheter (black arrow). bilateral “ground-glass” infiltrates. bilateral alveolar infiltrates without pleural effusions. Copyright © 2008 The McGraw-Hill Companies. All rights reserved. .

Copyright © 2008 The McGraw-Hill Companies.e187 CHAPTER e24 Atlas of Chest Imaging FIGURE e24-30 Three examples of air bronchograms (red arrows) on chest CT. . All rights reserved.

Note that there is near total collapse of the right middle lobe (red arrow). All rights reserved. Copyright © 2008 The McGraw-Hill Companies. apical disease. “Tree in bud” refers to small nodules clustered around the centrilobular arteries as well as increased prominence of the centrilobular branching. FIGURE e24-33 CT scan of focal right middle lobe and lingular bronchiectasis (yellow arrows). These findings are consistent with bronchiolitis. FIGURE e24-34 “Tree in bud” opacities (red arrows) and bronchiectasis (yellow arrow) consistent with atypical mycobacterial infection. FIGURE e24-32 CT scan of diffuse.e188 BRONCHIECTASIS PART 10 Disorders of the Respiratory System FIGURE e24-31 Cystic fibrosis with bronchiectasis. . cystic bronchiectasis (red arrows) in a patient with cystic fibrosis.

FIGURE e24-36 Basilar pneumothorax with visible pleural reflection (red arrows). Copyright © 2008 The McGraw-Hill Companies. Pleural reflection highlighted with red arrows.PLEURAL ABNORMALITIES e189 CHAPTER e24 Atlas of Chest Imaging FIGURE e24-37 CT scan of large right-sided pneumothorax. The patient has severe underlying emphysema. . Pleural reflection highlighted with red arrows. patient has subcutaneous emphysema (yellow arrow). Also note. FIGURE e24-35 Large right pneumothorax with near complete collapse of right lung. All rights reserved. Note significant collapse of right lung with adhesion to anterior chest wall.

Note fluid in the major fissure (black arrow) visible on the lateral film as well as the meniscus of the right pleural effusion. FIGURE e24-39 Left pleural effusion with clear meniscus seen on both PA and lateral chest radiographs. All rights reserved.e190 PART 10 Disorders of the Respiratory System FIGURE e24-38 Small right pleural effusion (red arrows highlight blunted right costophrenic angles) with associated pleural thickening. Note calcified pleural plaques (red arrows). Copyright © 2008 The McGraw-Hill Companies. pleural thickening (black arrow) and subpleural atelectasis (green arrows). . FIGURE e24-40 Asbestosis.

Copyright © 2008 The McGraw-Hill Companies. well-circumscribed nodules of different size.NODULES AND MASSES e191 CHAPTER e24 Atlas of Chest Imaging FIGURE e24-41 Left upper lobe mass. FIGURE e24-42 Solitary pulmonary nodule on the right (red arrow) with a spiculated pattern concerning for lung cancer. Note also that the patient is status-post left upper lobectomy with resultant volume loss and associated effusion (black arrow). Note the multiple. All rights reserved. . FIGURE e24-43 Metastatic sarcoma. which biopsy revealed to be squamous cell carcinoma.

All rights reserved. Disorders of the Respiratory System FIGURE e24-45 CT scan of soft tissue mass encircling the trachea (red arrow) and invading tracheal lumen. . Fungal ball (red arrow) growing in preexisting cavity on the left. Copyright © 2008 The McGraw-Hill Companies. Biopsy demonstrated adenoid cystic carcinoma (cylindroma). FIGURE e24-44 Left lower lobe lung mass (red arrow) abutting pleura. Biopsy demonstrated small cell lung cancer. Right upper lobe has a large bulla (black arrow).e192 PART 10 FIGURE e24-46 Mycetoma.

Note the markedly enlarged pulmonary arteries (red arrow). FIGURE e24-47 Pulmonary arteriovenous malformation (AVM) demonstrated on reformatted CT angiogram (red arrow). All rights reserved.PULMONARY VASCULAR ABNORMALITIES e193 CHAPTER e24 Atlas of Chest Imaging FIGURE e24-50 CT scan of the same patient as in Fig. . e24-49. Copyright © 2008 The McGraw-Hill Companies. FIGURE e24-48 Large bilateral pulmonary emboli (intravascular filling defects in contrast scan identified by red arrows). Note the enlarged pulmonary arteries (red arrows) visible on both PA and lateral films. FIGURE e24-49 CXR of a patient with severe pulmonary hypertension.

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Pink tongues of Barrett’s mucosa extending proximally from the gastro-esophageal junction. Ischemic colitis with patchy mucosal edema. adherent pseudomem- branes. MD. FIGURE e25-3 Barrett’s esophagus. Please visit the Video Bank on the DVD to view the videos. B. vascular. Malignant gastric ulcer involving greater curvature of stomach. The images shown in this Atlas are also found in Chap. Endoscopic treatment modalities for gastrointestinal bleeding. D. Tumor extends into the esophageal submucosa (arrow). Copyright © 2008 by Louis Michel Wong-Kee-Song. A. for all Videos. and neoplastic conditions.If you have downloaded this PDF to your computer. Mark Topazian Gastrointestinal endoscopy is an increasingly important method for diagnosis and treatment of disease. Copyright © 2008 The McGraw-Hill Companies. Pseudomembranous colitis with yellow. Severe Crohn’s colitis with deep ulcers. and biliary stones are demonstrated in video clips. Barrett’s esophagus with locally advanced adenocarcinoma. MD. Barrett’s esophagus with a suspicious nodule (arrow) identified during endoscopic surveillance. polyps. A. 285 of the book. Benign gastric ulcer. Ulcer with a visible vessel (arrow) in a patient with recent hemorrhage. FIGURE e25-2 Gastric ulcers. C. B. FIGURE e25-4 Causes of colitis. Chronic ulcerative colitis with diffuse ulcerations and exudates. A. you will not be able to view the videos using the links in the PDF. . Cancer screening and prevention are common indications for gastrointestinal endoscopy. B. All rights reserved. and cyanosis. Ulcer with a clean base. CHAPTER e25 Video Atlas of Gastrointestinal Endoscopy FIGURE e25-1 Duodenal ulcers. subepithelial hemorrhage. e195 e25 Video Atlas of Gastrointestinal Endoscopy Louis Michel Wong-Kee-Song. This atlas demonstrates endoscop- ic findings in a variety of gastrointestinal infectious. C. inflammatory. D. A. B. and the premalignant conditions of Barrett’s esophagus and colonic polyps are illustrated. and Mark Topazian. Histologic finding of intramucosal adenocarcinoma in the endoscopically resected nodule.

MD. All rights reserved. Bile duct stones are extracted with a balloon catheter.e196 PART 13 Disorders of the Gastrointestinal System FIGURE e25-5 Colonic polyps. (Image courtesy of Dr. Copyright © 2008 The McGraw-Hill Companies. D. Copyright © 2008 by Louis Michel Wong-Kee-Song. B. Final appearance of the sphincterotomy. for all Videos. A. A small abscess communicates with the left hepatic duct. A normal-appearing ampulla of Vater. FIGURE e25-6 Colon adenocarcinoma growing into the lumen. C. FIGURE e25-8 Radiograph of a double-balloon enteroscope in the small intestine. B. A. the stones are extracted with a Dormia basket. Sessile rectal polyp. Ananya Das. FIGURE e25-10 Endoscopic sphincterotomy. B.) FIGURE e25-9 Endoscopic retrograde cholangiopancreatography (ERCP) for bile duct stones with cholangitis. A. with permission. After endoscopic sphincterotomy. FIGURE e25-7 Capsule endoscopy image of jejunal vascular ectasia. MD. Pedunculated colon polyp on a thick stalk covered with normal mucosa (arrow). Sphincterotomy is performed with electrocautery. . Faceted bile duct stones are demonstrated in the common bile duct. and Mark Topazian.

Copyright © 2008 by Louis Michel Wong-Kee-Song. with permission. and Mark Topazian.e197 CHAPTER e25 Video Atlas of Gastrointestinal Endoscopy FIGURE e25-11 Endoscopic diagnosis. FIGURE e25-13 Local staging of gastrointestinal cancers with endoscopic ultrasound. In each example the white arrowhead marks the primary tumor and the black arrow indicates the muscularis propria (mp) of the intestinal wall. Contrast leaks from a small right intrahepatic duct into the gallbladder fossa. T3 esophageal cancer. D. and focally abuts the aorta. Endoscopic placement of bilateral self-expanding metal stents relieves the biliary obstruction. Chacho. for all Videos. T1 gastric can- cer. then flows into the pigtail of a percutaneous drainage catheter. A. B. The tumor extends through the mp into the surrounding tissue. The tumor invades the mp. (Image B courtesy of Dr. MD. The tumor does not invade the mp. Intraductal biopsy obtained during ERCP demonstrates malignant cells infiltrating the submucosa of the bile duct wall (arrow). ERCP in a patient with obstructive jaundice demonstrates a malignant appearing stricture of the biliary confluence extending into the left and right intrahepatic ducts. T2 esophageal cancer. MD.) Copyright © 2008 The McGraw-Hill Companies. Mary S. FIGURE e25-14 Endoscopic ultrasound (EUS)–guided fine-needle aspiration (FNA). staging. C. A. and palliation of hilar cholangiocarcinoma. Intraductal ultrasound of the biliary stricture demonstrates marked bile duct wall thickening due to tumor (T) with partial encasement of the hepatic artery (arrow). B. “AO” indicates aorta. All rights reserved. FIGURE e25-12 Bile leak (arrow) from a duct of Luschka after laparoscopic cholecystectomy. A. C. . Micrograph of aspirated malignant cells. B. Ultrasound image of a 22-gauge needle passed through the duodenal wall and positioned in a hypoechoic pancreatic head mass.

Gastric antral ulcer with a clean base. with permission. A persistent caliber artery (arrows) is present in the gastric submucosa.e198 PART 13 Disorders of the Gastrointestinal System FIGURE e25-15 Stigmata of hemorrhage in peptic ulcers. There is no underlying mucosal lesion. Histology of a gastric Dieulafoy’s lesion. for all Videos. Duodenal ulcer with a dense adherent clot. MD. C. A. and hemoclips. Duodenal ulcer with active spurting (arrow). actively bleeding gastric varix treated with endoscopic cyanoacrylate injection. E. . B. VIDEO e25-3 (Play video) Large. Actively spurting jejunal Dieulafoy’s lesion. D. B. (Video courtesy of Dr. FIGURE e25-17 Dieulafoy’s lesion. Duodenal ulcer with flat pigmented spots. immediately beneath the mucosa. and Mark Topazian.) VIDEO e25-4 (Play video) Dieulafoy’s lesion treated endoscopically. VIDEO e25-1 (Play video) Actively bleeding duodenal ulcer treated with endoscopic epinephrine injection. Gastric ulcer with a pigmented protuberance/visible vessel. VIDEO e25-2 (Play video) Actively bleeding varices treated with endoscopic band ligation. Copyright © 2008 by Louis Michel Wong-Kee-Song. FIGURE e25-18 Mallory-Weiss tear at the gastroesophageal junction. MD. FIGURE e25-16 Esophageal varices. All rights reserved. Copyright © 2008 The McGraw-Hill Companies. thermal probe application. Navtej Buttar. A.

for all Videos. Endoscopic placement of a self-expanding metal stent. CHAPTER e25 Video Atlas of Gastrointestinal Endoscopy FIGURE e25-20 Sigmoid volvulus with the characteristic radiological appearance of a “bent inner tube. All rights reserved. or ”watermelon stomach. Radiograph of expanded stent across the obstructing tumor with a residual waist (arrow).” characterized by prominent flat or raised red angioectatic stripes radiating in a spoke-like fashion from the pylorus to the antrum. . Glenn Alexander. and Mark Topazian. Cecal vascular ectasias. B. VIDEO e25-5 (Play video) Actively bleeding colon diverticulum treated with dilute epinephrine injection. Radiation-induced vascular ectasias of the rectum in a patient previously treated for prostate cancer. (Image A courtesy of Dr. A. Copyright © 2008 by Louis Michel Wong-Kee-Song.) Copyright © 2008 The McGraw-Hill Companies. with permission. Colonic adenocarcinoma causing marked luminal narrowing of the descending colon. MD. A. C.” FIGURE e25-21 Obstructing colonic carcinoma. C. Gastric antral vascular ectasias.e199 FIGURE e25-19 Gastrointestinal vascular ectasias. B. MD.

FIGURE e25-23 Causes of esophagitis. D. FIGURE e25-26 Eosinophilic esophagitis with multiple circular rings of the esophagus creating a corrugated appearance. Endoscopic ultrasound (EUS). MD. for all Videos. Arrowheads indicate the common bile duct. Cytomegalovirus esophagitis. All rights reserved. B. VIDEO e25-6 (Play video) Impacted biliary stones removed during endoscopic retrograde cholangiopancreatography. A. The diagnosis requires biopsy with histologic finding of ≥20 eosinophils/high power field. Arrows mark bile duct stones.e200 PART 13 Disorders of the Gastrointestinal System FIGURE e25-22 Methods of bile duct imaging. and Mark Topazian. A. Severe reflux esophagitis with mucosal ulceration and friability. C. . Candida esophagitis with white plaques adherent to the esophageal mucosa. Copyright © 2008 by Louis Michel Wong-Kee-Song. C. Copyright © 2008 The McGraw-Hill Companies. B. and an impacted grape at the narrowed esophagogastric junction. and the asterisk marks the portal vein. Magnetic resonance cholangiopancreatography (MRCP). Herpes simplex virus esophagitis with numerous shallow ulcerations. FIGURE e25-25 Schatzki’s ring at the gastro-esophageal junction. FIGURE e25-24 Peptic esophageal stricture associated with ulceration and scarring of the distal esophagus. CT. MD.

(Images courtesy of Dr. (Image courtesy of Dr.) FIGURE e25-28 Capsule endoscopy images of a mildly scalloped jejunal fold (left) and an ileal tumor (right) in a patient with celiac sprue.e201 CHAPTER e25 Video Atlas of Gastrointestinal Endoscopy FIGURE e25-27 Scalloped duodenal folds in a patient with celiac sprue. with permission. FIGURE e25-31 Internal hemorrhoids with bleeding (arrow) as seen on a retroflexed view of the rectum. for all Videos. All rights reserved. with permission. and Mark Topazian. MD. FIGURE e25-29 Innumerable colon polyps of various sizes in a patient with familial adenomatous polyposis syndrome. Copyright © 2008 by Louis Michel Wong-Kee-Song. FIGURE e25-30 Virtual colonoscopy image of a colon polyp (arrow).) VIDEO e25-7 (Play video) Pedunculated colonic polyp removed with snare cautery during colonoscopy. MD. . Copyright © 2008 The McGraw-Hill Companies. Jeff Fidler. Elizabeth Rajan. VIDEO e25-8 (Play video) Organized pancreatic necrosis treated by transduodenal endoscopic drainage.

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viral inclusion bodies). autoimmune hepatitis. an important diagnostic hallmark of primary biliary cirrhosis as well as of liver allograft rejection. ACKNOWLEDGMENTS The authors wish to thank Zachary Goodman. Department of Pathology. in nonalcoholic fatty liver disorders. 20×). and others involving the portal tracts (e. .g. injury of bile ducts in the portal tract. plasma cell infiltration common in autoimmune hepatitis. MD. and central zones. Washington. Bhan e203 CHAPTER e26 Atlas of Liver Biopsies Although clinical and laboratory features yield clues to the extent of inflammatory processes (disease grade). in metabolic disorders—including mitochondrial injury—and in patients with chronic viral hepatitis). MD. FIGURE e26-2 Acute hepatitis. DC. and the central zone consists of the central vein (CV). some involving the lobular areas (e. A normal liver lobules consists of portal.g. and Joseph Misdraji. The lobular area contains cords of liver cells surrounded by vascular sinusoids. hepatocellular ballooning. and the nature of the disease process. Atul K.. All rights reserved. higher magnification.e26 Atlas of Liver Biopsies Jules L. virus antigen localization in hepatocyte cytoplasm and/or nuclei. the degree of scarring and architectural distortion (disease stage). FIGURE e26-3 Chronic hepatitis C with portal lymphoid infiltrate and lymphoid follicle containing germinal center (H&E. Dienstag. 10×). Massachusetts General Hospital. lobular. and liver allograft rejection). and acidophilic bodies (arrows) (H&E. the liver biopsy is felt to represent the “gold standard” for assessing the degree of liver injury and fibrosis. Armed Forces Institute of Pathology. The portal tract contains the hepatic artery (HA) and portal vein (PV) that represent the dual vascular supply to the liver as well as the bile duct (BD).. and portal inflammation affecting portal veins (“endothelialitis”) in liver allograft rejection. Examination of liver histology provides not only a basis for quantitative scoring of disease activity and progression but also a wealth of qualitative information that can direct and inform diagnosis and management. FIGURE e26-1 Acute hepatitis with lobular inflammation and hepatocellular ballooning (H&E. the terminal branch of the hepatic vein (see figure below). the portal mononuclear infiltrate that expands and spills over beyond the border of periportal hepatocytes in chronic hepatitis C. Other histologic features of importance include hepatic steatosis (observed in alcoholic liver injury. 10×). Copyright © 2008 The McGraw-Hill Companies. Boston. for their assistance and sharing of liver biopsies. the lobular inflammatory changes of acute hepatitis. showing lobular inflammation. Liver cells BD HA CV PV Sinusoids Portal tract Included in this atlas of liver biopsies are examples of common morphologic features of acute and chronic liver disorders. apoptotic hepatocyte degeneration in acute and chronic hepatitis.

Copyright © 2008 The McGraw-Hill Companies. interface hepatitis. FIGURE e26-6 Lobular inflammation with acidophilic body (apoptotic body) surrounded by lymphoid cells (H&E. All rights reserved. FIGURE e26-9 Autoimmune hepatitis with portal and lobular inflammation. . 40×). 20×). FIGURE e26-5 Chronic hepatitis C with portal inflammation and interface hepatitis (erosion of the limiting plate of periportal hepatocytes by infiltrating mononuclear cells) (H&E. FIGURE e26-8 Chronic hepatitis B with hepatocellular nuclear staining for hepatitis B core antigen (immunoperoxidase. 10×).e204 PART 13 Disorders of the Gastrointestinal System FIGURE e26-4 Chronic hepatitis C with portal and lobular inflammation and steatosis (H&E. 20×). 20×). and cholestasis (H&E. FIGURE e26-7 Chronic hepatitis B with hepatocellular cytoplasmic staining for hepatitis B surface antigen (immunoperoxidase. 10×).

40×). neutrophils) of the portal tract as well as endothelialitis of the portal vein (arrow) and bile duct injury (H&E. 10×). FIGURE e26-15 Liver allograft with cytomegalovirus infection showing hepatocytes with nuclear inclusions (arrows) surrounded by a neutrophilic and lymphoid infiltrate (H&E. 10×). All rights reserved.e205 CHAPTER e26 Atlas of Liver Biopsies FIGURE e26-10 Autoimmune hepatitis. FIGURE e26-12 Chronic hepatitis C with bridging fibrosis (arrow) (Masson trichrome. . FIGURE e26-14 Acute cellular rejection of orthotopic liver allograft demonstrating a mixed inflammatory cell infiltrate (lymphoid cells. FIGURE e26-13 Cirrhosis with architectural alteration resulting from fibrosis and nodular hepatocellular regeneration (Masson trichrome. 2×). showing dense plasma cell infiltrate in the portal and periportal regions (H&E. 40×). eosinophils. 10×). Copyright © 2008 The McGraw-Hill Companies. FIGURE e26-11 Primary biliary cirrhosis with degenerating bile duct epithelium (“florid ductular lesion”) (arrow) surrounded by epithelioid granulomatous reaction and lymphoplasmacytic infiltrate (H&E. higher magnification.

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polyendocrinopathy. type 1b (G6PT1) Hyperzincemia with functional zinc depletion Orotic aciduria I (UMPS) Transcobalamin 2 deficiency (TCN2) aMutant genes are indicated in parentheses. congenital ichthyosis (ERCC2/XPD or ERCC3/XPB) Immunodeficiency with Generalized Growth Retardation Schimke immuno-osseous dysplasia (SMARCAL1) Dubowitz syndrome Kyphomelic dysplasia with SCID Mulibrey nanism (TRIM37 ) Progeria (Hutchinson-Gilford syndrome) (LMNA) Thumb agenesis. Jr. type 1 (AIRE ) Immunodysregulation. All rights reserved. Table e27-1 categorizes conditions in which the immunodeficiency is an integral component or a secondary consequence. e207 Immunodeficiency is seen as an associated feature in a wide variety of inherited disorders or may be acquired as a consequence of infection or drug treatments. Schroeder. TABLE e27-1 IMMUNODEFICIENCIES ASSOCIATED WITH OR SECONDARY TO OTHER CONDITIONS a Chromosomal Instability or Defective Repair Ataxia-telangiectasia (ATM) Bloom syndrome (BLM helicase) DNA ligase IV deficiency (LIG4) Fanconi anemia (multiple complementation groups) Immunodeficiency-centromeric instability-facial anomalies (ICF) syndrome (DNMT3B DNA methyltransferase. and immunodeficiency X-linked agammaglobulinemia with growth hormone deficiency (BTK ) Infectious Diseases Congenital rubella Congenital infection with cytomegalovirus Congenital infection with Toxoplasma gondii Epstein-Barr virus Human immunodeficiency virus Malignancy Chronic lymphocytic leukemia Immunodeficiency with thymoma Other Cartilage-hair hypoplasia (endoribonuclease RMRP) Chronic mucocutaneous candidiasis Hereditary or congenital hyposplenia or asplenia (Ivemark syndrome) Liver transplantation Mannose binding lectin deficiency (MBL2) Omenn syndrome (AIRE. beta subunit. zinc deficiency type (SLC39A4) Propionyl-CoA carboxylase.e27 Primary Immunodeficiencies Associated with or Secondary to Other Diseases Max D. short stature. other) Nijmegen breakage syndrome (Nibrin) Seckel syndrome (ATR) Xeroderma pigmentosum (multiple complementation groups) Chromosomal Defects Deletions or rings of chromosome 18 (18p– and 18q–) Down syndrome (trisomy 21) Monosomy 22 Trisomy 8 Turner syndrome (X chromosome monosomy) Drug-Induced Hypogammaglobulinemia Antimalarial agents Captopril Carbamazepine Glucocorticoids Fenclofenac Gold salts Lamotrigine Penicillamine Phenytoin Sulfasalazine Hereditary Defects of T Cell Regulation Autoimmune Lymphoproliferative Syndrome (ALPS) ALPS 1A (CD95) ALPS 1B (CD95L) ALPS2A (CASP10) ALPS2B (CASP8) Autoimmune polyendocrinopathy syndrome (APECED). with T cell deficiency. autosomal dominant (NFKBIA) Ectrodactyly-ectodermal dysplasia-clefting syndrome Griscelli syndrome. anhidrotic. X-linked (IPEX) (FOXP3) Hereditary Metabolic Defects α-Mannosidosis (MAN2B1) Acrodermatitis enteropathica. CHAPTER e27 Primary Immunodeficiencies Associated with or Secondary to Other Diseases Hypercatabolism of Immunoglobulin Familial hypercatabolism Intestinal lymphangiectasia Immunodeficiency with Dermatologic Defects Dyskeratosis congenita Autosomal dominant (TERC) Autosomal recessive X-linked. partial albinism (RAB27A) Netherton syndrome (SPINK5) Trichothiodystrophy. IL7RA. Gene mutations have now been identified as the cause of many primary immunodeficiencies. and enteropathy. RAG 1/2) Copyright © 2008 The McGraw-Hill Companies. Artemis. Harry W. Table e27-2 categorizes currently recognized aberrant genes according to the predominant immunologic deficit or well-defined syndrome. Cooper. . Zinsser-Cole-Engman syndrome (dyskerin) Ectodermal dysplasia. deficiency (PCCB) Chédiak-Higashi syndrome (CHS1) Glycogen storage disease.

3-q22 Gene or Locus Chromosome Severe Combined Immunodeficiency (SCID) Adenosine deaminase deficiency Artemis deficiency (SCIDA) DNA ligase IV deficiency CD45 deficiency DNA-dependent protein kinase deficiency Interleukin receptor γ chain deficiency Janus-associated kinase 3 deficiency Recombinase activating gene deficiency ADA ARTEMIS LIG4 CD45 PRKDC IL2RG JAK3 RAG1.e208 TABLE e27-2 GENES OR GENETIC LOCI ASSOCIATED WITH PRIMARY IMMUNODEFICIENCIES Disorder Gene or Locus Chromosome Disorder Predominantly Antibody Deficiencies 20q13.2 12q23-q24.3 2p12 22q11 10p13 5p13 1p34. 5 (group C) Regulatory factor X–associated protein (group D) Zeta chain–associated protein kinase deficiency Purine nucleotide phosphorylase deficiency TAP1.1q13. and Joints Primary T Cell Immunodeficiency Antigen peptide transporter deficiency CD8 deficiency diGeorge syndrome Interleukin 7 receptor α deficiency LCK deficiency Nude syndrome T cell receptor deficiency CD3γ CD3δ. ankyrin repeat– containing (group B) Regulatory factor X.22 Xq25 Copyright © 2008 The McGraw-Hill Companies.2 12p13 20q12-q13.1 2q32 12q12 2q21 Xp11.3-1p35 17q11-q12 7q35 11q23 1q22-q23 16p13 19p12 1q21.31 16p11.3 13q14 2q12 14q13. NEMO CD79B IGHG1 BLNK IGLL1 LRRC8 BTK 6p21.1 11p13 IgA deficiency/common variable immunodeficiency TACI deficiency (autosomal dominant) Common variable immunodeficiency ICOS deficiency (autosomal recessive) BAFF-R CD19 deficiency (autosomal recessive) Hyper-IgM syndrome Activation-induced cytidine deaminase deficiency CD40 deficiency Uracil-DNA glycosylase (UNG) deficiency X-linked hyper-IgM syndrome (XHM) XHM with ectodermal dysplasia (XHM-ED) Immunoglobulin-associated beta (Igβ) deficiency Immunoglobulin heavy chain deficiencies BLNK deficiency Surrogate light chain deficiency LRRC8 truncation X-linked agammaglobulinemia MHC TNFRSF13B ICOS TNFRSF13C CD19 HIGM2 HIGM3 HIGM5 HIGM1 IKBKG. familial Interferon γ receptor 1 deficiency Interferon γ receptor 2 deficiency Interleukin 12 deficiency Interleukin 12 receptor deficiency STAT1 deficiency Interleukin 1 receptor–associated kinase 4 deficiency WHIM syndrome Wiskott-Aldrich syndrome X-linked lymphoproliferative syndrome IFNGR1 IFNGR2 IL12B IL12RB1 STAT1 IRAK4 CXCR4 WAS SH2D1A/SAP 6q23-q24 21q22. CD3ε CD3ζ MHC class II deficiency MHC class II transactivator (group A) Regulatory factor X.2 2q33 22q13.3 17p11.33 10q23.1-22.2 22q11.1 Other Well-Defined Immunodeficiency Syndromes Atypical mycobacteriosis.2 5q31-q33 19p13.1-q21. All rights reserved.23p11. TAP2 CD8 DGCR1 DGCR2 IL7R LCK WHN CD3G CD3D. Connective Tissue.1 Xq26 Xq28 17q23 14q32. RAG2 PART 14 Disorders of the Immune System.21 9q34. CD3E CD3Z CIITA RFXANK RFX5 RFXAP ZAP70 NP 6p21.11 10p 13q22-q34 1q31-32 8q11 Xq13 19p13.13 Xq21. .

can guide the differential diagnosis and the subsequent assessment or treatment plan. and catheter-directed dye arteriography.or medium-sized blood vessels. when taken together with the history. MRI. . Pulmonary imaging is also important to detect complications of vasculitis therapy such as opportunistic pneumonias as well as medication-related pneumonitis. The images provided in this Atlas highlight the utility of diagnostic imaging in the vasculitic diseases and the improvements in the care of vasculitis patients that have resulted from radiologic innovations. Catheterdirected dye arteriography offers the most precise information regard- ing the vessel lumen but carries risks related to dye exposure and the e209 invasive nature of the procedure.Clinical e28 Atlas ofVasculiticImaging of the Diseases Carol A. monitor. positron emission tomography. Langford. diagnostic imaging plays an essential role in detecting tissue injury that occurs as result of blood vessel and tissue inflammation. A diverse range of imaging techniques are utilized in the assessment of vasculitis including plain radiography. and laboratory determinations. Advancements in MR and CT arteriography have brought about noninvasive options to view the lumen and vessel wall. These procedures have specific utilities that can allow differing perspectives on the spectrum and severity of vasculitis. For vasculitic diseases that involve the large. 80% of patients may have pulmonary involvement during their disease course. Copyright © 2008 The McGraw-Hill Companies. and diagnose vasculitis noninvasively. arteriography provides information regarding blood vessel stenoses or aneurysms that can support the diagnosis. FIGURE e28-2 Computed tomography of the chest in two patients with Wegener’s granulomatosis demonstrating (A) single and (B) mul- tiple cavitary lung lesions. Imaging contributes unique information about the patient that. as up to one-third of patients with radiographic abnormalities are asymptomatic. All rights reserved. In Wegener’s granulomatosis. thus enhancing the ability to perform serial studies for patient monitoring. Although vasculitis involving the small blood vessels cannot be directly visualized. ultrasonography. Fauci Diagnostic imaging represents a critical assessment tool in patients who are known or suspected to have a systemic vasculitic disease. With the rapid growth in precision and techniques. Anthony S. CHAPTER e28 Atlas of Clinical Imaging of the Vasculitic Diseases FIGURE e28-1 Bilateral nodular infiltrates seen on computed tomography of the chest in a 40-year-old woman with Wegener’s granulomatosis. physical examination. the role of diagnostic imaging will continue to enhance the ability of physicians to detect. Chest imaging should be obtained whenever active disease is suspected. CT.

All rights reserved. Collapse of the left upper lobe secondary to endobronchial stenosis from Wegener’s granulomatosis also is seen on this image. and Joints FIGURE e28-3 Bilateral ground-glass infiltrates due to alveolar hemorrhage from pulmonary capillaritis as seen in the same patient by (A) chest radiograph and (B) computed tomography. The image demonstrates inflammatory tissue extending from the ethmoid sinus through the lamina papyracea and filling the orbital space.e210 PART 14 Disorders of the Immune System. FIGURE e28-5 Computed tomography of the orbits in a patient with Wegener’s granulomatosis who presented with right eye proptosis. . This manifestation can occur in Wegener’s granulomatosis or microscopic polyangiitis. FIGURE e28-4 Computed tomography of the chest demonstrating a dense infiltrate with air bronchograms involving a segment of the right upper lobe due to bacterial pneumonia in an immunosuppressed patient with Wegener’s granulomatosis. Connective Tissue. Copyright © 2008 The McGraw-Hill Companies.

All rights reserved.e211 CHAPTER e28 Atlas of Clinical Imaging of the Vasculitic Diseases FIGURE e28-6 Computed tomography of the sinuses in two patients with Wegener’s granulomatosis. Copyright © 2008 The McGraw-Hill Companies. endocarditis. Cardiac involvement is an important cause of morbidity and mortality in Churg-Strauss syndrome and can include myocarditis. . FIGURE e28-8 Arteriogram of a 40-year-old man with polyarteritis nodosa demonstrating microaneurysms in the hepatic circulation. (A) Mucosal thickening of the bilateral maxillary sinuses and a perforation of the nasal septum. and pericarditis. (B) Osteitis with obliteration of the left maxillary sinus in a patient with long-standing sinus disease. FIGURE e28-7 Computed tomography of the chest demonstrating a large pericardial effusion in a patient with Churg-Strauss syndrome.

FIGURE e28-10 Upper-extremity arteriogram demonstrating a long stenotic lesion of the axillary artery in a 75-year-old female with giant cell arteritis.e212 PART 14 Disorders of the Immune System. . All rights reserved. FIGURE e28-11 Magnetic resonance imaging demonstrating extensive aneurysmal disease of the thoracic aorta in an 80-yearold female. Connective Tissue. and Joints FIGURE e28-9 Cerebral arteriogram demonstrating beading along branches of the internal carotid artery in a patient with isolated central nervous system vasculitis. The patient had been diagnosed with biopsy-proven giant cell arteritis 10 years prior to presenting with this aneurysm. This 20-year-old female presented with syncope and was subsequently diagnosed with Takayasu’s arteritis. Copyright © 2008 The McGraw-Hill Companies. FIGURE e28-12 Arteriogram of the aortic arch demonstrating complete occlusion of the left common carotid artery just after its origin from the aorta.

e213 CHAPTER e28 Atlas of Clinical Imaging of the Vasculitic Diseases FIGURE e28-14 Arteriogram of the hand demonstrating arterial skip lesions and vessel cutoffs in a patient with cryoglobulinemia due to multiple myeloma. FIGURE e28-13 Arteriogram demonstrating stenosis of the abdominal aorta in a 25-year-old female with Takayasu’s arteritis. All rights reserved. Copyright © 2008 The McGraw-Hill Companies. .

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or Wilson disease. 355) result from a variety of defects. or pyrimidines. 62). and enzyme replacement (Chap. Lipoprotein disorders (Chap. including screening programs. hyperglycemia. This atlas provides a visual survey of selected metabolic disorders with references to the topics elsewhere in the text. 359). such as the Online Metabolic and Molecular Bases of Inherited Disease (OMMBID): (http://genetics. The authors encourage submission of additional illustrations that might be used to facilitate learning among our peers and thereby enhance the recognition and care of patients with these disorders. Over the years. Alport syndrome) or in other extracellular matrix structural proteins such as fibrillin (Marfan syndrome). usually involving transporters of amino acids. usually in a lysosomal enzyme. Membrane defects (Chap. (Chaps. Many metabolic disorders originate from defects in enzymes involved in the synthesis or degradation of amino acids. 71. lichenified. 350) are caused by defects in a wide array of cellular pathways including membrane receptors (LDL-R). and scaly skin on the dorsa of the hands. gene therapy.fcgi?db=OMIM). intermediary metabolism describes the myriad cellular pathways that convert energy sources from one form to another (e. carrier proteins (apoB100).ncbi. Hartnup disease. citric acid cycle). hypertriglyceridemia. causing accumulation of a substrate within the lysosome. sugars. metabolic diseases really reflect disorders of cell biology.com/) and the Online Mendelian Inheritance in Man (OMIM): (http://www. 71. variable expressivity. lipids. cause disorders such as cystinuria. In practice. enzyme defects (lipoprotein lipase). or transporters (ABCA1).g. Perifollicular hemorrhage on the leg. For example. Indurated. Connective tissue diseases (Chap.accessmedicine. the metabolic syndrome (Chap. or ions. homeless male. Cushing syndrome reflects the metabolic effects of excess cortisol on multiple tissues (Chap. 236) includes a constellation of clinical features (central obesity. a structural protein in the nuclear envelope. 336). See Chap. Fortunately. and hypertension). Copyright © 2008 The McGraw-Hill Companies. comprehensive reference sources exist.gov/entrez/query. All rights reserved. numbering in the thousands. purines. to change. CHAPTER e29 Atlas of Clinical Manifestations of Metabolic Diseases FIGURE e29-2 Scurvy (vitamin C deficiency). This broader definition results in a plethora of metabolic diseases. phenotypic variation. nlm. Larry Jameson The term metabolism is derived from the Greek metabol. . 357) frequently involve defects in collagen synthesis or structure (osteogenesis imperfecta. It includes the broad array of chemical pathways that are necessary for normal development and homeostasis.Atlas of Clinical Manifestations e29 of Metabolic Diseases J. The emerging field of metabolomics is based on the premise that the identification and measurement of metabolic products will enhance our understanding of physiology and disease. lysosomal storage diseases (Chap. 356. 353. metabolic abnormalities induce compensatory physiologic responses that reflect the interactions of multiple different metabolic pathways. The follicles are often plugged by keratin (perifollicular hyperkeratosis). See Chap..nih. The study of metabolic diseases has been invaluable for advancing our understanding of human genetics by providing insight into principles such as patterns of inheritance. 358). Alternatively. and novel approaches to therapy. e215 FIGURE e29-1 “Gauntlet” of pellagra (niacin deficiency). who also had bleeding gums and loose teeth. This eruption occurred in a 46-year-old alcoholic. clinicians generally use the term metabolism in reference to energy utilization for anabolism or catabolism. pigmented. It likely has multiple genetic and environmental origins. the classification of metabolic diseases has extended beyond traditional pathways involved in fuel metabolism to include disorders such as lysosomal storage diseases or connective tissue diseases. Thus. For example. blood and organ transplantation. carbohydrates. Certain lipodystrophies and cardiomyopathies can be caused by mutations in lamin A. In some instances. Ehlers-Danlos syndrome. low HDL cholesterol.

the face and neck and supraclavicular areas (not depicted here) show increased deposition of fat. Storrow. Savitt. (Courtesy of Daniel L. 336. with permission. with permission. MD.) Copyright © 2008 The McGraw-Hill Companies. (Courtesy of Alan B.) PART 15 FIGURE e29-3 Podagra with gouty inflammation of the first metatarsophalangeal (MTP) joint. The finger is an unusual site for gouty arthritis. . MD. Large tophi of gout located in and around the right knee. Note the swelling and erythema of the left first MTP. 327 and 353. Examination of the synovial fluid confirmed the diagnosis. MD. All rights reserved.) Endocrinology and Metabolism FIGURE e29-6 Cushing’s syndrome. (Courtesy of Kevin J. See Chaps. with permission. MS. 327 and 353. FIGURE e29-4 Gout. See Chaps. Knoop. See Chap. Plethoric moon facies with erythema and telangiectases of cheek and forehead.e216 FIGURE e29-5 Gout. See Chaps. 327 and 353.

taken when the male patient was 45 years of age (A) and when he was 65 years of age (B). Note the multiple neuromas on the lips and tongue and the marfanoid facies. 345. 338. raised. FIGURE e29-8 Patient with multiple endocrine neoplasia 2B syndrome. well-demarcated. Copyright © 2008 The McGraw-Hill Companies. All rights reserved.e217 CHAPTER e29 Atlas of Clinical Manifestations of Metabolic Diseases FIGURE e29-7 Necrobiosis lipoidica diabeticorum. 349. See Chap. A large. The central parts of the lesions are depressed with atrophic changes of epidermal thinning and telangiectasis against yellow background. . firm borders and a yellow center in the pretibial regions of a 28-year-old diabetic female. FIGURE e29-9 Early and late radiographs of Paget disease of the tibia. See Chap. symmetric plaque with active tan-pink. See Chap.

and acetabulum. This image is shown to demonstrate the color of xanthomas in black skin. See Chap. . ribs. Copyright © 2008 The McGraw-Hill Companies. FIGURE e29-12 Papular eruptive xanthomas. PART 15 Endocrinology and Metabolism FIGURE e29-10 Bone scan of patient with severe Paget disease of the skull. A. Note localization of bone-seeking isotope (99mTc-labeled bisphosphonate) in these areas. B. All rights reserved. right femur. See Chap. lesions were present on both elbows and buttocks. Papular eruptive xanthomas on the elbows and lower arms in an African American. 350. discrete. spine. Multiple. Large subcutaneous tumors adherent to the Achilles tendons. pelvis. See Chap. red-to-yellow papules becoming confluent on the elbow of an individual with uncontrolled diabetes mellitus.e218 FIGURE e29-11 Tendinous xanthomas. 350. 349.

with permission. Cutaneous planar xanthomas. (Courtesy of Drs. Arcus corneae. E. (Courtesy of Dr.) See Chap. Thomas P. B. which usually have a bright orange hue.. 350. Peter Herbert. Antonio M.) See Chap. . FIGURE e29-14 Examples of xanthomas in type III hyperlipoproteinemic subjects. FIGURE e29-15 A 17-year-old patient with abetalipoproteinemia with generalized weakness. with permission. A. Tuberous xanthomas of the digits and xanthomas of the palmar creases (xanthoma striata palmaris) (arrows). Jr. Tuberoeruptive xanthomas of the elbows. C. Tendon and tuberous xanthomas. Gerd Assmann. Tuberous xanthomas on the elbows. B.) See Chap. A. Bersot.e219 CHAPTER e29 Atlas of Clinical Manifestations of Metabolic Diseases FIGURE e29-13 Forms of xanthomas and other lipid deposits frequently seen in familial hypercholesterolemia homozygotes. and lordosis. C and D. and F. Copyright © 2008 The McGraw-Hill Companies. with permission. All rights reserved. and Donald Fredrickson. 350. Khachadurian. (Panel H reproduced through the courtesy of Dr. 350. kyphoscoliosis. Gotto. A. H.

and both have gout. multiple liver adenomas. hepatomegaly. Periorbital and malar violaceous coloration. and follow-up at age 33 years. See Chap. bullae. Copyright © 2008 The McGraw-Hill Companies. B. hyperpigmentation. and a progressive renal disease.e220 FIGURE e29-16 Porphyria cutanea tarda. Another type Ia patient at age 10 years. A. 352. 356. FIGURE e29-18 Growth and development in two patients with type Ia glycogen storage disease. the patient had short stature. crusts. The patient had a severe hearing loss and wore hearing aids. In adulthood. and skeletal involvement. both patients continue to be short. Both patients survive despite their disease not being adequately treated. Diagnosis was made at the age of 15 months. however. PART 15 Endocrinology and Metabolism FIGURE e29-17 Mucopolysaccharidosis type IH (Hurler syndrome) in a 4-year-old boy. at which time he had developmental delay. See Chap. Verbal language skills consisted of four to five words. and hydrocephalus. 355. stiff joints. Note that the abdomen is less protuberant with age. Patient at age 7 years and at 39 years old. . All rights reserved. and hypertrichosis on the face. Hypoglycemia also improves with age. persistent nasal discharge. At the time of the picture. an enlarged tongue. and scars on the dorsa of the hands. See Chap.

and growth retardation. 356. As a child. long fingers. . and genu valgum. All rights reserved. hypoglycemia. he no longer had hepatomegaly. See Chap. this progressed to a pronounced muscle atrophy at age 53 years (two right panels). 357. After puberty. FIGURE e29-20 Skeletal features of Marfan syndrome in a 16year-old girl. scoliosis. and his final height is normal. Note the muscle wasting in the lower legs and both hands at age 44 years (left panel).e221 CHAPTER e29 Atlas of Clinical Manifestations of Metabolic Diseases FIGURE e29-19 Progressive myopathy in a patient with type IIIa glycogen storage disease. Copyright © 2008 The McGraw-Hill Companies. he had hepatomegaly. See Chap. Note the long limbs that are associated with disproportionate tall stature. The patient has a debrancher deficiency in both liver and muscle (subtype IIIa).

e222 PART 15 Endocrinology and Metabolism FIGURE e29-21 Marfan’s syndrome. narrow face. Long. Copyright © 2008 The McGraw-Hill Companies. High-arched palate. B. C. 357. Arachnodactyly and positive wrist sign. All rights reserved. Ectopia lentis associated with aortic aneurysm and severe aortic regurgitation in a teenage girl. . D. See Chap. A.

(From http://www. 355.nei. W. A. This develops in Wilson’s disease from copper deposition in Descemet’s membrane. 1972. New York. See Chap. A 44-year-old patient with type B NPD. See Chap. 358. DC. It should not be confused with the yellow-white lipid ring of arcus senilis. HR Sloan. 3d ed. Horton.gov/resources/eyegene. PhD. (Courtesy of Jonathan C.nih. in JB Stanbury et al: The Metabolic Basis of Inherited Disease. Used by permission.) FIGURE e29-26 Kayser-Fleischer ring. See Chap. 355. 355. H. . A 4. with permission. McGraw-Hill. producing brownish discoloration of the peripheral cornea. 354. (Courtesy of Dr.asp.) B. with permission. (From DS Fredrickson. Washington. FIGURE e29-24 Two patients with type B Niemann-Pick disease (NPD). which is common in the elderly and occasionally signifies hyperlipidemia. MD.) Copyright © 2008 The McGraw-Hill Companies.7-year-old patient with type B NPD. FIGURE e29-23 Clusters of dark-red to blue angiokeratomas (telangiectases) on the buttocks (A) and in the umbilical area (B) of a hemizygote with Fabry disease.) See Chap. See Chap. especially when it appears at a young age.e223 CHAPTER e29 Atlas of Clinical Manifestations of Metabolic Diseases FIGURE e29-22 Ochronotic pigmentation of the femur of a 56year-old alkaptonuric patient. FIGURE e29-25 “Cherry red” spot in the eye of a Tay-Sachs patient. Edmonds of the Washington Hospital Center. All rights reserved.

com. neck.com Figure e29-9: HB Skinner: Current Diagnosis & Treatment in Orthopedics. JS Stapcynski (eds): Tintinalli’s Emergency Medicine: A Comprehensive Guide. with permission. Familial partial lipodystrophy. umbilical hernia. e29-22 to e29-24: CR Scriver.com Figures e29-3. New York. 2007.com Figures e29-13 to e29-15. severe acanthosis nigricans affecting axillae and abdomen. www. McGrawHill.accessmedicine. trunk.) PART 15 Endocrinology and Metabolism SOURCES FOR FIGURES Figures e29-1. D Suurmond: Fitzpatrick’s Color Atlas & Synopsis of Clinical Dermatology. e29-2.com Figures e29-8.ommbid. with permission. 2006. e29-16: K Wolff. 11th ed. McGraw-Hill. New York. New York. There is accumulation of excess fat in the hips and other regions of lower limbs. Acquired partial lipodystrophy: a 30year-old woman with onset of lipodystrophy at age 14 years shows loss of fat from the face. 1998. C. et al (eds): Hurst’s The Heart. and anterior thighs. e29-4. 2004.accessmedicine.accessmedicine. 2005. B. McGraw-Hill. RA Johnson.accessmedicine. GD Kelen. e29-10: DG Gardner. 2004. upper limbs. Dunnigan variety: a 43-year-old woman with marked loss of subcutaneous fat from both the limbs and trunk and excess fat deposition in the face. e29-11. 1999. McGraw-Hill.com Copyright © 2008 The McGraw-Hill Companies. and labia majora. 8th ed. D Shoback (eds): Greenspan’s Basic & Clinical Endocrinology. 4th ed. New York. D. e29-12. www. RA O’Rourke. RW Alexander. e29-6. A. chin. e29-7. www.292. acromegaloid features.com Figure e29-21: V Fuster. D Valle (eds): The Metabolic and Molecular Bases of Inherited Disease online. from JM Peters et al: Nat Genet 18. (A from A Garg et al: J Clin Endocrinol Metab 84:3390. New York. McGraw-Hill. www. e29-5: JE Tintinalli. AL Beaudet. B. Congenital generalized lipodystrophy: a 16-year-old girl with generalized loss of fat. 5th ed. e29-17 to e29-20.accessmedicine. 6th ed. All rights reserved. supraclavicular area. Acquired generalized lipodystrophy: a 10-year-old boy who developed generalized loss of fat that also affected the palms and soles after panniculitis at the age of 3 months. www. www. New York. . 8th ed. McGraw-Hill. WS Sly.e224 FIGURE e29-27 Anterior view of patients with different forms of lipodystrophy.

axial FLAIR (C. D).e30 Atlas of Neuroimaging Andre Furtado. and axial T2-weighted (E) MR images demonstrate abnormal high signal involving the bilateral mesial tem- poral lobes (arrowheads) including the hippocampi (left greater than right) without significant mass effect (arrows). B). Dillon e225 CHAPTER e30 Atlas of Neuroimaging FIGURE e30-1 Limbic encephalitis (Chap. 97) Coronal (A. William P. . There was no enhancement on post-gadolinium images (not shown). (continued) Copyright © 2008 The McGraw-Hill Companies. All rights reserved.

All rights reserved. Axial T1-weighted MR images post-gadolinium (B. 158) Axial T2-weighted MRI (A) demonstrates multiple lesions (arrows) with peripheral high signal and central low signal.e226 FIGURE e30-1 (Continued ) PART 16 Neurologic Disorders FIGURE e30-2 CNS tuberculosis (Chap. located predominantly in the cortex and subcortical white matter. (continued) Copyright © 2008 The McGraw-Hill Companies. as well as in the basal ganglia. . C) demonstrate ring enhancement of the lesions (arrows) and additional lesions in the subarachnoid space (arrowheads).

All rights reserved.e227 CHAPTER e30 Atlas of Neuroimaging FIGURE e30-2 (Continued ) Sagittal T2-weighted MR image of the cervical spine (D) demonstrates a hypointense lesion in the subarachnoid space at the level of T5 (arrow). Copyright © 2008 The McGraw-Hill Companies. Sagittal T1-weighted MR image post-gadolinium of the cervical spine (E) demonstrates enhancement of the lesion in the subarachnoid space at the level of T5 (arrow). .

162) Case I Axial T2-weighted MR images (A.e228 PART 16 Neurologic Disorders FIGURE e30-3 Neurosyphilis (Chap. (continued) Copyright © 2008 The McGraw-Hill Companies. B) demonstrate well-defined areas of abnormal high signal in the basal ganglia bilaterally and in a wedgeshaped distribution in the right parietal lobe (arrows). Axial (C. All rights reserved. . D) T1-weighted images post-gadiolinium.

All rights reserved.e229 FIGURE e30-3 (Continued ) Coronal (E. CHAPTER e30 Atlas of Neuroimaging Copyright © 2008 The McGraw-Hill Companies. F) T1-weighted images post-gadolinium demonstrate irregular ring enhancement of the lesions (arrows). .

All rights reserved. Copyright © 2008 The McGraw-Hill Companies. 162) Case II Axial T2-weighted MRI (A) demonstrates a dural-based. .e230 PART 16 Neurologic Disorders FIGURE e30-4 Neurosyphilis (Chap. Axial (B) and coronal (C) T1-weighted MR images post-gadolinium demonstrate peripheral enhancement of the lesion (arrows). peripherally hyperintense and centrally hypointense lesion located lateral to the left frontal lobe (arrows).

Axial T1-weighted MR image post-gadolinium (C) demonstrates ring enhancement of the lesion in the right pons (arrows). there was no evidence of restricted diffusion (not shown). All rights reserved. Of note. Copyright © 2008 The McGraw-Hill Companies. . 192) Axial FLAIR (A) and T2-weighted (B) MR images demonstrate a low signal mass in the right pons (arrow) with surrounding vasogenic edema.e231 CHAPTER e30 Atlas of Neuroimaging FIGURE e30-5 Histoplasmosis of the pons (Chap.

as well as the sylvian and interhemispheric fissures. Copyright © 2008 The McGraw-Hill Companies.e232 PART 16 Neurologic Disorders FIGURE e30-6 Coccidiomycosis meningitis (Chap. . 193) Axial post-contrast CT (A) and axial (B) and coronal (C) T1-weighted MR images post-gadolinium demonstrate enhancement of the perimesencephalic cisterns (arrows). All rights reserved.

e233 CHAPTER e30 Atlas of Neuroimaging FIGURE e30-7 Candidiasis in a newborn (Chap. 196) Axial T2-weighted MR image (A) demonstrates multiple punctate foci of low signal diffusely distributed in the brain parenchyma (arrowheads). . All rights reserved. E) demonstrates restricted diffusion of water molecules in the lesions (arrowheads). Axial T1-weighted MR images post-gadolinium (B. Copyright © 2008 The McGraw-Hill Companies. ADC map (D. C) demonstrate marked enhancement of the lesions (arrowheads).

Axial T2-weighted MR images (C.e234 PART 16 Neurologic Disorders FIGURE e30-8 CNS aspergillosis (Chap. 197) Axial FLAIR MR images (A. D) demonstrate intrinsic low signal in the lesions (arrows). Some of the lesions also show vasogenic edema. There is also abnormal high signal in the subarachnoid space adjacent to the lesions (arrowhead) that can correspond to blood or high protein content. . (continued) Copyright © 2008 The McGraw-Hill Companies. B) demonstrate multiple areas of abnormal high signal in the basal ganglia as well as cortex and subcortical white matter (arrows). All rights reserved. suggesting the presence of blood products.

All rights reserved. T1-weighted image pre-gadolinium demonstrates enhancement of lesion (arrow). 197) Axial T2-weighted MR image (A) demonstrates an irregularly shaped low signal lesion involving the left orbital apex (arrow). (continued) Copyright © 2008 The McGraw-Hill Companies. B.e235 FIGURE e30-8 (Continued ) Coronal (E) and axial (F) T1-weighted MR images post-gadolinium demonstrate peripheral enhancement of the lesions (arrows). CHAPTER e30 Atlas of Neuroimaging FIGURE e30-9 Invasive sinonasal aspergillosis (Chap. .

caused primarily by vasculitis and in some cases demyelinating lesions. following gadolinium administration. All rights reserved. the lesion was nonenhancing (not shown). T1-weighted image post-gadolinium demonstrates enhancement of lesion (arrow). PART 16 Neurologic Disorders FIGURE e30-10 Behçet’s disease (Chap. Copyright © 2008 The McGraw-Hill Companies.e236 FIGURE e30-9 (Continued ) C. 320) Axial FLAIR MRI demonstrates abnormal high signal involving the anterior pons (arrow). Brainstem lesions are typical of Behçet’s disease. .

All rights reserved. .e237 FIGURE e30-11 Neurosarcoid (Chap. 322) Case I Axial (A) and coronal (B) T1-weighted images post-gadolinium with fat suppression demonstrate a homogeneously enhancing well circumscribed mass centered in the left Meckel’s cave (arrows). 322) Case II Axial (A. CHAPTER e30 Atlas of Neuroimaging FIGURE e30-12 Neurosarcoid (Chap. (continued) Copyright © 2008 The McGraw-Hill Companies. B) and sagittal (C) T1-weighted images post-gadolinium with fat suppression demonstrate a homogeneously enhancing mass involving the hypothalamus and the pituitary stalk (arrows).

dorsal pons. . and pineal region (arrows) without significant mass effect. 322) Case III Axial FLAIR images (A–E) demonstrate abnormal high signal and slight expansion in the midbrain. (continued) Copyright © 2008 The McGraw-Hill Companies.e238 FIGURE e30-12 (Continued ) PART 16 Neurologic Disorders FIGURE e30-13 Neurosarcoid (Chap. All rights reserved.

e239 CHAPTER e30 Atlas of Neuroimaging FIGURE e30-13 (Continued ) Sagittal T1-weighted images post-gadolinium (F) with fat suppression demonstrate abnormal enhancement in the midbrain. All rights reserved. Copyright © 2008 The McGraw-Hill Companies. . and pineal region (arrows). dorsal pons.

(continued) Copyright © 2008 The McGraw-Hill Companies.e240 PART 16 Neurologic Disorders FIGURE e30-14 Neurosarcoid (Chap. bilateral cerebral peduncles. right frontal lobe periventricular white matter. 322) Case IV Axial T2-weighted images (A–D) demonstrate numerous areas of abnormal hyperintensity involving the corpus callosum. left internal capsule and globus pallidus. and patchy areas in bilateral temporal lobes. bilateral gyrus rectus. . All rights reserved.

. Copyright © 2008 The McGraw-Hill Companies. All rights reserved.e241 CHAPTER e30 Atlas of Neuroimaging FIGURE e30-14 (Continued) T1-weighted images post-gadolinium (E–H) demonstrate abnormal enhancement of those areas with high T2 signal.

334) Sagittal T1-weighted image (A) demonstrates enlargement of the pituitary stalk (arrow) and absence of the posterior pituitary intrinsic T1 hyperintensity (arrowhead). Copyright © 2008 The McGraw-Hill Companies. C) demonstrate enhancement of the pituitary stalk and infundibulum (arrows).e242 PART 16 Neurologic Disorders FIGURE e30-15 Histiocytosis (Chap. All rights reserved. . Sagittal and coronal T1-weighted images post-gadolinium (B.

364) Time-of-flight (TOF) MR angiography (MRA) (A. CHAPTER e30 Atlas of Neuroimaging Copyright © 2008 The McGraw-Hill Companies. .e243 FIGURE e30-16 Middle cerebral artery stenosis (Chap. All rights reserved. B) reveals narrowing within the left M1 segment that is likely secondary to atherosclerosis (arrows).

Diffusion-weighted image (C) and apparent diffusion coefficient (ADC) map (D) demonstrate restricted water motion in the lesion of the posterior limb of the right internal capsule. A small area of slight hypodensity is also seen in the posterior limb of the right internal capsule that can correspond to an acute infarct (arrowhead). There is no evidence of restricted diffusion in the old infarct (arrow). suggestive of an old infarction (arrow). A small area of slight hyperintensity is also seen in the posterior limb of the right internal capsule that can correspond to an acute lacunar infarct (arrowhead). Axial FLAIR MRI (B) demonstrates abnormal high signal involving the left anterior putamen and anterior limb of internal capsule with exvacuo dilatation of the adjacent frontal horn of the left lateral ventricle. All rights reserved. suggestive of an old infarction (arrow). 364) Axial noncontrast CT (A) demonstrates abnormal hypodensity involving the left anterior putamen and anterior limb of internal capsule with ex-vacuo dilatation of the adjacent frontal horn of the left lateral ventricle.e244 PART 16 Neurologic Disorders FIGURE e30-17 Lacunar infarction (Chap. . Copyright © 2008 The McGraw-Hill Companies. strongly suggestive for an acute lacunar infarct (arrowhead).

All rights reserved. Coronal FLAIR MRI (C. . there are small areas of tissue loss (encephalomalacia) (arrowheads). D) demonstrates multiple patchy areas of abnormal high signal in the periventricular white matter bilaterally. including the temporal lobes (arrows). 364) Axial T2-weighted MR images (A. Copyright © 2008 The McGraw-Hill Companies.e245 CHAPTER e30 Atlas of Neuroimaging FIGURE e30-18 Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (Chap. B) demonstrate multiple patchy areas of abnormal high signal in the periventricular white matter (arrows). In some of these areas.

some of which have associated adjacent areas of focal arterial dilatation. 364) Axial noncontrast CT (A) demonstrates a large hyperdense intraparenchymal hematoma surrounded by hypodense vasogenic edema in the right parietal lobe. These abnormalities are suggestive of vasculitis. Axial T2-weighted MRI (B) demonstrates a large hypointense intraparenchymal hematoma surrounded by hyperintense vasogenic edema in the right parietal lobe. . All rights reserved.e246 PART 16 Neurologic Disorders FIGURE e30-19 CNS vasculitis (Chap. Conventional angiography (C) demonstrates multiple segments of intracranial arterial narrowing. Copyright © 2008 The McGraw-Hill Companies.

These findings are suggestive of vasogenic edema with subarachnoid hemorrhage (arrowheads).e247 CHAPTER e30 Atlas of Neuroimaging FIGURE e30-20 Superior sagittal sinus thrombosis (Chap. Axial T1-weighted MRI (B) demonstrates absence of flow void in the superior sagittal sinus. All rights reserved. suggestive of thrombosis. suggestive of thrombosis (arrow). 364) Noncontrast CT of the head (A) demonstrates increased density in the superior sagittal sinus. (continued) Copyright © 2008 The McGraw-Hill Companies. Coronal FLAIR images (C. as well as the adjacent sulci. . suggestive of subarachnoid hemorrhage (arrowheads). D) demonstrate areas of abnormal high signal involving the gray and the subcortical white matter of the right frontal and left parietal lobes. and small linear hyperdensities in some temporal lobe sulci.

e248 PART 16 Neurologic Disorders FIGURE e30-20 (Continued) Diffusion-weighted images (E. suggestive of infarct. F) and ADC maps (G. (continued) Copyright © 2008 The McGraw-Hill Companies. . H) demonstrate restricted diffusion of the abnormal areas on FLAIR. All rights reserved.

All rights reserved. and left transverse sinus and jugular vein. Copyright © 2008 The McGraw-Hill Companies.e249 CHAPTER e30 Atlas of Neuroimaging FIGURE e30-20 (Continued) Phase-contrast venography of the brain (I) demonstrates absence of signal in the superior sagittal sinus down to the torcular herophili. suggestive of thrombosis. . Axial (J) and coronal (K) T1-weighted images post-gadolinium demonstrate a filling defect in the superior sagittal sinus.

e250

FIGURE e30-21 Multiple system atrophy (Chap. 366) Axial T2-weighted MR image (A) reveals symmetric poorly circumscribed abnormal high signal in the middle cerebellar peduncles bilaterally (arrowheads).

Sagittal T1-weighted MR image (B) demonstrates pontine atrophy and enlarged cerebellar fissures as a result of cerebellar atrophy (arrows).

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FIGURE e30-22 Huntington’s disease (Chap. 367) Axial noncontrast CT (A) demonstrates symmetric bilateral severe atrophy involving the caudate nuclei, putamen, and globus pallidi bilaterally with consequent enlargement of the frontal horns of the lateral ventricles (arrows). There is also diffuse prominence of the sulci indicating generalized cortical atrophy.

Axial (B) and coronal (C) FLAIR images demonstrate bilateral symmetric abnormal high signal in the caudate and putamen. Coronal T1-weighted image (D) demonstrates enlarged frontal horns with abnormal configuration. Also note diffusely decreased marrow signal, which could represent anemia or myeloproliferative disease.

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FIGURE e30-23 Bell’s palsy (Chap. 371) Axial T1-weighted images post-gadolinium with fat suppression (A–C) demonstrate diffuse smooth linear enhancement along the left facial nerve, involving the second and third segments (genus, tympanic, and mastoid) within the temporal bone (arrows). Note that there is no evidence of a mass lesion. A potential pitfall for facial nerve enhancement in the stylomastoid foramen is the enhancement of the stylomastoid artery that enters the foramen and supplies the tympanic cavity, the tympanic antrum, mastoid cells, and the semicircular canals. Coronal T1-weighted images post-gadolinium with fat suppression (D, E) demonstrate the course of the enhancing facial nerve (arrows). Although these findings are highly suggestive of Bell’s palsy, the diagnosis is established on clinical grounds.
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.

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FIGURE e30-24 Spinal cord infarction (Chap. 372) Sagittal T2-weighted MR image of the lumbar spine (A) demonstrates poorly defined areas of abnormal high signal in the conus medullaris and mild cord expansion (arrow). T1-weighted MR image of the lumbar spine post-gadolinium (B) dem-

onstrates mild enhancement (arrow). Sagittal diffusion-weighted MR image of the lumbar spine (C) demonstrates restricted diffusion (arrow) in the areas of abnormal high signal on the T2-weighted image (A).

CHAPTER e30 Atlas of Neuroimaging

FIGURE e30-25 Acute transverse myelitis (Chap. 372) Sagittal T2-weighted MR image (A) demonstrates abnormal high signal in the cervical cord extending from C1 to T1 with associated cord expansion (arrows).

Sagittal T1-weighted MR image post-gadolinium (B) demonstrates abnormal enhancement in the posterior half of the cord from C2 to T1 (arrows).

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FIGURE e30-26 Acute disseminated encephalomyelitis (ADEM) (Chap. 375) Axial T2-weighted (A) and coronal FLAIR (B) images demonstrate abnormal areas of high signal involving predominantly the subcortical white matter of the frontal lobe bilaterally, and left caudate head. Following administration of gadolinium, corresponding axial (C) and coronal (D) T1-weighted images demonstrate irregular enhancement consistent with blood-brain barrier breakdown and inflammation; some lesions show incomplete rim enhancement, typical for demyelination.
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FIGURE e30-27 Balo’s concentric sclerosis (a variant of multiple sclerosis) (Chap. 375) Coronal FLAIR MRI (A) demonstrates multiple areas of abnormal high signal in the supratentorial white matter bilaterally. The lesions are ovoid in shape, perpendicular to the orientation of the lateral ventricles, and with little mass effect.

Axial (B) and sagittal (C–E) T2-weighted MR images demonstrate multiple areas of abnormal high signal in the supratentorial white matter bilaterally, as well as the involvement of the body and splenium of the corpus callosum and the callosal-septal interface (arrowhead). Some of the lesions reveal concentric layers, typical of Balo’s concentric sclerosis (arrows). (continued)

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FIGURE e30-27 (Continued) Sagittal (F) and axial (G, H) T1-weighted MR images post-gadolinium demonstrate abnormal enhancement of all lesions with some of the lesions demonstrating concentric ring enhancement (arrows).
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.

There is also a small area of abnormal high signal in the precentral gyrus. 376) Axial FLAIR (A) demonstrates focal area of abnormal high signal involving the gray and white matter in the left frontal lobe. Copyright © 2008 The McGraw-Hill Companies. .e257 CHAPTER e30 Atlas of Neuroimaging FIGURE e30-28 Hashimoto’s encephalopathy (Chap. C) pre. Axial T1-weighted images (B. All rights reserved.and post-gadolinium demonstrate cortical/pial enhancement in the region of high signal on FLAIR.

. sagittal (B). D) short tau inversion recovery (STIR) MR images demonstrate abnormal enlargement and abnormal high signal involving the right C6.e258 PART 16 Neurologic Disorders FIGURE e30-29 Brachial plexopathy (Chap. (continued) Copyright © 2008 The McGraw-Hill Companies. C7. and the trunks and divisions that originate from these roots (arrows). All rights reserved. and C8 nerve roots. 379) Axial (A). and coronal (C.

CHAPTER e30 Atlas of Neuroimaging Copyright © 2008 The McGraw-Hill Companies. C8 nerve roots and their corresponding trunks and divisions (arrow). . These findings are compatible with radiation-induced brachial plexopathy.e259 FIGURE e30-29 (Continued) Diffusion-weighted MR imaging (E) demonstrates abnormal reduced diffusion within the right C6. All rights reserved. C7.

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oscilloscope. the alpha rhythm is attenuated when the eyes are opened (Fig. a at the left of each panel and accord with the international 10:20 system. T. Such procedures However. and this generally C D also involves recording from intracraniFIGURE e31-1 A. Abnormal EEG showing irregular diffuse slow activity in an obtunded patient with en. Continuous monitoring for prolonged perion a computer monitor. Normal EEG showing a posteriorly situated 9-Hz alpha rhythm that attenuates with ally placed electrodes (which may be eye opening. central. especially when such events occur unpremon reference point (referential derivation) is amplified and displayed dictably or infrequently. the initial routine interictal EEG may be normal up to 60% of the time. the Eyes open EEG cannot establish the diagnosis of epilepsy in many cases. temporal. Right-sided placements are indicated by even than otherwise. A. rhythmic activity having an abrupt onset and termination and a characteristic evolution—clearly establishes the diagnosis. the alpha rhythm is also at. and EMG commonly include hyperventilation (for 3 or 4 min). It is often not possible to obtain an EEG during clinical events or between individual scalp electrodes and a relatively inactive com.and determining the frequency of epileptic events. C. C. The EEG findings may also be helpful in the interictal period by ta) activity (>13 Hz). left-sided placements by odd numbers. on a diffusely slowed background. e31-2). D. With generalized tonis easily recorded from electrodes placed on the scalp. The presence of delta (<4 Hz) ranges becomes more conspicuous. Evoked Potentials. even in an individual who is known to have epilepsy. The findings in the routine scalppatient with a right parietal glioma. CHAPTER e31 Electrodiagnostic Studies of Nervous System Disorders . an 8.showing certain abnormalities that are strongly supportive of a diagtenuated. the EEG is always abnormal during the epdifference between pairs of electrodes on the scalp (bipolar derivation) isode. Irregular slow activity in the right central region. extradural. or paper. because there may be no change in the scalp-recorded The electrical activity of the brain [the electroencephalogram (EEG)] EEG during simple or complex partial seizures. of abnormal. Periodic complexes occurring once every second in a patient with Creutzfeldt-Jakob disease. and activating procedures are generally un.to 13-Hz alpha rhythm is seen posteriorly in occurring. O.e. B. Aminoff itive. During drowsiness. All rights reserved. These latter seizures may have no correlates in the scalp-recorded EEG F3-A1 or may be associated with abnormal Fp1-F3 rhythmic activity of variable frequency. C3-P3 P3-A1 and a stereotyped pattern that varies P3-O1 O1-A1 with the patient.e261 tion. In normal awake adults lying quietly by these means is sometimes helpful in confirming that seizures are with the eyes closed. Electroencephalography is relatively inexpensive and may aid clinical management in several different contexts.) In this and the following figure. Focal or lateralized epiFp2-F4 leptogenic lesions are important to F4-A2 F4-C4 recognize. repetMichael J. especially if surgical treatC4-A2 C4-P4 ment is contemplated. Intensive longP4-A2 P4-O2 term monitoring of clinical behavior and the EEG is required for operative O2-A2 candidates. parietal. F. The absence of such electrocerebral accompaniment does not exclude a seizure disorELECTROENCEPHALOGRAPHY der. P. normal EEG implies a better prognosis Fp. Copyright © 2008 The McGraw-Hill Companies. frontal polar. however. electrode placements are indicated nosis of seizure disorders: in general. The EEG is best recorded from several different electrode arrange.subdural. F3-C3 Fp1-F3 The EEG findings have been used in F3-C3 C3-P3 classifying seizure disorders and selectC3-P3 P3-O1 ing appropriate anticonvulsant medication for individual patients (Fig. dertaken in an attempt to provoke abnormalities.greater prevalence in epileptic patients than in normal individuals.that may represent seizures. characterizing the nature of clinically equivocal episodes. whereas an abnormal background or profuse epileptiform numbers. The potential ic-clonic seizures. Thus. Horizontal calibration: 1 s. photic stimula. slower activity in the theta (4–7 Hz) and nosis of epilepsy. and midline placements by Z. intermixed with a variable amount of generalized faster (be. frontal. however.. 300 μV in recorded EEG may indicate the progother panels. Monitoring is characterized by its frequency.24 h or longer in ambulatory patients has made it easier to capture the tentials of vertically oriented pyramidal cells of the cerebral cortex and electrocerebral accompaniments of such clinical episodes. or intracerebral in cephalitis.epileptiform activity is not specific for epilepsy. occipital. 1999. sleep. in a location). The characteristics of ods in video-EEG telemetry units for hospitalized patients or the use the normal EEG depend on the patient’s age and level of arousal. (From Aminoff. the EEG. earlobe.e31 THE EEG AND EPILEPSY The EEG is most useful in evaluating patients with suspected epilepsy. a C3-A1 F3-C3 localized or generalized distribution. e31-1). but it has a much ments (montages) in turn. P3-O1 F4-C4 The episodic generalized spike-wave acFp2-F4 C4-P4 tivity that occurs during and between F4-C4 P4-O2 seizures in patients with typical absence C4-P4 T3-CZ epilepsy contrasts with focal interictal epileptiform discharges or ictal patterns P4-O2 CZ-T4 found in patients with complex partial A B seizures. The presence of electrographic seizure activity—i. however. vertical calibration: 200 μV in A. The of portable equipment to record the EEG continuously on cassettes for rhythmic activity normally recorded represents the postsynaptic po. with light sleep. and sleep deprivation on the night prior to the recording. Such epileptiform activity consists of bursts of abnormal discharges containing spikes or sharp waves. Electrodiagnostic Studies of Nervous System Disorders: EEG.

for example. or brain tumors will go on to develop seizures.. with bursts of mixed-frequency activity separated by intervals of relative cerebral inactivity. or more generalized electrocerebral disturbances are common findings but provide no reliable indication about the nature of the underlying pathology. In patients with clinically suspected brain death. In patients with an acute encephalopathy. All rights reserved. Onset of a tonic seizure showing generalized repetitive sharp activity with synchronous onset over both hemispheres. electrocerebral silence in a technically satisfactory record implies that useful cognitive recovery will not occur. e31-1). THE EEG AND COMA In patients with an altered mental state or some degree of obtundation. CT scanning and MRI have taken the place of EEG as a noninvasive means of screening for focal structural abnormalities of the brain. the EEG findings are useful in indicating the level of anesthesia and whether seizures are occurring. although infratentorial or slowly expanding lesions may fail to cause any abnormalities. In most patients with dementias. an EEG. or hematomas (Fig. vertical calibration: 400 μV in A. 1999. the EEG shows repeated electrographic seizures or continuous spike-wave discharges. In patients with severe cerebral anoxia. because it may occur in hypothermic patients or with drug overdose. and periodic lateralized epileptiform discharges (PLEDs) are commonly found with acute hemispheric pathology such as a hematoma. hypothermia or drug intoxication) must be excluded. suggest a diagnosis of herpes simplex encephalitis. e311). Generalized 3-Hz spikewave activity occurring synchronously over both hemispheres during an absence (petit mal) attack. Serial records provide a better guide to prognosis than a single record and supplement the clinical examination in following the course of events. The EEG findings in dementia are usually nonspecific and do not distinguish between the different causes of cognitive decline except in rare instances when. may not occur despite a continuing EEG abnormality. C. abscess. because in such circumstances epileptiform activity is commonly encountered regardless of whether seizures occur. the EEG is still used for this purpose in many parts of the world. the EEG becomes nonreactive and may show a burst-suppression pattern. as when electrographic seizures are found or there is a focal abnormality indicating a structural lesion.) activity suggests a poor outlook. However. sometimes with a sharpened outline. conversely. In patients treated by pentobarbitalinduced coma for refractory status epilepticus. regardless of the underlying cause (Fig. The EEG is usually normal in patients with locked-in syndrome and helps in distinguishing this disorder from the comatose state with which it is sometimes confused clinically. depends upon the clinical context in which it is found. less commonly. may be confirmatory by showing electrocerebral silence. or rapidly expanding tumor. The findings do not permit differentiation of the underlying metabolic disturbance but help to exclude other encephalopathic processes by indicating the diffuse extent of cerebral dysfunction. the EEG is normal or diffusely slowed. when recorded using appropriate technical standards. stroke. The presence of residual EEG activity in suspected brain death fails to confirm the diagnosis but does not exclude it. Focal slow-wave disturbances. Nonetheless. The EEG findings are sometimes used to determine whether anticonvulsant medication can be discontinued in epileptic patients who have been seizure-free for several years. Such electrocerebral silence does not necessarily reflect irreversible brain damage. Burst of repetitive spikes occurring with sudden onset in the right temporal region during a clinical spell characterized by transient impairment of external awareness. Other findings may also be present and may suggest diagnostic possibilities. infarcts. .g. The EEG generally slows in metabolic encephalopathies. when recorded using an adequate technique. and triphasic waves may be present. and 750 μV in C. e31-1) or subacute sclerosing panencephalitis. B. During status epilepticus. repetitive electrographic seizures (complex partial status epilepticus). As the depth of coma increases. The prognosis of electrocerebral silence. The response of the EEG to external stimulation is helpful prognostically because electrocerebral responsiveness implies a lighter level of coma than a nonreactive EEG. complicating disorders that may produce a similar but reversible EEG appearance (e. focal or lateralized periodic slow-wave complexes. 200 μV in B. and the EEG find- B Fp1-F7 F7-T3 T3-T5 T5-O1 Fp2-F8 F8-T4 T4-T6 T6-O2 C Fp1-A1 F7-A1 T3-A1 T5-A1 Fp2-A2 F8-A2 T4-A2 T6-A2 PART 16 Neurologic Disorders FIGURE e31-2 Electrographic seizures. the presence of complexes occurring with a regular repetition rate (so-called periodic complexes) supports a diagnosis of Creutzfeldt-Jakob disease (Fig. The EEG has no role in the management of tonic-clonic status epilepticus except when there is clinical uncertainty whether seizures are Copyright © 2008 The McGraw-Hill Companies. In nonconvulsive status epilepticus. a localized loss of electrocerebral activity. (From Aminoff. In other instances there is a reduction in amplitude of the EEG until eventually activity cannot be detected. A. a disorder that may not be recognized unless an EEG is performed. for example. and the EEG does not have a useful role in this context except for providing guidance when there is clinical ambiguity or the patient requires reassurance about a particular course of action.e262 A F3-C3 C3-P3 P3-O1 F4-C4 C4-P4 P4-O2 T3-CZ CZ-T4 continuing in a comatose patient. The EEG findings are not helpful in determining which patients with head injuries. THE EEG IN OTHER NEUROLOGIC DISORDERS In the developed countries. the EEG tends to become slower as consciousness is depressed. such as tumors. the EEG may also show continuous spike-wave activity (“spike-wave stupor”) or. The decision to discontinue anticonvulsant medication is made on clinical grounds. but the findings provide only a general guide to prognosis: further seizures may occur after withdrawal of anticonvulsant medication despite a normal EEG or. Horizontal calibration: 1 s.

but changes in size are much less helpful for the recognition of pathology. is averaged out by this procedure. The configuration. COGNITIVE EVOKED POTENTIALS Certain EP components depend on the mental attention of the subject and the setting in which the stimulus occurs. neurosyphilis. Visual evoked potentials (VEPs) are elicited by monocular stimulation with a reversing checkerboard pattern and are recorded from the occipital region in the midline and on either side of the scalp. The diagnostic utility of the electrophysiologic findings therefore depends on the circumstances in which they are found. and evaluating comatose patients. rather than simply on the physical characteristics of the stimulus. The component of major clinical importance is the so-called P100 response. occurs in the first 10 ms after the stimulus and represents in part the sequential activation of different structures in the pathway between the auditory nerve (wave I) and the inferior colliculus (wave V) in the midbrain. the P100 is frequently lost or grossly attenuated. The background EEG activity. The procedure is painless and apparently safe. MOTOR EVOKED POTENTIALS The electrical potentials recorded from muscle or the spinal cord following stimulation of the motor cortex or central motor pathways are referred to as motor evoked potentials. The P3 component is prolonged in latency in many patients with dementia. A series of potentials. In patients with clinical evidence of only one lesion. although a response of normal latency does not exclude dementia. Abnormalities have been described in several neurologic disorders with clinical or subclinical involvement of central motor pathways. and deficiency of vitamin E or B12. A strong but brief magnetic field is produced by passing a current through a coil. Visual and auditory acuity may be determined using EP techniques in patients whose age or mental state precludes traditional ophthalmologic or audiologic examinations. in suggesting the likelihood of recovery of motor function after stroke) and is useful as a means of monitoring intraoperatively the functional integrity of central motor tracts. For clinical purposes such responses are recorded most often as the compound muscle action potentials elicited by transcutaneous magnetic stimulation of the motor cortex. Brainstem auditory evoked potentials (BAEPs) are elicited by monaural stimulation with repetitive clicks and are recorded between the vertex of the scalp and the mastoid process or earlobe. Amplitude may also be measured. All rights reserved. designated by roman numerals. The number of motor units in a muscle ranges from approximately 10 in the extraocular muscles to several thousand in the large muscles of the legs.g.. They have been used particularly to investigate patients with suspected multiple sclerosis (MS).e263 physiologic grounds are misleading because the generators of many components of the EP are unknown. and latency of the responses depend on the nerve that is stimulated and on the recording arrangements. VEPs are most useful in detecting dysfunction of the visual pathways anterior to the optic chiasm. latency. they may occur in AIDS. polarity. in the innervation ratio of different muscles. Normal VEPs may be elicited by flash stimuli in patients with cortical blindness. familial spastic paraplegia. but attempts at precise localization on electro. In patients with spinal cord injuries. EVOKED POTENTIALS SENSORY EVOKED POTENTIALS The noninvasive recording of spinal or cerebral potentials elicited by stimulation of specific afferent pathways is an important means of monitoring the functional integrity of these pathways but does not indicate the pathologic basis of lesions involving them. ERPs are therefore sometimes helpful in making this distinction when there is clinical uncertainty. and interpeak latency of the first five positive potentials recorded at the vertex are evaluated. Such evoked potentials (EPs) are so small compared to the background EEG activity that the responses to a number of stimuli have to be recorded and averaged with a computer in order to permit their recognition and definition. Its presence. such as ischemia or compression by a tumor. Such “event-related” potentials (ERPs) or “endogenous” potentials are related in some manner to the cognitive aspects of distinguishing an infrequently occurring target stimulus from other stimuli occurring more frequently. There is considerable variation in the average number of muscle fibers within the motor units of an individual muscle. The presence. the diagnosis of which requires the recognition of lesions involving several different regions of the central white matter.e. Clinical Utility of SEPs EP studies may detect and localize lesions in afferent pathways in the central nervous system (CNS). In addition to a possible role in the diagnosis of neurologic disorders or in evaluating the extent of pathologic involvement. In patients with acute severe optic neuritis. preserved BAEPs suggest either a metabolic-toxic etiology or bihemispheric disease. The EP findings are sometimes of prognostic relevance. Lyme disease. In patients who are comatose for uncertain reasons.. and EP studies may also be useful in evaluating patients with suspected brain death. i. They may also be abnormal with ocular abnormalities and with other causes of optic nerve disease. among other disorders. It is defined as an anterior horn cell. and symmetry over the two sides of the scalp are noted. detecting brainstem pathology. whereas it is generally normal in patients with depression or other psychiatric disorders that might be mistaken for dementia. and this induces stimulating currents in the subjacent neural tissue. Somatosensory evoked potentials (SEPs) are recorded over the scalp and spine in response to electrical stimulation of a peripheral (mixed or cutaneous) nerve. systemic lupus erythematosus. The presence or early return of a cortically generated response to stimulation of a nerve below the injured segment of the cord indicates an incomplete lesion and thus a better prognosis for functional recovery than otherwise. SEPs are used to evaluate proximal (otherwise inaccessible) portions of the peripheral nervous system and the integrity of the central somatosensory pathways. intraoperative EP monitoring of neural structures placed at risk by the procedure may permit the early recognition of dysfunction and thereby permit a neurologic complication to be averted or minimized. the technique provides information of prognostic relevance (e. a positive peak having a latency of approximately 100 ms. attention has been directed particularly at the so-called P3 component of the ERP. Bilateral loss of SEP components that are generated in the cerebral cortex implies that cognition may not be regained in posttraumatic or postanoxic coma. which is also designated the P300 component because of its positive polarity and latency of approximately 300–400 ms after onset of an auditory target stimulus. In surgery. For clinical purposes. which has no fixed temporal relationship to the stimulus. SEPs have been used to indicate the completeness of the lesion. and all the muscle fibers innervated by the axon. latency. the P100 is restored but with an increased latency that generally remains abnormally prolonged indefinitely. as clinical recovery occurs and visual acuity improves.ings alone cannot indicate whether a patient is demented or distinguish between dementia and pseudodementia. Thus the innervation ratio is <25 in the human external rectus or platysma muscle and between 1600 and 1700 in the Copyright © 2008 The McGraw-Hill Companies. including MS and motor neuron disease. . The BAEPs are normal in coma due to metabolic/toxic disorders or bihemispheric disease but abnormal in the presence of brainstem pathology. CHAPTER e31 Electrodiagnostic Studies of Nervous System Disorders ELECTROPHYSIOLOGIC STUDIES OF MUSCLE AND NERVE The motor unit is the basic element subserving motor function. The VEP findings are therefore helpful in indicating previous or subclinical optic neuritis. spinocerebellar degenerations. Multimodality EP abnormalities are not specific for MS. The findings are helpful in screening for acoustic neuromas. Abnormalities may aid in the localization of lesions to broad areas of the CNS. the electrophysiologic recognition of abnormalities in other sites helps to suggest or support the diagnosis but does not establish it unequivocally. its axon and neuromuscular junctions.

but their duration is normally between 5 and 15 ms. The number of units activated depends on the degree of voluntary activity. of the compound muscle action potential) to stimulation of its motor nerve at a distal site are also compared with values defined in normal subjects. once present. By contrast. amplitude is between 200 μV and 2 mV. limb plexus. and peripheral nerve to their terminal arborizations. so many motor units are normally activated that individual motor unit action potentials can no longer be distinguished. Electrical silence characterizes the involuntary. disorders. Slight voluntary contraction of a muscle leads to activation of a small number of motor units. In adults. The findings may provide a guide to the severity of an acute disorder of a peripheral or cranial nerve (by indicating whether denervation has occurred and the completeness of the lesion) and whether the pathologic process is active or progressive in chronic or degenerative disorders such as amyotrophic lateral sclerosis. The incidence of small. the electromyogram (EMG)]. EMG enables disorders of the motor units to be detected and characterized as either neurogenic or myopathic. short-duration. medial head of the gastrocnemius muscle. in particular. The potentials generated by any muscle fibers of these units that are within the pick-up range of the needle electrode will be recorded (Fig.e.. especially those with degeneration of anterior horn cells (such as amyotrophic lateral sclerosis). All rights reserved. Spontaneous fibrillation potentials and positive sharp waves. the loss of motor units that occurs in neuropathic disorders leads to a reduction in number of units activated during a maximal contraction and an increase in their firing rate.e. hemifacial spasm. having more than four phases) is usually increased in myopathic muscle. rarer... The nature and pattern of abnormalities relate to disorders at different levels of the motor unit. e31-3). Fasciculation potentials (which reflect the spontaneous activity of individual motor units) are characteristic of slowly progressive neuropathic disorders. With a full contraction. Long-duration polyphasic motor unit action potential such as may be seen in neuropathic disorders. B. After an acute neuropathic lesion.e264 A 10 ms B 100 ms 100 µV C D E 100 µV 100 µV 10 ms FIGURE e31-3 Activity recorded during EMG. and an excessive number of units is activated for a specified degree of voluntary activity. A. polyphasic motor unit action potentials (i. all of the muscle fibers are of the same type. as reinnervation occurs. especially those associated with denervation or inflammatory changes in affected muscle. triple. In neurogenic disorders. or myokymia. The technique of single-fiber EMG is discussed separately below. and in the legs is between 40 and 60 m/s. Relaxed muscle normally is electrically silent except in the end plate region. the pattern of affected muscles may localize the lesion to the anterior horn cells or to a specific site as the axons traverse a nerve root. Various quantitative EMG approaches have been developed. so that double. they are found earlier in proximal rather than distal muscles and sometimes do not develop distally in the extremities for 4–6 weeks. and characteristic responses to fatigue. i. or multiple discharges are recorded. C.e.or triphasic. The parameters of normal motor unit action potentials depend on the muscle under study and age of the patient. may be recorded from a needle electrode inserted into the muscle. short-duration. which is designated a contracture. E. The configuration and dimensions of the potentials may also be abnormal. Within each motor unit. histochemical stains. except in conjunction with the clinical findings and results of other laboratory studies. the spatial and temporal distribution of activity in individual units. enabling the presence and extent of peripheral nerve pathology to be determined. Such information is important for prognostic purposes. depending on the duration of the neuropathic process and on whether reinnervation has occurred. NERVE CONDUCTION STUDIES Recording of the electrical response of a muscle to stimulation of its motor nerve at two or more points along its course (Fig. They are particularly helpful in determining whether sensory symptoms are arising from pathology proximal or distal to the dorsal root ganglia (in the former instance. An increase in muscle contraction is associated with an increase in the number of motor units that are activated (recruited) and in the frequency with which they discharge. conduction velocity in the arms is normally between 50 and 70 m/s. they may persist indefinitely unless reinnervation occurs or the muscle degenerates so completely that no viable tissue remains. especially in tetany. Action potentials from the same motor unit sometimes fire with a consistent temporal relationship to each other. polyphasic motor unit action potential such as is commonly encountered in myopathic disorders. but abnormal spontaneous activity (Fig.. The surviving motor units are initially normal in configuration but. sustained muscle contraction that occurs in phosphorylase deficiency. Scanning EMG is a computer-based technique that has been used to study the topography of motor unit action potentials and. Fibrillation potentials and positive sharp waves (which reflect muscle fiber irritability) and complex repetitive discharges are most often—but not always—found in denervated muscle and may also occur after muscle injury and in certain myopathic disorders. both at rest and during activity. The muscle fibers of individual motor units are divided into two general types by distinctive contractile properties. Sensory nerve conduction studies are performed by determining the conduction velocity and amplitude of action potentials in sensory fibers when these fibers are stimulated at one point and the responses are recorded at another point along the course of the nerve. Complex repetitive discharges recorded in partially denervated muscle at rest. ELECTROMYOGRAPHY The pattern of electrical activity in muscle [i. e31-4) permits conduction velocity to be determined in the fastest-conducting motor fibers between the points of stimulation. there is an incomplete or reduced interference pattern. Small. D. The most common is to determine the mean duration and amplitude of 20 motor unit action potentials using a standardized technique. The findings do not enable a specific etiologic diagnosis to be made. Myotonic discharges—high-frequency discharges of potentials derived from single muscle fibers that wax and wane in amplitude and frequency—are the signature of myotonic disorders such as myotonic dystrophy or myotonia congenita but occur occasionally in polymyositis or other. however. e31-3) occurs in various neuromuscular disorders.e. The technique of macro-EMG provides information about the number and size of muscle fibers in a larger volume of the motor unit territory and has also been used to estimate the number of motor units in a muscle. and most are bi. peripheral sensory conduction studies will be normal) and whether neuromuscular dysfunction relates PART 16 Neurologic Disorders Copyright © 2008 The McGraw-Hill Companies. and a complete interference pattern is said to have been produced. . e31-3). Nerve conduction studies complement the EMG examination. The latency and amplitude of the electrical response of muscle (i. especially inflammatory disorders such as polymyositis. Normal triphasic motor unit action potential. they increase in amplitude and duration and become polyphasic (Fig.

maximal between 2 and 4 min after the conditioning period and lasting for as long as 10 min or so. If sensory nerve action potentials can be recorded normally at the wrist following stimulation of the digital fibers in the affected finger. i. metachromatic leukodystrophy.) to peripheral nerve disease. C8/T1 radiculopathy. This postactivation facilitation of neuromuscular transmission is followed by a longer-lasting period of depression. brachial plexopathy (lower trunk or medial cord).e. This is because more acetylcholine is normally released than is required to bring the motor end plate potentials to the threshold for generating muscle fiber action potentials.e265 tensive (thereby favoring a plexopathy). Numbness and paresthesia of the little finger and associated wasting of the intrinsic muscles of the hand may result from a spinal cord lesion. may lead to a depression of neuromuscular transmission. an important distinction because of the etiologic implications. In general. sensory nerve action potentials are small or absent. such as a radiculopathy. however. Responses are recorded with a surface electrode from the abductor digiti minimi muscle to supramaximal stimulation of the nerve at different sites. There is normally little or no change in size of the compound muscle action potential following repetitive stimulation of a motor nerve at 2–3 Hz with stimuli delivered at intervals after voluntary contraction of the muscle for about 20–30 s. absence of the sensory potentials. Conduction velocity is often markedly slowed. In Lambert-Eaton myasthenic syndrome. terminal motor latencies are prolonged. The electrophysiologic findings thus permit a definitive diagnosis to be made and specific treatment instituted in circumstances where there is clinical ambiguity.Recording electrodes Reference Active Cathode Anode Stimulating electrodes Stimulation site Wrist Stimulating electrodes Ground muscles conforms to radicular or ulnar nerve territory. and compound motor and sensory nerve action potentials may be dispersed in the demyelinative neuropathies (such as in Guillain-Barré syndrome. the clinical utility of F wave studies has been disappointing. All rights reserved. except perhaps in Guillain-Barré syndrome. toward the spinal cord) as well as orthodromically (to the nerve terminals). conduction velocity is normal or slowed only mildly. Thus in myasthenia gravis. where they are often absent or delayed. EMG examination will indicate whether the pattern of affected Copyright © 2008 The McGraw-Hill Companies. or certain hereditary neuropathies). F WAVE STUDIES Stimulation of a motor nerve causes impulses to travel antidromically (i. determining the extent and severity of the underlying pathology. even though preceding activity in the junctional region influences the release of acetylcholine and thus the size of the end plate potentials elicited by a test stimulus. Nerve conduction studies provide a means of following the progression and therapeutic response of peripheral nerve disorders and are being used increasingly for this purpose in clinical trials. providing a guide to prognosis. . Ulnar motor conduction studies will generally also distinguish between a radiculopathy (normal findings) and ulnar neuropathy (abnormal findings) and will often identify the site of an ulnar nerve lesion: the nerve is stimulated at several points along its course to determine whether the compound action potential recorded from a distal muscle that it supplies shows a marked alteration in size or area or a disproportionate change in latency. particularly at a rate of between 2 and 5 Hz. In patients with a mononeuropathy. indicating that more muscle fibers are responding. or a lesion of the ulnar nerve. during which responses are reduced in size. repetitive stimulation. by contrast. It is elicited by low-intensity stimulation of the tibial nerve and represents a monosynaptic reflex in which spindle (Ia) afferent fibers constitute the afferent arc and alpha motor axons the efferent pathway. In disorders of neuromuscular transmission this safety factor is reduced. MUSCLE RESPONSE TO REPETITIVE NERVE STIMULATION The size of the electrical response of a muscle to supramaximal electrical stimulation of its motor nerve relates to the number of muscle fibers that are activated. and may therefore be helpful in detecting abnormalities when conventional nerve conduction studies are normal. Neuromuscular transmission can be tested by several different protocols. with a decrement in size of the response recorded from affected muscles. Decrementing responses to repetitive stimulation at 2–5 Hz are common in myasthenia gravis but may also occur in the congenital myasthenic syndromes.. or is more ex. single or repetitive stimuli of the motor nerve may elicit larger muscle responses than before. immediately after a period of maximal voluntary activity. producing a small motor response that occurs considerably later than the direct response elicited by nerve stimulation. 1998. suggests distal pathology. they are invaluable as a means of localizing a focal lesion. They enable a polyneuropathy to be distinguished from a mononeuropathy multiplex when this is not possible clinically. The F wave so elicited is sometimes abnormal (absent or delayed) with proximal pathology of the peripheral nervous system. Such antidromic impulses cause a few of the anterior horn cells to discharge. and there is EMG evidence of denervation in axonal neuropathies such as occur in association with metabolic or toxic disorders. The H reflexes are often absent bilaterally in elderly patients or with polyneuropathies and may be lost unilaterally in S1 radiculopathies. there is a radiculopathy or more central lesion. in which there is defective release of acetylcholine at the neuromuscular junction.. By contrast. (From Aminoff. H REFLEX STUDIES The H reflex is easily recorded only from the soleus muscle (S1) in normal adults. the pathology is probably proximal to the dorsal root ganglia. Similarly. the compound muscle action potential elicited by a single stimulus is Below elbow Above elbow Axilla 10 ms 5 mV CHAPTER e31 Electrodiagnostic Studies of Nervous System Disorders FIGURE e31-4 Arrangement for motor conduction studies of the ulnar nerve. and are shown in the lower panel. They may suggest the underlying pathologic basis in individual cases. and detecting subclinical involvement of other peripheral nerves. chronic inflammatory polyneuropathy. with stimulation at a particular site. conduction block is frequent in acquired varieties of these neuropathies.e. The utility and complementary role of EMG and nerve conduction studies are best illustrated by reference to a common clinical problem. but the most helpful is to record with surface electrodes the electrical response of a muscle to supramaximal stimulation of its motor nerve by repetitive (2–3 Hz) shocks delivered before and at selected intervals after a maximal voluntary contraction.

SINGLE-FIBER ELECTROMYOGRAPHY This technique is particularly helpful in detecting disorders of neuromuscular transmission. 3d ed. 1998 ——— (ed): Electrodiagnosis in Clinical Neurology. although the findings are somewhat more variable and not all muscles are affected. respectively. 3d ed. the first few responses may decline in size. Philadelphia. New York. 2003 HOLMES GL et al: Clinical Neurophysiology of Infancy. Abnormalities of either nerve or intrinsic lesions of the medulla or pons may lead to uni. and in some instances impulses in individual muscle fibers may fail to occur because of impulse blocking at the neuromuscular junction. A special needle electrode is placed within a muscle and positioned to record action potentials from two muscle fibers belonging to the same motor unit. BLINK REFLEXES Electrical or mechanical stimulation of the supraorbital nerve on one side leads to two separate reflex responses of the orbicularis oculi—an ipsilateral R1 response having a latency of approximately 10 ms and a bilateral R2 response with a latency in the order of 30 ms. In patients with botulism. Churchill Livingstone. 2006 KIMURA J: Electrodiagnosis in Diseases of Nerve and Muscle. but subsequent responses increase. The trigeminal and facial nerves constitute the afferent and efferent arcs of the reflex. This value is increased when neuromuscular transmission is disturbed for any reason. New York. The time interval between the two potentials will vary in consecutive discharges. but this is of less immediate clinical relevance. The jitter can be quantified as the mean difference between consecutive interpotential intervals and is normally between 10 and 50 μs.e266 generally very small.. FURTHER READINGS AMINOFF MJ: Electromyography in Clinical Practice: Electrodiagnostic Aspects of Neuromuscular Disease. Churchill Livingstone. and the findings may therefore be helpful in identifying or localizing such pathology. 2001 PART 16 Neurologic Disorders Copyright © 2008 The McGraw-Hill Companies. Childhood. . New York. All rights reserved. Philadelphia. and Adolescence. With repetitive stimulation at rates of up to 10 Hz. Lippincott Williams & Wilkins. Saunders. Butterworth Heinemann. If faster rates of stimulation are used (20–50 Hz).or bilateral loss of the response. Philadelphia. the response to repetitive stimulation is similar to that in Lambert-Eaton syndrome. 2005 BROWN WF et al (eds): Neuromuscular Function and Disease. PEDLEY TA (eds): Current Practice of Clinical Electroencephalography. Oxford University Press. 5th ed. this is called the neuromuscular jitter. 2002 EBERSOLE JS. 3d ed.e. Single-fiber EMG can also be used to determine the mean fiber density of motor units (i. Single-fiber EMG is more sensitive than repetitive nerve stimulation or determination of acetylcholine receptor antibody levels in diagnosing myasthenia gravis. mean number of muscle fibers per motor unit within the recording area) and to estimate the number of motor units in a muscle. the increment may be dramatic so that the amplitude of compound muscle action potentials eventually reaches a size that is several times larger than the initial response.

new-onset seizure. IMAGING AND LABORATORY STUDIES PRIOR TO LP Patients with an altered level of consciousness. The patient is asked to lie on his or her side. Stephen L. Topical anesthesia can be achieved by the application of a lidocaine-based cream.) ward onto a bedside table top. Anxiety can be allayed by the use of lorazepam. trying to touch the nose to the umbilicus.e32 Technique of Lumbar Puncture Elizabeth Robbins. The procedure should be performed on a firm surface. over a period of ~5 min. 3– 5 mL total. the stylet is reinserted and the needle is advanced slightly. and radicular pain or numbness. Imaging studies should include the spine in patients with symptoms suggesting cord compression. In 1 most adults. or an immunocompromised state are at increased risk for potentially fatal cerebellar or tentorial herniation following LP. All rights reserved. the needle is not usually withdrawn between injections. If on the second attempt the needle still hits bone (indicating lack of success in introducing it between the spinous processes). ANALGESIA Anxiety and pain can be minimized prior to beginning the procedure. each one progressively deeper than the last. injury to the spinal cord or nerve roots. The second attempt is sometimes more successful if the patient CHAPTER e32 Technique of Lumbar Puncture Copyright © 2008 The McGraw-Hill Companies. lidocaine/prilocaine requires 60–120 min. the platelet count. A useful anatomic guide is a line drawn between the posterior superior iliac crests. Local anesthetic. post-LP headache. such as back pain. the needle is advanced 4–5 cm (1 -. either of which can produce permanent nerve injury and/or paralysis. the needle is partially withdrawn and reinserted at a different angle. Patients receiving low-molecular-weight heparin are at increased risk of post-LP spinal or epidural hematoma. POSITIONING Proper positioning of the patient is essential.to 22-gauge) is inserted in the midline. Approximately 0. if the procedure is to be performed at the bedside. LP should not be performed through infected skin as organisms can be introduced into the subarachnoid space (SAS). preferably following blood culture. If there is still no fluid. the bevel should be maintained in the vertical position. A disadvantage of the seated position is that measurement of opening pressure may not be accurate. The interspace is chosen following gentle palpation to identify the spinous processes at each lumbar level. parallel to the direction of the dural fibers and with the flat portion of the bevel pointed upward. The goal is to inject each mini-bolus of anesthetic into an area of skin that has become numb from the preceding injection. bedside ultrasound to guide needle placement may be employed. The cream should be applied in a thick layer so that it completely covers the skin.000/μL and an INR ≤ 1. the LP should be delayed for 10–15 min following the completion of the injection of anesthetic. and partial thromboplastin time should be checked prior to lumbar puncture. or infection. It is important that the patient not simply lean forL3-L4 inner space FIGURE e32-1 Proper positioning of a patient in the lateral decubitus position. 1–2 mg given PO 30 min prior to the procedure or IV 5 min prior to the procedure. e32-1). the conus extends to the L2-L3 interspace. should precede the neuroimaging study.” If no fluid appears despite apparently correct needle placement. administration of antibiotics. as this is not an optimal position for opening up the spinous processes.” The neck is gently ante-flexed and the thighs pulled up toward the abdomen. When lumbar puncture is performed in patients who are sitting. the examiner usually recognizes entry as a sudden release of resistance. LP is sometimes more easily performed in obese patients if they are sitting. Bleeding complications rarely occur in patients with platelet counts ≥ 50. and doses should be held for 24 h before the procedure. Approximately 5–10 mini-boluses are injected. The LP needle (typically 20. The patient is instructed to curl forward. Patients receiving therapeutic anticoagulation or those with coagulation defects including thrombocytopenia are at increased risk of post-LP spinal subdural or epidural hematomas. the shoulders and pelvis should be vertically aligned without forward or backward tilt (Fig. the patient should be positioned at the edge of the bed and not in the middle. the torso is perpendicular to the bed. After cleansing the skin with povidone-iodine or similar disinfectant. is injected into the subcutaneous tissue.5–1 mL of lidocaine is injected at a time. with feet supported on a chair. A pause of ~15 s between injections helps to minimize the pain of the subsequent injection. Major complications are extremely uncommon but can include cerebral herniation. this significantly decreases and can even eliminate pain from the procedure. If possible. if the patient experiences sharp radiating pain down one leg. midway between two spinous processes. and slowly advanced. the examiner should put on sterile gloves. If the needle cannot be advanced because it hits bone. Neuroimaging should be obtained in these patients prior to LP to exclude a focal mass lesion or diffuse swelling. Even a delay of 5 min will help to reduce pain. a “pop. serial injections. lumbar puncture (LP) is usually a safe procedure. papilledema. using a total of ~5 mL of lidocaine. an occlusive dressing is used to keep the cream in place.) before the SAS is 2 reached. a count of <20. which corresponds closely to the level of the L3-L4 interspace. If a bleeding disorder is suspected. The bevel of the needle should be maintained in a horizontal position. An alternative to the lateral recumbent position is the seated position. Proper local disinfection reduces the risk of introducing skin bacteria into the SAS or other sites. Lidocaine 4% is effective when applied 30 min prior to the procedure. In the remaining 6%. TECHNIQUE Once the desired target for needle insertion has been identified.000/μL is considered to be a contraindication to LP. facing away from the examiner. then the needle should be completely withdrawn and the patient should be repositioned.–2 in. this minimizes injury to the fibers as the dura is penetrated. in nonemergency situations a topical anesthetic cream can be applied (see above). urinary retention. the area is draped with a sterile cloth. (From Straus et al. There are no data available to assess the safety of LP in patients with low platelet counts. In situations in which LP is difficult using palpable spinal landmarks. When time permits. and to “roll up into a ball. The spinal cord terminates at approximately the L1 vertebral level in 94% of individuals. pain associated with the injection of lidocaine can be minimized by slow. In patients with suspected meningitis who require neuroimaging prior to diagnostic LP. a focal neurologic deficit. international normalized ratio (INR). Minor complications occur with greater frequency and can include backache. Note that the shoulders and hips are in a vertical plane. Hauser Vertical alignment of shoulders and pelvis e267 In experienced hands. hemorrhage. the needle insertion site is blotted dry using a sterile gauze pad. Some examiners halt needle advancement periodically to remove the stylet and check for flow of cerebrospinal fluid (CSF).5. typically 1% lidocaine. then the needle may be rotated 90°–180°. The patient sits at the side of the bed. LP is therefore performed at or below the L3-L4 interspace. or incontinence. or if no fluid appears (“dry tap”). leg weakness. .

however.. given the flexibility of the small-diameter stylet. tinnitus. compared to 5–12% when a 24. the normal white blood cell count is fewer than five mononuclear cells (lymphocytes and monocytes) per μL. The “atraumatic” needle has its opening on the top surface of the needle. herpes simplex virus. breakage. which does not have the customary cutting. For patients with persistent pain. whereas blood due to SAH does not. occurring in 10–30% of patients. however. Strategies to decrease the incidence of post-LP headache are listed in Table e32-1. suggesting that the customary practice of remaining in a recumbent position post-LP may be unnecessary. fungal. The upper limit of normal opening pressure with the patient supine is 180 mmH2O in adults but may be as high as 200–250 mmH2O in obese adults. TABLE e32-1 REDUCING THE INCIDENCE OF POST-LP HEADACHE Effective Strategies Use of small-diameter needle (22-gauge or smaller) Use of atraumatic needle (Sprotte and others) Replacement of stylet prior to removal of needle Insertion of needle with bevel oriented in a cephalad to caudad direction (when using standard needle) Ineffective Strategies Bed rest (up to 4 h) following LP Supplemental fluids Minimizing the volume of spinal fluid removed Immediate mobilization following LP Patients may obtain relief by lying in a comfortable position. (7) antibody levels against microorganisms. because atraumatic needles are more difficult to use. resulting in pain. There is a low risk of needle damage. Nausea and stiff neck often accompany headache. In general. (2) protein and glucose concentrations. The longer the patient is upright. xanthochromic CSF may also be present in patients with liver disease and when the CSF protein concentration is markedly elevated [>1. could be responsible for subsequent CSF fluid leak and post-LP headache. latex agglutination) (6) polymerase chain reaction (PCR) amplification of DNA or RNA of microorganisms (e. However.. mycobacterial. Younger age and female gender are associated with an increased risk of post-LP headache. Post-LP headache usually resolves without specific treatment. The needle can then be reinserted at the same level or at an adjacent one. the patient is customarily positioned in a comfortable. there is relief upon reclining or with abdominal compression. Symptoms usually resolve over a few days but may on occasion persist for weeks to months. NORMAL VALUES (See Table e32-2) In uninfected CSF. so that when a patient is upright there is probably dilation and tension placed on the brain’s anchoring structures. In these situations a specimen of CSF should be centrifuged immediately after it is obtained. rather than penetrate. Although intracranial hypotension is the usual explanation for severe LP headache. The pain is usually a dull ache but may be throbbing. the stylet is reinserted to avoid the possibility of entrapment of a nerve root in the dura as the needle is being withdrawn. A bloody tap due to penetration of a meningeal vessel (a “traumatic tap”) may result in confusion with subarachnoid hemorrhage (SAH). Depending on the clinical indication. Injury is unlikely. e32-2). recumbent position for 1 h before rising. In addition to SAH.” or “non-cutting”) needle also reduces the incidence of moderate to severe headache compared with standard LP (Quinke. beveled tip.0 g/L (150–200 mg/dL)]. whereas xanthochromic supernatant suggests SAH. the risk of headache following use of a 20.or 22-gauge standard (Quinke) needle was 20–40%. enteroviruses). (From Thomas et al. with its potential risk of causing a needle-stick injury to the examiner. The mechanism for these treatment effects is not straightforward.g. a manometer is attached to the needle and the opening pressure measured.to 27gauge needle was used.g.. 12)] and antiemetics. Following LP. POST-LP HEADACHE The principal complication of LP is headache. the yield of fungal and mycobacterial cultures and cytology increases when larger volumes are sampled. All rights reserved. treatment with IV caffeine (500 mg in 500 mL saline administered over 2 h) may be effective. Use of an “atraumatic” (Sprotte. photophobia. its location is occipitofrontal. Gram’s and acid-fast stained smears). fluid is then obtained for studies including: (1) cell count with differential. or “traumatic”) needles (Fig. more attempts may be required to perform the LP. it begins when the patient sits or stands upright. PART 16 Neurologic Disorders FIGURE e32-2 Comparison of the standard (“traumatic” or Quinke) LP needle with the “atraumatic” (Sprotte). Polymorphonuclear leukocytes (PMNs) are not found in normal unconcentrated CSF. entrapment could result in a dural CSF leak. CSF is allowed to drip into collection tubes. “pencil point.. Prior to removing the LP needle. the longer the latency before head pain subsides. the pain-sensitive dural sinuses. Headache usually begins within 48 h but may be delayed for up to 12 days. although recent data suggests that assuming a recumbent position may be unnecessary as it does not appear to affect the development of headache (see below).g.g. rare PMNs can be found in centrifuged or concentrated CSF specimens such as those utilized for cytologic examination. Another strategy to decrease the incidence of headache is to replace the stylet before removing the LP needle. it should not be withdrawn with a syringe. nonsteroidal anti-inflammatory drugs.5–2. by protruding through the dura. Some practitioners question the safety of this maneuver. and vertigo. Post-LP headache is caused by a drop in CSF pressure related to persistent leakage of CSF at the site where the needle entered the subarachnoid space. . The smallest gauge needles usually require the use of an introducer needle and are associated with a slower CSF flow rate. The blood patch has an immediate effect. particularly in overweight patients. on contact. the syndrome can occur in patients with normal CSF pressure. In general 20–30 mL may be safely removed from adults. Use of a smaller caliber needle is associated with a lower risk: in one study.) Copyright © 2008 The McGraw-Hill Companies. bloody CSF due to the penetration of a meningeal vessel clears gradually in successive tubes. Although 15 mL of CSF is sufficient to obtain all of the listed studies. an epidural blood patch accomplished by injection of 15 mL of autologous whole blood is usually effective. making it unlikely that sealing off a dural hole with blood clot is its sole mechanism of action.e268 straightens the spine completely prior to repositioning. For patients who do not respond to caffeine. Loss of CSF volume decreases the brain’s supportive cushion. Once the SAS is reached. (5) antigen tests (e. causing headache. It may also be necessary to use an introducer with the atraumatic needle. opioids (Chap. Head pain is dramatically positional. (8) immunoelectrophoresis for determination of γ-globulin level and oligoclonal banding. e. For some patients beverages with caffeine can provide temporary pain relief. clear supernatant following CSF centrifugation supports the diagnosis of a bloody tap. atrial fibrillation is an uncommon side effect. and (9) cytology. (3) culture (bacterial. This procedure is usually performed by a pain specialist or anesthesiologist. (4) smears (e. Studies comparing mobilization immediately following LP with bed rest for up to 4 h show no significant differences in the incidence of headache. a design intended to reduce the chance of cutting dural fibers that. and occasionally. which tends to bend. and care is largely supportive with oral analgesics [acetaminophen. The examiner should look for normal oscillations in CSF pressure associated with pulse and respirations. viral). patients report blurred vision. with the Sprotte atraumatic needle.

if RBC are present e269 from a traumatic tap. Neurology 55:909.442 g/L 0. SHEPHERD DB: Post-dural puncture headache: Pathogenesis.TABLE e32-2 CEREBROSPINAL FLUID a Constituent Glucose Lactate Total protein Lumbar Cisternal Ventricular Albumin IgG IgG indexb Oligoclonal bands (OGB) Ammonia CSF pressure CSF volume (adult) Red blood cells Leukocytes Total Differential Lymphocytes Monocytes Neutrophils SI Units 2. there is a time lag in attainment of equilibrium.59 <2 bands not present in matched serum sample 15–47 μmol/L ∼150 mL 0 0–5 mononuclear cells per mm3 60–70% 30–50% None Conventional Units 40–70 mg/dL 10–20 mg/dL 15–50 mg/dL 15–25 mg/dL 6–15 mg/dL 6. BMJ 321:986. . 2006 PETERSON MA. 2000 LAVI R et al: Standard vs atraumatic Whitacre needle for diagnostic lumbar puncture: A randomized trial. Neurology 67:1492.6–44. EVANS RW: Addendum to assessment: Prevention of postlumbar puncture headaches: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.2 mmol/L (<40 mg/dL) are abnormal.29–0.06–0. their number decreases as additional CSF is collected. Br J Anaesth 91:718. Neurologist 12:224. 2005 RICHMAN JM et al: Bevel direction and postdural puncture headache: A meta-analysis. 2005 ELLENBY MS et al: Lumbar puncture (video). CSF glucose concentrations <2. FURTHER READINGS ARMON C. bIgG index = CSF IgG(mg/dL) × serum albumin(g/dL)/Serum IgG(g/dL) × CSF albumin(mg/dL). measurements of the same parameters in blood plasma obtained at the same time are recommended. N Engl J Med 355:e12.25 g/L 0. 2006 EVANS RW et al: Assessment: Prevention of post-lumbar puncture headaches: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. However. 1998 THOMAS SF et al: Randomised controlled trial of atraumatic versus standard needles for diagnostic lumbar puncture.15–0. and cerebrospinal levels of plasma constituents that can fluctuate rapidly (such as plasma glucose) may not achieve stable values until after a significant lag phase.89 mmol/L 1–2 mmol/L 0.057 g/L 0.22–3. J Neurol 245:589. All rights reserved. 2006 STRAUS SE et al: How do I perform a lumbar puncture and analyze the results to diagnose bacterial meningitis? JAMA 296:2012. 2000 TURNBULL DK.15 g/L 0.9–5. ABELE J: Bedside ultrasound for difficult lumbar puncture. 2006 STRUPP M et al: Incidence of post-lumbar puncture syndrome reduced by reinserting the stylet: A randomized prospective study of 600 patients. Neurology 65:510.5 g/L 0. 2003 25–80 μg/dL 50–180 mmH2O 0 aSince cerebrospinal fluid concentrations are equilibrium values. CHAPTER e32 Technique of Lumbar Puncture Copyright © 2008 The McGraw-Hill Companies.2 mg/dL 0. prevention and treatment. J Emerg Med 28:197.15–0.009–0.7 mg/dL Red blood cells (RBC) are not normally present in CSF.066–0.

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. and seizures. 363). these etiologies should be treated promptly. or focal deficits. including secondary causes such as renovascular hypertension. vasogenic edema is likely due primarily to dysfunction of the capillary endothelium itself. Nonconvulsive seizures have been described in hyperperfusion states. resulting in autoregulation working over a much higher range of pressures (e. It is useful to separate disorders of hyperperfusion into those caused primarily by increased pressure and those due mostly to endothelial dysfunction from a toxic or autoimmune etiology (Table e33-1). The clinical presentation of the hyperperfusion syndromes is similar. methotrexate) Glucocorticoids Erythropoietin HELLP syndrome (hemolysis. rather than purely white matter as the word “leukoencephalopathy” intimates. and management of coma and other critical conditions (Chaps. Other ancillary studies such as cerebrospinal fluid (CSF) analysis often yield nonspecific results. In these cases. The diagnosis in all of these conditions is clinical. Modern imaging techniques and experimental models suggest that vasogenic edema is usually the primary process leading to neurologic dysfunction. It appears as if the rapidity of rise rather than the absolute value of pressure is the most important risk factor. Previously this classic radiographic appearance had been termed reversible posterior leukoencephalopathy (RPLE). MRI has improved the ability of clinicians to diagnose hyperperfusion syndromes. In conditions where increased cerebral blood flow plays a role. POST-CARDIAC BYPASS BRAIN INJURY Central nervous system (CNS) injuries following open heart or coronary artery bypass grafting (CABG) surgery are common and include CHAPTER e33 Special Issues in Inpatient Neurologic Consultation Copyright © 2008 The McGraw-Hill Companies. It is reasonable to lower mean arterial pressure by ~20% initially. range from mild to severe. altered mental status (Chap. While elevated or relatively elevated blood pressure is common in many of these disorders. and resulting edema. breakthrough of autoregulation occurs. and these can be of multiple types depending on the severity and location of the edema. These seemingly diverse syndromes include hypertensive encephalopathy. examination of the inpatient vital signs record will usually reveal a systemic blood pressure that is increased above baseline.g. including discontinuation of offending substances such as calcineurin inhibitors in toxic processes. In patients with chronic hypertension. therefore a low threshold for obtaining an electroencephalogram (EEG) in these patients should be maintained. Imaging with CT is less sensitive but may show a pattern of patchy hypodensity in the involved territory. so a long differential diagnosis should be entertained. The symptoms of these disorders are common and nonspecific. However. elevated liver enzyme levels. Common reasons for neurologic consultation include stroke (Chap. Anticonvulsants are effective. In cases of hyperperfusion syndromes. It should be noted that many of the substances that have been implicated. both of these pathophysiologic processes are likely playing some role in each of these disorders. low platelet count) Thrombotic thrombocytopenic purpura (T TP) Hemolytic uremic syndrome (HUS) Systemic lupus erythematosus (SLE) Wegener’s granulomatosis e271 Inpatient neurologic consultations usually involve questions about specific disease processes or prognostication after various cerebral injuries. Headaches have no specific characteristics. CONSULTATIONS REGARDING CENTRAL NERVOUS SYSTEM DYSFUNCTION HYPERPERFUSION STATES A group of neurologic disorders shares the common feature of hyperperfusion playing a key role in pathogenesis. headache (Chap. focal deficits. often necessitating continuous EEG monitoring. pheochromocytoma. Samuels TABLE e33-1 SOME COMMON ETIOLOGIES OF HYPERPERFUSION SYNDROME Disorders in which increased capillary pressure dominates the pathophysiology Hypertensive encephalopathy. e33-1). this cerebral autoregulation curve is shifted. emphasizing the vasogenic rather than cytotoxic nature of this edema. cocaine use. there is good evidence to support the use of magnesium sulfate for seizure control. not respecting any single vascular territory (Fig. . 268 and 269). Patients classically exhibit the high T2 signal of edema primarily in the posterior occipital lobes. some hyperperfusion states such as calcineurin-inhibitor toxicity occur with no apparent pressure rise. this term has fallen out of favor because none of its elements are completely accurate: the radiographic and clinical changes are not always reversible. often through an arterial line. cisplatin. and prompt delivery of the fetus in eclampsia. any focal deficit can occur depending on the area affected. 364). In these hypertensive patients. In cases where there is an identified cause of the syndrome. the territory involved is not uniquely posterior. and may be accompanied by alterations in consciousness ranging from confusion to coma. azathioprine. capillary leakage into the interstitium. Hypertension plays a key role commonly. etc. The predilection of all of the hyperperfusion disorders to affect the posterior rather than anterior portions of the brain may be due to a lower threshold for autoregulatory breakthrough in the posterior circulation.\ e33 Special Issues in Inpatient Neurologic Consultation S. and judicious lowering of the blood pressure with IV agents such as labetolol or nicardipine is advised along with continuous cardiac and blood pressure monitoring. eclampsia. but a rapid lowering of pressure can more easily lead to ischemia on the lower end of the autoregulatory curve. leading to breakdown of the bloodbrain barrier. seizures. and gray matter may be affected as well. seizures (Chap. as further lowering of the pressure may cause secondary ischemia as pressure drops below the lower range of the patient’s autoregulatory capability. All rights reserved. but in the special case of eclampsia. 26). 70–175 mmHg).. However. normal serum levels of these medications do not exclude them as inciting agents. When the systemic blood pressure exceeds the limits of this mechanism. The typical focal deficit in hyperperfusion states is cortical visual loss. This autoregulatory phenomenon is achieved through both myogenic and neurogenic influences causing small arterioles to contract and dilate. and toxicity from calcineurin-inhibitor medications. with prominent headaches. including consideration of other causes of confusion. given the tendency of the process to involve the occipital lobes. The brain’s autoregulatory capability successfully maintains a fairly stable cerebral blood flow in adults despite alterations in systemic mean arterial pressure (MAP) ranging from 50–150 mmHg. Andrew Josephson. after carotid endarterectomy. Martin A. although cases have been reported with normal imaging. exhibit neurologic dysfunction in the ipsilateral newly reperfused hemisphere. treatment should commence urgently once the diagnosis is considered. 15). 5-fluorouracil. Post-carotid endarterectomy syndrome Preeclampsia/eclampsia High-altitude cerebral edema Disorders in which endothelial dysfunction dominates the pathophysiology Calcineurin-inhibitor toxicity Chemotherapeutic agent toxicity (e. resulting in hyperperfusion via increased cerebral blood flow. Therefore. In reality. post-carotid endarterectomy syndrome. can cause this syndrome even at low doses or after years of treatment. This chapter focuses on additional common reasons for consultation that are not addressed elsewhere in the text. therefore prompt recognition and management of this condition should allow for clinical recovery if superimposed hemorrhage or infarction has not occurred. Seizures must be identified and controlled. headache.g. cerebral blood flow is kept steady at higher MAP. cytarabine. Seizures may be present. such as cyclosporine. as evidenced by patients who. treatment of immune-mediated disorders such as thrombotic thrombocytopenic purpura (TTP). Diffusion-weighted images are typically normal.

releasing a shower of particulate matter into the cerebral circulation. All rights reserved.e272 FIGURE e33-1 Axial fluid-attenuated inversion recovery (FLAIR) MRI of the brain in a patient taking cyclosporine after liver transplantation who presented with seizures. like delirium. headache. Hypoperfusion and embolic disease are frequently involved in the pathogenesis of these syndromes. e33-2). and many of these compounds have well-described neurologic complications. acute encephalopathy. In patients with headache. This neurotoxicity occurs mainly with cyclosporine and tacrolimus and can present even in the setting of normal serum drug levels. whereas others with higher reserves may remain asymptomatic despite a similar dose of microemboli. however. especially for patients at high risk of developing cognitive dysfunction after surgery due to advanced age. Histologic studies indicate that literally millions of tiny emboli may be released. It should be noted that some of the emboli that are found histologically in these patients are too small to be detected by standard imaging sequences. a single large embolus leads to an isolated largevessel stroke that presents with obvious clinical focal deficits. although multiple mechanisms may be involved in these critically ill patients who are at risk for various metabolic and polypharmaceutical complications. cognitive deficit. Filters placed in the aortic arch may have some promise in capturing these emboli. Occasionally. consistent with a hyperperfusion state secondary to calcineurin-inhibitor exposure. especially when it is administered intrathecally or with concurrent radiotherapy. a negative MRI after surgery does not exclude the diagnosis of embolirelated complications. and cortical blindness. has very few recorded cases of neurotoxicity and may be a reasonable alternative for some patients. More commonly. the diagnosis of hyperperfusion syndrome should be considered. sirolimus. cardiac surgery may serve to unmask the early manifestations of disorders such as vascular dementia and Alzheimer’s disease. as a “stress test for the brain. Other examples of immunosuppressive medications and their neurologic complications include OKT3-associated akinetic mutism and the leukoencephalopathy seen with methotrexate. but the patient may suffer a chronic cognitive deficit. the emboli released are multiple and smaller. even using modern surgical techniques. seizures. and a chronic syndrome of cognitive impairment. Cross-clamping of the aorta. This shower of microemboli results in a number of clinical syndromes. manipulation of the heart. presenting as either a hyperactive or hypoactive confusional state. or severe atheromatous disease of the carotid arteries or aortic arch. previous stroke. arrhythmias such as atrial fibrillation. Development of successful endovascular operative approaches may provide a reasonable alternative to conventional CABG procedures. The frequency of hypoxic injury secondary to inadequate blood flow intraoperatively has been markedly decreased by the use of modern surgical and anesthetic techniques. some recent data suggests that off-pump CABG does not preserve cognitive function compared with on-pump CABG. Thrombus in the heart itself as well as atheromas in the aortic arch can become dislodged during cardiac surgeries. Since modern techniques have successfully minimized hypoperfusion complications during these surgeries. Cardiac surgery can be viewed. Embolic infarctions classically complicate cardiac transplantation. When cerebral embolization accompanies renal or liver transplantation surgery. and introduction of air through suctioning have all been implicated as potential sources of emboli. Increased signal is seen bilaterally in the occipital lobes predominantly involving the white matter. some patients still experience neurologic complications from cerebral hypoperfusion or may suffer focal ischemia from tight carotid or focal intracranial stenoses in the setting of regional hypoperfusion. especially in the setting of systemic hypotension during cardiac transplant surgery. no acute syndrome is recognized. . although convincing evidence is currently lacking. therefore. Treatment primarily involves lowering the drug dosage or discontinuing the drug. A related newer agent. Diffusion-weighted MRI sequences demonstrated restricted diffusion in these same locations. Despite these advances. Off-pump CABG surgeries have the advantages of reducing length of stay and perioperative complications. suggesting acute infarction. stroke. as discussed above. POST-SOLID ORGAN TRANSPLANT BRAIN INJURY Patients who have undergone solid organ transplantation are at risk for neurologic injury in the postoperative period and for the months to years thereafter.” Some patients with a low cerebral reserve due to underlying cerebrovascular disease or an early neurodegenerative process will develop a chronic. When the burden of microemboli is lower. Cerebrovascular complications of solid organ transplant are often first recognized in the immediate postoperative period. but all solid organ transplant procedures place patients at risk for systemic emboli. much attention is now focused on reducing this inevitable shower of microemboli. Embolic disease is likely the predominant mechanism of cerebral injury during cardiac surgery as evidenced by diffusion-weighted MRI and intraoperative transcranial Doppler studies. Border zone territory infarctions can occur. Increased signal is seen in the border zones bilaterally between the middle cerebral artery and anterior cerebral artery territories. In any solid organ transplant patient with neurologic complaints. a careful search for PART 16 Neurologic Disorders FIGURE e33-2 Coronal fluid-attenuated inversion recovery (FLAIR) MRI of the brain in a patient presenting with altered mental status after an episode of hypotension during coronary artery bypass grafting (CABG). In this manner. an acute encephalopathy can occur postoperatively. the latter of which is frequently and incorrectly ascribed to depression. When there is a high burden of these small emboli. which is now increasingly recognized. Immunosuppressive medications are administered in high doses to patients after solid organ transplant. or focal neurologic deficits taking calcineurin inhibitors. Neurologic consultants should view these patients as a special population at risk for both unique neurologic complications as well as for the usual disorders found in any critically ill inpatient. Copyright © 2008 The McGraw-Hill Companies. Postoperative infarcts in the border zones between vascular territories commonly are blamed on systemic hypotension although some have suggested that these infarcts can also result from embolic disease (Fig. a careful examination of the medication list is required to search for these possible drug effects. extracorporeal circulation techniques (“bypass”).

less commonly. Causes of neurologic relevance include central diabetes insipidus. Starting in the second month posttransplant. as well as looking for intrapulmonary shunting. 126).5 mmol/L (>5. If treatment of hyponatremia results in a rapid rise in serum sodium. with generalized seizures or unilateral movement disorders. Hyperosmolality itself can lead to a generalized encephalopathy that is nonspecific and without focal findings. especially when chronic. Hyperosmolality is usually due to hypernatremia. occurs either because of excessive potassium losses (from the kidneys or gut) or due to an abnormal potassium distribution between the intracellular and extracellular spaces. opportunistic infections of the CNS become more common. All rights reserved. for unclear reasons.5 mmol/L). Some patients with hyperosmolality from severe hyperglycemia can present. SIADH) is managed with water restriction or administration of ADH antagonists. or oral sodium may need to be given in a judicious fashion in order to avoid complications from cerebral edema. cytomegalovirus. and β2-agonist medications). hyperglycemia. Hypernatremia leads to the loss of intracellular water. which usually respond to lowering of the serum glucose. Neurologic symptoms occur at different levels of low sodium. resulting often from pituitary injury in the setting of surgery. also become more common after the first month posttransplant. In patients with hyponatremia that develops over hours. Despite this corrective mechanism. Finally. eliminating β2-adrenergic agonist medications). Correction of hyponatremia. cellular metabolic processes fail and encephalopathy will result. In the cells of the brain. common pathogens include the usual bacterial organisms associated with surgical procedures and indwelling catheters. 269-6). Hypertonic hyponatremia treatment focuses on the underlying condition. infiltrative processes. In these cases. most commonly. and large amounts of saline. producing focal signs. . Given that patients with solid organ transplants are chronically immunosuppressed. hypertonic saline. or focal deficit. Treatment of hypokalemia is dependent on the etiology but usually includes replacement of potassium through oral or IV routes as well as correcting the cause of potassium balance problems (e. and increase potassium removal (through sodium polystyrene sulfonate. and varicella. and viral infections but can also suffer late CNS infectious complications such as progressive multifocal leukoencephalopathy (PML) associated with JC virus and Epstein-Barr virus–driven clonal expansions of B cells resulting in CNS lymphoma. an underlying lesion such as a mass can become symptomatic under the metabolic stress of a hyperosmolar state. insulin. CALCIUM DISTURBANCES Hypercalcemia usually occurs in the setting of either hyperparathyroidism or systemic malignancy.g.right-to-left shunting should include evaluation of the heart with agitated saline echocardiography. Cells in the brain swell in hypotonic hyponatremic states but may compensate over time by excreting solute into the extracellular space. defined as a serum potassium level < 3. some patients with more chronic hyponatremia that has slowly developed over months to years may be asymptomatic even with serum levels < 110 mmol/L. There are many etiologies of hypernatremia including. HYPONATREMIA e273 Hyponatremia is commonly defined as a serum sodium < 135 mmol/L (<135 meq/L). Treatment of hyponatremia is dependent on the cause. or the addition of extrinsic osmoles such as mannitol. such as hyperglycemia. confusion. Imaging with CT or MRI with diffusion is advised when cerebrovascular complications are suspected to confirm the diagnosis and to exclude intracerebral hemorrhage. including Nocardia and Toxoplasma species as well as fungal infections such as aspergillosis.5 mmol/L (<3. leading to restoration of cell volume when water follows the solute out of the cells. The most common pathogens responsible for CNS infections in these patients vary based on time since transplant. and gastrointestinal tract are addressed. Neurologic manifestations include encephalopathy as well as muscle weakness due to reduced neuromuscular excitability. After 6 months posttransplant. leading to cell shrinkage. adrenals. however. but neurologic manifestations are usually seen only at levels >325 mOsm/kg. promote potassium redistribution into cells (with glucose. cells in the brain may quickly shrink. 46. when hypernatremia is severe [serum sodium > 160 mmol/L (>160 meq/L)] or occurs rapidly. which is commonly used in critically ill neurologic patients. Hyperkalemia becomes life threatening when it produces electrocardiographic abnormalities such as peaked T waves or a widened QRS complex. The treatment of all forms of hyperosmolality involves calculation of apparent water losses and slow replacement so that the serum sodium declines no faster than 2 mmol/L (2 meq/L) per hour. infections are a common concern (Chap. in hypovolemic hypotonic hyponatremia. hypokalemia may be life threatening due to the risk of cardiac arrhythmia and may present neurologically with severe muscle weakness and paralysis. renal and extrarenal losses of water. In contrast. Seizures can occur but are more common in states of low calcium. In the first month posttransplant. COMMON NEUROLOGIC COMPLICATIONS OF ELECTROLYTE DISTURBANCES A wide variety of neurologic conditions can result from abnormalities in serum electrolytes. life-threatening seizures and cerebral edema may occur at values as high as 125 mmol/L. but now has been described elsewhere in the CNS. which most often occurs in the setting of coagulopathy secondary to liver failure or after cardiac bypass procedures. volume is replaced with isotonic saline while underlying conditions of the kidneys. immunosuppressed patients still remain at risk for these opportunistic bacterial. One neurologic cause of hypovolemic hypotonic hyponatremia is the cerebral salt-wasting syndrome that accompanies subarachnoid hemorrhage and. Isovolemic hyponatremia (syndrome of inappropriate antidiuretic hormone. such as nephrotic syndrome or congestive heart failure. A complete general discussion of fluid and electrolyte imbalance and homeostasis can be found in Chap. depending not only on the absolute value but also on the rate of fall. where hyperosmolality is accompanied by submaximal urinary concentration due to inadequate release of antidiuretic hormone (ADH) from the posterior pituitary. fungal. or cerebral herniation. loop diuretics. prompt treatment is essential and consists of strategies that protect the heart against arrhythmias (calcium gluconate administration). must take place slowly in order to avoid additional neurologic complications. At very low levels (<1.. HYPOKALEMIA Hypokalemia. Viral infections that can affect the brain of the immunosuppressed patient.5 meq/L). solutes such as glutamine and urea are generated under these conditions in order to minimize this shrinkage. a process that previously was thought to be limited exclusively to the brainstem (central pontine myelinolysis. azotemia. other cerebral processes such as meningitis or stroke. and consideration of electrolyte disturbances should be part of any inpatient neurologic consultation. such as herpes simplex virus. Hypokalemic periodic paralysis is a rare disorder caused by excessive intracellular potassium uptake in the setting of a calcium or sodium channel mutation. see Fig. or hemodialysis). HYPERKALEMIA Hyperkalemia is defined as a serum potassium level > 5. hemorrhage. Renal and some cardiac transplant patients often have advanced atherosclerosis. the diagnosis of a nervous system infection should be considered and evaluated through imaging (usually MRI) and possibly lumbar puncture. In these cases. In any transplant patient with new CNS signs or symptoms such as seizure.5 meq/L) and can neurologically present as muscle weakness with or without paresthesias. HYPERNATREMIA AND HYPEROSMOLALITY The normal range of serum osmolality is around 275–295 mOsm/kg. leading to osmotic demyelination. providing yet another mechanism for stroke. The management of choice for patients with hypervolemic hypotonic hyponatremia is free-water restriction and treatment of the underlying edematous disorder. CHAPTER e33 Special Issues in Inpatient Neurologic Consultation Copyright © 2008 The McGraw-Hill Companies. the degree of renal sodium excretion can be remarkable.

When intractable seizures occur in the setting of hypomagnesemia. and myoclonus. In the inpatient setting. Treatment consists mainly of avoidance of repetitive trauma but may also include surgical approaches to relieve pressure on the nerve. Mechanisms for perioperative mononeuropathy include traction. if necessary. Sparing of the triceps is the rule when the nerve is injured in this location. however. Symptoms usually begin with tingling in the ulnar distribution. depending on the site of injury. 379). MAGNESIUM DISTURBANCES Disorders of magnesium are difficult to correlate with serum levels because a very small amount of total-body magnesium is located in the extracellular space. hence the tendency of patients to complain of increasing paresthesias at night when the arm is flexed at the elbow during sleep. compression. Compression at the level of the axilla. E. brachioradialis. A more common site of compression occurs in the spiral groove of the upper arm in the setting of a humerus fracture or from sleeping with the arm draped over a bench or chair (“Saturday night palsy”). resulting from use of crutches. and ischemia of the nerve. tremor. and supinator muscles in addition to wrist drop.g. . only administration of magnesium will lead to resolution. in contrast. D. Because extensors of the upper extremity are injured preferentially in radial nerve injury. Motor dysfunction can be dis- CONSULTATIONS REGARDING PERIPHERAL NERVOUS SYSTEM DYSFUNCTION ENTRAPMENT NEUROPATHIES Polyneuropathy is a common cause of outpatient neurologic consultation (Chap. including the fourth and fifth digits of the hand (Fig. Peroneal nerve. Femoral nerve. Tetany is due to spontaneous. Sensory loss is in the distribution of the radial nerve. C. repetitive action potentials in peripheral nerves and remains the classic sign of symptomatic hypocalcemia. lead to CNS depression. which includes the dorsum of the hand (Fig. Hypomagnesemia presents neurologically with seizures. Hypermagnesemia usually only occurs in the setting of renal failure and can lead to confusion and muscular paralysis when severe. the diagnosis can be made through the Copyright © 2008 The McGraw-Hill Companies. e. Ulnar nerve. especially the entrapment neuropathies that complicate many surgical procedures and medical conditions. Hypocalcemia in adults often follows surgical treatment of the thyroid or parathyroid. Imaging with MR neurography may allow these causes to be distinguished definitively.. these lesions may be mistaken for the pyramidal distribution of weakness that accompanies upper motor neuron lesions from brain or spinal cord processes. Lateral femoral cutaneous nerve. includes weakness of the triceps. High levels of magnesium. but it is rarely a cause for inpatient consultation. In all cases of mononeuropathy. Sensory symptoms may be worsened by elbow flexion due to increased pressure on the nerve. Ulnar Neuropathy Compression of the ulnar nerve is the second most common entrapment neuropathy after carpal tunnel syndrome. Radial Neuropathy Radial nerve injury classically presents with weakness of extension of the wrist and fingers (“wrist drop”) with or without more proximal weakness of extensor muscles of the upper extremity. All rights reserved. e33-3B). Median neuropathy at the wrist (carpal tunnel syndrome) is the most frequent entrapment neuropathy by far. Seizures and altered mental status dominate the neurologic picture and usually resolve with calcium repletion. B. A. clinical examination and then confirmed with electrodiagnostic studies in the subacute period. The most frequent site of compression is at the elbow where the nerve passes superficially in the ulnar groove.e274 A Radial nerve Sensory distribution of the radial nerve Lateral cutaneous nerve of arm Posterior cutaneous nerve of arm Posterior cutaneous nerve of forearm Superficial branch B Ulnar nerve C Peroneal nerve Sensory distribution of the peroneal nerve Lateral cutaneous nerve of calf Sensory distribution of the ulnar nerve Superficial peroneal nerve Deep peroneal nerve D Sensory distribution of the femoral nerve Anterior femoral cutaneus nerve Medial femoral cutaneus nerve E Lateral femoral cutaneus nerve Saphenous nerve PART 16 Neurologic Disorders FIGURE e33-3 Sensory distribution of peripheral nerves commonly affected by entrapment neuropathies. mononeuropathies are more frequent. e33-3A). Radial nerve.

2004 VAN DIJK D et al: Cognitive and cardiac outcomes 5 years after offpump vs. usually in the setting of tight-fitting belts. extreme hip flexion or extension. including that of pregnancy. SHEFNER JM: Electrodiagnosis in common mononeuropathies and plexopathies.” include sensory loss. or recent weight gain. In intoxicated or comatose patients. 2005 KUMAR S et al: Central pontine myelinolysis. Sparing of inversion. an update. Etiologies of ulnar entrapment include trauma to the nerve (hitting the “funny bone”). Conservative methods of treatment are often the first step. Circulation 113:2784. following trauma. Symptoms often are worsened by standing or walking. Radiculopathy due to a herniated lumbar disc is not common during pregnancy. electrodiagnostic studies can definitively distinguish between plexus and ulnar nerve lesions a few weeks after the injury. 2007 Copyright © 2008 The McGraw-Hill Companies. on-pump coronary artery bypass graft surgery. femoral neuropathy when the thigh is abducted severely in an effort to facilitate delivery of the fetal shoulder. commonly known as “meralgia paresthetica. but a variety of surgical approaches may be effective. Rarely. e33-3D). Patients present with weakness of foot dorsiflexion (“foot drop”) as well as with weakness in eversion but not inversion at the ankle. which is a function of muscles innervated by the tibial nerve. 2005 KARNAD DR. The differential diagnosis of these symptoms includes hip problems such as trochanteric bursitis. These plexus injuries are more frequent with cephalopelvic disproportion and often present with a painless unilateral foot drop which must be distinguished from a peroneal neuropathy caused by pressure on the nerve while in lithotomy position during delivery.701. carpal tunnel syndrome. GUNTUPALLI KK: Neurologic disorders in pregnancy. and thin individuals and those with recent weight loss are at increased risk. and an absent patellar reflex. . pants. Sensory loss involves the lateral aspect of the leg as well as the dorsum of the foot (Fig. or after intrapelvic surgeries such as renal transplantation. J Neuroimaging 14:89. corsets.abling and involves most of the intrinsic hand muscles. 2006 LAMY C et al: Neuroimaging in posterior reversible encephalopathy syndrome. Peroneal Neuropathy The peroneal nerve winds around the head of the fibula in the leg below the lateral aspect of the knee. There is also a clear association between pregnancy and an increased frequency of idiopathic facial palsy (Bell’s palsy). JAMA 297. and dysesthesia in part of the area supplied by the nerve (Fig. e33-3E). 2006 JILLAPALLI D. Lateral Femoral Cutaneous Nerve The symptoms of lateral femoral e275 cutaneous nerve entrapment. The latter presents with medial thigh pain that may be accompanied by weakness of thigh adduction. and its superficial location at this site makes it vulnerable to trauma. Adduction of the thigh is spared as these muscles are supplied by the obturator nerve. When a perioperative ulnar nerve injury is considered. Bleeding into the pelvis resulting in hematoma can occur spontaneously. stretch injury or trauma to the lower trunk of the brachial plexus should be entertained as well since its symptoms can mimic those of an ulnar neuropathy. attempts at femoral vein or arterial puncture can be complicated by injury to this nerve. The sensory loss found is in the distribution of the femoral nerve sensory branches on the anterior part of the thigh (Fig. Compressive lesions from retroperitoneal hematomas or masses are common. malpositioning during anesthesia for surgical procedures. including anterior ulnar nerve transposition and release of the flexor carpi ulnaris aponeurosis. pain. and a CT of the pelvis should be obtained in all cases of femoral neuropathy to exclude these conditions. Tight-fitting stockings or casts of the upper leg can also cause a peroneal neuropathy. Semin Neurol 25:196. CHAPTER e33 Special Issues in Inpatient Neurologic Consultation FURTHER READINGS JENSEN BO et al: Cognitive outcomes in elderly high-risk patients after off-pump versus conventional coronary artery bypass grafting: A randomized trial. Proximal Femoral Neuropathy Lesions of the proximal femoral nerve are relatively uncommon but may present dramatically with weakness of hip flexion. Crit Care Med 33:S362. but compressive injuries of the lumbosacral plexus do occur secondary to either the fetal head passing through the pelvis or the use of forceps during delivery. helps to distinguish peroneal neuropathies from L5 radiculopathies. Fractures of the fibular head may be responsible for peroneal neuropathies. weakness of knee extension (often manifesting with leg-buckling falls). Neurol Res 28:360. Other compressive mononeuropathies of pregnancy include meralgia paresthetica. and obturator neuropathy during lithotomy positioning. but in the perioperative setting poorly applied braces exerting pressure on the nerve while the patient is unconscious are more often responsible. There is no motor component to the nerve. limiting dexterity and strength of grasp and pinch. quadriceps atrophy. All rights reserved. e33-3C). Compression of the nerve occurs where it enters the leg near the inguinal ligament. OBSTETRIC NEUROPATHIES Pregnancy and delivery place women at special risk for a variety of nerve injuries. and therefore weakness is not a part of this syndrome. If the clinical examination is equivocal. stretch injuries to the femoral nerve are seen following prolonged. and chronic arthritis of the elbow. thereby distinguishing a femoral neuropathy from a more proximal lumbosacral plexus lesion.

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Bone pain.S. (no seafood × 24 h). acute tubular necrosis. toxicity. microcytic hypochromic anemia unresponsive to iron therapy. vitamin D for osteomalacia. and mercury). such as copper and selenium. increased urinary β2. and coal. serum cadmium >500 nmol/L (5 μg/dL). lungs. and Mees’ lines (transverse white striae of the fingernails).microglobulin. Contamination was formerly considered only a problem with deep wells. minor LFT elevations. blood is the main medium for its transport.e34 Heavy Metal Poisoning Howard Hu Metals pose a significant threat to health through occupational as well as environmental exposures. calciuria. exhalation. the geology of this region allows most residents only a few alternatives for potable drinking water. succimer (DMSA. . with the precise kinetics dependent on diffusibility. Arsenic exposure from natural contamination of shallow tube wells inserted for drinking water is a huge environmental problem for millions of residents in parts of Bangladesh and Western India. filtered at the glomerulus. diagnosis. poorly excreted). Absorbed through ingestion or inhalation. distal weakness. T-wave flattening. The principal chelating agents are dimercaprol (British Anti-Lewisite. noncardiogenic pulmonary edema. Most metals are excreted through renal clearance and gastrointestinal excretion. Indeed. The first. Metal-plating. Chronic arsenic exposure causes diabetes. Some metals. One indication of their importance relative to other potential hazards is their ranking by the U. Metal poisoning can also result from exposure to vapors (e. BAL). and nails. With ingestion: nausea. folk remedies. Acute arsenic poisoning results in necrosis of intestinal mucosa with hemorrhagic gastroenteritis. and kidney) sequester metals in relatively high concentrations for years. All rights reserved. and a faster decline in height in both men and women. peripheral vascular insufficiency and gangrene. protein binding. contaminant of deep-water wells. If acute ingestion. ef- CHAPTER e34 Heavy Metal Poisoning Diagnosis Arsenic Treatment Smelting and microelectronics industries. and GI tract. availability of intracellular ligands. arsenic. including sources and metabolism. and other factors. exfoliative dermatitis. cyanosis. emphysema. spleen. The intrinsic stability of metals facilitates tracing and measurement in biologic material. dyspnea.. respectively. although the clinical significance of the levels measured is not always clear. ipecac to induce vomiting. if recent exposure. fever. and cadmium. proteinuria. some proportion is also excreted through salivation. Genetic factors also may modify the impact of metals on health and thereby account. Supportive care in ICU. bone. Some organs (e.9 μmol/L (7 μg/dL). perspiration. liver. and plastics industries. Avoidance of further exposure. tobacco. biomethylation results in detoxification. hair. is summarized in Table e34-1. lung. In addition to the information provided in Table e34-1. but reabsorbed by proximal tubules (thus. and the appropriate treatment for poisoning. however. Biologic 1/2 life: 10–30 y. such as lead and mercury. Serious cadmium poisoning from the contamination of food and water by mining effluents in Japan contributed to the 1946 outbreak of “itai-itai” (“ouch-ouch”) disease. fungicides. dimercaprol can exacerbate nephrotoxicity). garlicky odor on breath. and cancer of skin. but is nontoxic. ingestion of food that concentrates cadmium (grains. vomiting. Lethal dose: 120–200 mg (adults). and loss of hair and nails. so named because of cadmium-induced bone toxicity that led to painful bone fractures.g. then q12h × 10 days. Others. dimercaptosuccinic acid). lead. their gastrointestinal absorption varies greatly with the specific chemical form of the metal and the nutritional status of the host. peripheral neuropathy. leading to chronic renal failure. bladder. Concentrates in liver and kidneys. battery. osteomalacia. High arsenic in hair or nails. which lists all hazards present in toxic waste sites according to their prevalence and the severity of their toxicity. ST depression. q6h × 1 day. Chronic exposure causes anosmia. several other aspects of exposure. Acute cadmium inhalation causes pneumonitis after 4–24 h. and fractures. Agency for Toxic Substances and Disease Registry. herbicides. diarrhea. Chelating agents are used to bind metals into stable cyclic compounds with relatively low toxicity and to enhance their excretion. Cadmium Nausea. fluid loss. hypotension. hyperpigmentation. Metals are inhaled primarily as dusts and fumes (the latter defined as tiny particles generated by combustion). sequesters in liver. rates of biotransformation. incineration of these products. Activated charcoal does not bind metals and thus is of limited usefulness in cases of acute metal ingestion. are essential to normal metabolic function as trace elements (Chap. Modest exposures from environmental contamination near a smelter in Belgium were recently associated with a lower bone density. for individual susceptibility to metal effects. 24-h urinary arsenic >67 μmol/d or 50 μg/d. and sixth hazards on the list are heavy metals: lead. abdominal pain. serum arsenic >0. kidneys. vasospasm. lactation. 2 mg/kg (children). tachycardia. With inhalation: pleuritic chest pain. delayed cardiomyopathy. toxic effects produced.g. vomiting. calcium for binding sites. kidney. at least in part. arsenocholine) is ingested in seafood and fish. smelting. gastric lavage. skin exfoliation. coma. The most important component of treatment for metal toxicity is the termination of exposure. QT prolongation. much research is currently focused on the contribution of low-level xenobiotic metal exposure to chronic diseases and to subtle changes in health that may have significant public health consequences. sensory and motor polyneuritis. Urinary cadmium >100 nmol/L (10 μg/g creatinine) and/or urinary β2-microglobulin >750 μg/g creatinine (but urinary β2microglobulin also increased in other renal diseases such as pyelonephritis). 71) but are toxic at high TABLE e34-1 HEAVY METALS Main Sources Metabolism Toxicity levels of exposure. When metals are ingested in contaminated food or drink or by hand-to-mouth activity (implicated especially in children). fractures with osteomalacia. If recent exposure. nausea. yellowing of teeth. mercury vapor in creating dental amalgams). third. Once a metal is absorbed. delirium. second. or management are worthy of discussion with respect to the four most hazardous toxicants (arsenic. bound by metallothionein. Dimercaprol 3–5 mg/kg IM q4h × 2 days. competes with zinc. hyperkeratosis. their specific use depends on the metal involved and the clinical circumstances. are xenobiotic e277 and theoretically are capable of exerting toxic effects at any level of exposure. inorganic arsenic is readily absorbed (lung and GI). cramps. Specific information pertaining to each of these metals. mercury. pigment. and penicillamine. and hemolysis. pesticides. Radiopaque sign on abdominal x-ray. seizures. residues persist in skin. a higher incidence of fractures. supportive therapy. cereals). acute ingestion causes gastroenteritis. alternative: oral succimer. activated charcoal with a cathartic. liver (angiosarcoma).. Binds cellular sulfhydryl groups. cadmium. ECG–QRS broadening. wood preservatives. There is no effective treatment for cadmium poisoning (chelation not useful. incineration of these products Organic arsenic (arsenobentaine. (continued) Copyright © 2008 The McGraw-Hill Companies. edetate (EDTA). diarrhea. but this process saturates.

normochromic anemia. firing ranges (from bullet dust). Acute ingestion of inorganic mercury causes gastroenteritis. ECG.g. CNS symptoms. hypertension.S. tachycardia.. ceramics. or penicillamine. hypertension. irritability. Mercury is dispersed by waste incineration. intensive care unit. IQ. arrhythmias. exposure to the combustion of leaded fuels. verbal and visual memory.. Convulsions. and cognitive dysfunction (e. CNS toxicity in children may derive from fetal exposures associated with maternal hair Hg > 30 nmol/g (6 μg/g). arthralgias. screening and reporting to local health boards of children with BPb > 10 μg/dL and workers with BPb > 40 μg/dL is required. contaminated herbal remedies. azotemia in children with blood lead level (BPb) >80 μg/ dL. In some U. tetraethyl lead) absorbed dermally. Chelate with dimercaprol (up to 24 mg/kg per day IM in divided doses). bridges. soldering. mercurous. Fanconi’s syndrome. Excreted mostly in urine. Centers for Disease Control and Prevention. In adults. enhances oxidation and cell apoptosis. basophilic stippling.. At higher levels of exposure (e. Acute exposure with blood lead levels (BPb) of > 60–80 μg/dL can cause impaired neurotransmission and neuronal cell death (with central and peripheral nervous system effects). and zinc will lower lead absorption and may also improve toxicity. may also see symptoms associated with higher BPb levels. with the addition of dimercaprol to prevent worsening of encephalopathy.g. lead pipes. and cardiovascular collapse. Diagnosis Treatment PART 17 Poisoning. calcium-dependent messengers. In blood.. anorexia. wrist drop. metal-processing. and motor delays on nerve conduction. coma at BPb > 120 μg/dL. coordination. environmental exposure to paint chips. interstitial nephritis and chronic renal failure. Mercury Metallic. plumbing. Interferes with mitochondrial oxidative phosphorylation. fishing weights. In adults. desquamation of palms and soles. excessive salivation or perspiration. behavior. Subclinical exposures in children (BPb 25–60 μg/dL) are associated with anemia. motor speed. Organic mercury exposure is best measured by levels in blood (if recent) or hair (if chronic). source identification and intervention is begun if the BPb > 10 μg/ dL. gray matter. Drug Overdose. Chronic inorganic mercury poisoning is best treated with N-acetyl penicillamine. timidity. High exposure during pregnancy causes derangement of fetal neuronal migration resulting in severe mental retardation. demyelinating peripheral neuropathy (mainly motor). gastrointestinal. BPb 20–40 μg/ dL) benefit from chelation. impaired short-term memory. automotive industries. etc. tachycardia. CDC. Identification and correction of exposure sources is critical. visuomotor coordination. loss of libido. Exposure to mercury stimulates the kidney to produce metallothionein. itching.g. anemia. hospitalization and IV or IM chelation with edentate calcium disodium (CaEDTA) may be required. deposits will remain in the kidney and brain for years. ECG conduction delays. hypertension. stained glass making. Copyright © 2008 The McGraw-Hill Companies. Mercury is excreted in urine and feces and has a 1/2 life in blood of ∼60 days. Organic mercury is well absorbed through inhalation and ingestion. Environmental bacteria convert inorganic to organic mercury. lethargy. depression. morbilliform rashes. impairments of reaction time. All rights reserved. Hg+. they are also in thermometers. Dimethylmercury. Chronic exposure to metallic mercury vapor produces a characteristic intention tremor and mercurial erethism: excitability. organic lead (e. with 5-day courses separated by several days of rest. motor function. but also appears in other fluids including breast milk. intelligence quotient. lab tests may reveal a normocytic.S. Toxicity from elemental or inorganic mercury exposure begins when blood levels >180 nmol/L (3. electrical-equipment. chronic subclinical exposures (BPb > 40 μg/dL) are associated with an increased risk of anemia. Impairment of IQ appears to occur at even lower levels of exposure with no measurable threshold above the limit of detection in most assays of 1 μg/dL. red blood cell. and school performance. and polyneuropathy.. Correction of dietary deficiencies in iron. Mercury binds sulfhydryl groups and interferes with a wide variety of critical enzymatic processes.7 mg/kg. Ingestion of organic mercury causes gastroenteritis. OSHA requires regular testing of lead-exposed workers with removal if BPb > 40 μg/dL. or extracorporeal regional complexing hemodialysis and succimer.g. In the highly exposed individual with symptoms. hearing. insomnia. however. central nervous system. house dust (in home built <1975). with 1/2 life ~30 days. pallor. candies. and lesions in the basal ganglia. Treat acute ingestion of mercuric salts with induced emesis or gastric lavage and polythiol resins (to bind mercury in the GI tract). In the U.e278 TABLE e34-1 HEAVY METALS (CONTINUED) Main Sources Metabolism Toxicity Lead Manufacturing of auto batteries. an elevated blood protoporphyrin level (free erythrocyte or zinc). is “supertoxic”—a few drops of exposure via skin absorption or inhaled vapor can cause severe cerebellar degeneration and death. or acute renal failure. and Envenomation Note: GI. swelling. CNS. Noticeable neurodevelopmental delays at BPb of 40–80 μg/dL.7 μmol/L (15 μg/dL). declines on the mini-mental status exam). balance. Inorganic mercury is absorbed through the gut and skin. 15% of dose sequestered in bone with 1/2 life of >20 years. Hg2+) exposures occur in some chemical. the nephritic syndrome. On neurobehavioral tests: decreased motor speed. demolition or sanding of leadpainted houses. lead crystal. coma. and cerebellum at doses >1. weakness. if acutely toxic. Absorbed through ingestion or inhalation. magnesium.. memory. and other pelagic fish. with death at a dose of 10–42 mg/kg. must measure lead in whole blood (not serum). visual scanning. Children exposed to mercury in any form may develop acrodynia (“pink disease”): flushing. liver function tests. RBC. Vitamin C is a weak but natural chelating agent. myalgias. Occupational Safety and Health Administration. spontaneous abortions. Abdominal pain. which provides some detoxification benefit. a compound only found in research labs. Mild exposures during pregnancy (from fish consumption) are associated with declines in neurobehavioral performance in offspring. BPb > 80–120 μg/dL). and death may occur. which then bioconcentrates up the aquatic food chain to contaminate tuna. hemodialysis. chelation is recommended with oral DMSA (succimer). ICU. calcium. see diagnosis). mental retardation. it will volatilize into highly absorbable vapor. It is uncertain whether children with asymptomatic lead exposure (e. Elemental and organic mercury cross the blood-brain barrier and placenta. acute exposure causes similar symptoms as in children as well as headaches. dental amalgams. impaired hematopoiesis and renal tubular dysfunction. memory loss. screening of all children when they begin to crawl (∼6 months) is recommended by the CDC. Exposures that ended years ago may result in a >20-μg increase in 24-h urine after a 2-g dose of succimer. DMSA (succimer). In the U. may also see epiphyseal plate “lead lines” on long bone x-rays. pyuria. and delirium (“mad as a hatter”). and mercuric mercury (Hg°. and deficits in language. diminished sperm counts. treat with peritoneal dialysis. If renal failure occurs. states. Physical exam may reveal a “lead line” at the gingiva-tooth border.S. 95–99% sequestered in RBCs—thus. .6 μg/ dL) and urine levels >0. food or water from improperly glazed ceramics. Chronic high exposure causes CNS toxicity (mercurial erethism. ATPases. Elemental mercury (Hg°) is not well absorbed. OSHA. electrocardiogram. however. Acute inhalation of Hg° vapor causes pneumonitis and noncardiogenic pulmonary edema leading to death. irritability. swordfish. lower exposures impair renal function.. LFT. acute encephalopathy with convulsions. batteries. Distributed widely in soft tissue.

and fireworks. Hexavalent chromium is corrosive and sensitizing. and arc welders) to manganese can cause a Parkinsonian syndrome within 1–2 years. as opposed to blood lead levels. and inhalation of nickel compounds with low aqueous solubility (e. Occupational exposure (e. 2003 MISRA UK: Thallium poisoning: Emphasis on early diagnosis and response to haemodialysis. A few additional metals deserve brief mention but are not covered in Table e34-1 because of the relative rarity of their being clinically encountered. and psychotic behavior. 2003 PARK S. and it cannot be concluded that aluminum is a causal agent or a contributing factor in neurodegenerative disease. gastrointestinal irritation. JOHNSON MA: Awareness of fish advisories and mercury exposure in women of childbearing age. 2006 SAPER RB et al: Heavy metal content of ayurvedic herbal medicine products. 2004 Copyright © 2008 The McGraw-Hill Companies. Workers in the chromate and chrome pigment production industries have consistently had a greater risk of lung cancer. JAMA 292: 2868. high maternal bone lead levels were found to predict lower birth weight. 2007 CENTENO JA et al: Pathology related to chronic arsenic exposure. however.. Nausea and vomiting. which mostly reflect recent exposure). CHAPTER e34 Heavy Metal Poisoning FURTHER READINGS BRODKIN E et al: Lead and mercury exposures: Interpretation and action. Environ Health Perspect 110(Suppl 5):883. Prussian blue prevents absorption and is given orally at 250 mg/kg in divided doses. Unlike other types of metal poisoning. abdominal pain. current evidence has not supported the recent contention that ethyl mercury. 347). Postgrad Med J 79:103. and coma. including tremor.g. Aluminum contributes to the encephalopathy in patients with severe renal disease who are undergoing dialysis (Chap. of miners. Thallium is radiopaque. convulsions. organic brain syndrome.e279 tion of methylcyclopentadienyl manganese tricarbonyl (MMT) as a gasoline additive. . postural instability. has played a significant role in causing neurodevelopmental problems such as autism. tremor. Advances in our understanding of lead toxicity have recently benefited by the development of K-x-ray fluorescence (KXRF) instruments for making safe in vivo measurements of lead levels in bone (which. depigmentation. 2002 JÄRUP L: Hazards of heavy metal contamination. thallium poisoning may be less severe when activated charcoal is used to interrupt its enterohepatic circulation. is absorbed through the skin as well as by ingestion and inhalation. The toxicity of low-level organic mercury exposure (as manifested by neurobehavioral performance) is of increasing concern based on studies of the offspring of mothers who ingested mercury-contaminated fish. With the introduc. The introduction of cobalt chloride as a fortifier in beer led to outbreaks of fatal cardiomyopathy among heavy consumers. CMAJ 176(1):59. Overexposure to selenium may cause local irritation of the respiratory system and eyes. and peritoneal dialysis. psychosis. Such research is creating concern that cadmium exposure may be contributing significantly to morbidity and mortality from osteoporosis in the general population. High levels of aluminum are found in the neurofibrillary tangles in the cerebral cortex and hippocampus of patients with Alzheimer’s disease. All rights reserved. High bone lead levels measured by KXRF have been linked to increased risk of hypertension in both men and women from an urban population. including gait disorders. liver inflammation. and neurodevelopmental performance in offspring by age 2. In addition. Severe poisoning follows a single ingested dose of >1 g or >8 mg/kg. reflect cumulative exposure over many years. The experimental and epidemiologic evidence for the aluminum–Alzheimer’s disease link is so far relatively weak. nickel subsulfide and nickel oxide) in occupational settings is associated with an increased risk of lung cancer. which is a component of some insecticides. and hematemesis precede confusion. head circumference.. and peripheral nerve damage.fects that may be related to cadmium’s calciuric effect on the kidney. Induced emesis or gastric lavage is indicated within 4–6 h of acute ingestion. expres- sionless face. Thallium. Other measures include forced diuresis. there is concern for the toxic potential of environmental manganese exposure. used as a preservative in multiuse vaccines administered in early childhood. Nutr Rev 64:250. hallucinations. treatment with potassium chloride (which promotes renal excretion of thallium). Nickel exposure induces an allergic response. and psychiatric symptoms. in turn.g. Br Med Bull 68:167. However. Workers exposed to certain organic forms of tin (particularly trimethyl and triethyl derivatives) have developed psychomotor disturbances. birth length. dry-battery manufacturers. as well as in the drinking water and soil of areas with an unusually high incidence of Alzheimer’s. loss of hair. or the uncertainty regarding their potential toxicities. a masked. metal alloys.

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cardiopulmonary system. available medications. substantial individual variability in the response to. rigidity. the time and type of first aid measures provided. and disposition of. abnormal distress. Obtaining a complete set of vital signs and reassessing them frequently are critical. Unintended poisonings may result from the recreational use of prescribed and over-thecounter drugs for psychotropic or euphoric effects (abuse) or excessive self-dosing (misuse). the dose makes the poison. markedly increased vital signs and organ ischemia suggest sympathetic poisoning. tremors. fasciculations. and the route of exposure. myoclonus. or lungs) or systemic depending on the chemical and physical properties of the poison. The odor of breath or vomitus and the color of nails. Overall. even in difficult or combative patients. or unable or unwilling to admit to one. occur in the home. can be consumed without ill effect. Occupational exposures require review of available MSDS (Material Safety Data Sheets) from the worksite. routine and toxicologic laboratory evaluations. and increased bowel activity with varying degrees of nausea. and their presence should prompt evaluation for a structural central nervous system (CNS) lesion. and neurologic status. however. Since sympathetics stimulate the peripheral nervous system more directly than do hallucinogens or drug withdrawal. temperature. Mycyk Poisoning refers to the development of dose-related adverse effects following exposure to chemicals. the name and amount of each drug. and puncture marks) may reveal findings of diagnostic value. The history should include the time. abdomen (for bowel activity and bladder size).g. When the history is unclear. pupil size and reactivity). respiratory rate. Overall. hallucinogen poisoning and drug withdrawal (Table e35-1). This approach is summarized below. neurologic status. It is much higher (1–2%) in hospitalized patients with intentional (suicidal) overdose. behavior changes. Mydriasis. Suspicious circumstances include unexplained illness in a previously healthy person. Unintentional exposures can result from the improper use of chemicals at work or play.. and intensive care unit admissions. dystonia. All rights reserved. Michael J. unaware of an exposure. and the medical and psychiatric history. Burns. its mechanism of action. comatose.4% of all exposures. pupils are also enlarged but some reactivity to light is observed. or medications. skin. discordant. recent changes in health.g. Increased pulse. respiratory rate. or ingredient involved. A search of clothes. police. since temperature elevation is the most reliable prognosticator of poor outcome in poisoning. Pharmaceuticals are involved in 47% of exposures and 84% of serious or fatal poisonings. Conversely. who account for the majority of serious poisonings. Mark B.. Findings helpful in suggesting the particular drug or class causing physiologic stimulation include reflex CHAPTER e35 Poisoning and Drug Overdosage Copyright © 2008 The McGraw-Hill Companies. substances commonly regarded as poisons. emergency department visits. blood pressure. product mislabeling. drugs. and other physical findings. Other features are noted in Table e35-2. pharmacists. and skin (for burns. and severity of symptoms. To paraphrase Paracelsus. nature. and occasionally diarrhea. . vomiting. hobbies. and 5% of all exposures require hospitalization. mistaken identification of unlabeled chemicals. pallor.e281 ter arriving from a foreign country or being arrested for criminal activity should be suspected of “body packing” or “body stuffing” (ingesting or concealing illicit drugs in a body cavity). Assessing the severity of physiologic derangements (Table e35-2) is useful in this regard and also for assessing the clinical course and response to treatment. or a regional poison information center. paramedics. label misreading. The physical examination should focus initially on the vital signs. chemical. Measuring core temperature is especially important. a computerized database. color. but this is not reflected in hospital or poison center statistics because patients with such poisoning are typically dead when discovered and are referred directly to medical examiners. and urinary retention (Table e35-1). or urine may provide diagnostic clues. Other stimulant toxidromes increase sympathetic activity and cause diaphoresis. Excluding the recreational use of ethanol. Linden. and dosing errors by nurses. and neuromuscular activity characterize the stimulant toxidromes: sympathetic.e35 Poisoning and Drug Overdosage Christopher H. Some of this variability is genetic. The neurologic examination should include documentation of neuromuscular abnormalities such as dyskinesia. The final step is to attempt to identify the particular agent involved by looking for unique or relatively poisonspecific physical or ancillary test abnormalities. temperature. duration. DIAGNOSIS Although poisoning can mimic other illnesses. the manufacturer. warmth. dry. and characteristic clinical course. or social relationships. route. Relevant history may be available from family. pressure sores. Poisonings account for 5– 10% of all ambulance transports. substances that are usually innocuous. or because of tolerance. Examination of the eyes (for nystagmus. The severity and reversibility of poisoning also depend on the functional reserve of the individual or target organ. and employers. Poisoning may be local (e. The anticholinergic (antimuscarinic) toxidrome is also distinguished by the presence of hot. and some is acquired on the basis of enzyme induction or inhibition. uninformed self-medication. involve a single agent. such as oxygen and water. pharmacists. In excessive amounts. and circumstances (location. bullae. and place of discovery may reveal a suicide note or a container of drugs or chemicals. Most are acute. and onset of illness while working with chemicals or after ingesting food. accidental (unintentional). surrounding events. blood pressure. a history of psychiatric problems (particularly depression). in sympathetic poisoning (e. in small doses. belongings. can cause poisoning. or other xenobiotics. The patient should also be examined for evidence of trauma and underlying illnesses. The first step is to assess the pulse. attempted suicide (deliberate self-harm) is the most common reason for intentional exposure. physicians. and neurologic status and characterize the overall physiologic state as stimulated. Patients who become ill soon af. physical examination. all orifices should be examined for the presence of chemical burns and drug packets. a given dose. In many cases the victim is confused. cocaine). About 25% of exposures require health professional evaluation. friends. carbon monoxide is the leading cause of death from poisoning. which is influenced by age and preexisting disease. There is. or normal (Table e35-1). parents. the time of onset. drink (especially ethanol). result in minor or no toxicity. and intent) of exposure. and involve children under 6 years of age. The imprint code on pills and the label on chemical products may be used to identify the ingredients and potential toxicity of a suspected poison by consulting a reference text. the mortality rate is low: 0. a characteristic feature of all stimulant toxidromes. Up to 30% of psychiatric admissions are prompted by attempted suicide via overdosage. depressed. and antecedent events. decreased bowel sounds. The next step is to consider the underlying causes of the observed physiologic state and attempt to identify a pathophysiologic pattern or toxic syndrome (toxidrome) based on further analysis of the vital signs. is most marked in antimuscarinic (anticholinergic) poisoning since pupillary reactivity relies on muscarinic control. who should be questioned regarding the patient’s habits. EPIDEMIOLOGY About 5 million poison exposures occur in the United States each year. the correct diagnosis can usually be established by the history. The diagnosis of poisoning in cases of unknown etiology primarily relies on pattern recognition. such as arsenic and cyanide. physicians. and the elderly. skin. Focal neurologic findings are uncommon in poisoning. economic status. moisture. flushed skin. eyes. antimuscarinic (anticholinergic). The absolute and relative degree of vital sign changes and neuromuscular hyperactivity can help distinguish among stimulant toxidromes. Acetaminophen is the pharmaceutical agent most often implicated in fatal poisoning.

Close attention to core temperature is critical in these patients.e282 TABLE e35-1 DIFFERENTIAL DIAGNOSIS OF POISONING BASED ON PHYSIOLOGIC STATE Stimulated Sympathetics Sympathomimetics Ergot alkaloids Methylxanthines Monoamine oxidase inhibitors Thyroid hormones Anticholinergics Antihistamines Antiparkinsonian agents Antipsychotics Antispasmodics Belladonna alkaloids Cyclic antidepressants Muscle relaxants Mushrooms and plants Hallucinogens Cannabinoids (marijuana) LSD and analogues Mescaline and analogues Mushrooms Phencyclidine and analogues Withdrawal syndromes Barbiturates Benzodiazepines Ethanol Opioids Sedative-hypnotics Sympatholytics Depressed Sympatholytics α1-Adrenergic antagonists α2-Adrenergic agonists ACE inhibitors Angiotensin receptor blockers Antipsychotics β-adrenergic blockers Calcium channel blockers Cardiac glycosides Cyclic antidepressants Cholinergics Acetylcholinesterase inhibitors Muscarinic agonists Nicotinic agonists Opioids Analgesics GI antispasmodics Heroin Sedative-hypnotics Alcohols Anticonvulsants Barbiturates Benzodiazepines GABA precursors Muscle relaxants Other agents GHB Products Discordant Asphyxiants Cytochrome oxidase inhibitors Inert gases Irritant gases Methemoglobin inducers Oxidative phosphorylation inhibitors AGMA inducers Alcohol (ketoacidosis) Ethylene glycol Iron Methanol Salicylate Toluene CNS syndromes Extrapyramidal reactions Hydrocarbon inhalation Isoniazid Lithium Neuroleptic malignant syndrome Serotonin syndrome Strychnine Membrane-active agents Amantidine Antiarrhythmics Antihistamines Antipsychotics Carbamazepine Cyclic antidepressants Local anesthetics Opioids (some) Orphenadrine Quinoline antimalarials Normal Nontoxic exposure Psychogenic illness Toxic time-bombs Slow absorption Anticholinergics Carbamazepine Concretion formers Dilantin Kapseals Drug packets Enteric-coated pills Lomotil Opioids Salicylates Sustained-release pills Slow distribution Cardiac glycosides Lithium Metals Salicylate Toxic metabolite Acetaminophen Carbon tetrachloride Cyanogenic glycosides Ethylene glycol Methanol Methemoglobin inducers Mushroom toxins Organophosphate insecticides Paraquat Metabolism disruptors Antineoplastic agents Antiviral agents Colchicine Hypoglycemic agents Immunosuppressive agents MAO inhibitors Metals Salicylate Warfarins PART 17 Poisoning. Other manifestations of grade 4 physiologic stimulation (Table e35-2) are likely only in sympathetic poisoning. orphenadrine. calcium-channel blockers. mydriasis [due to tricyclic antidepressants. cyclic antidepressants. some antiarrhythmics. and Envenomation Note: ACE. Other clues that suggest the cause of physiologic depression include cardiac arrhythmias and conduction disturbances (due to antiarrhythmics. psychogenic illness. in opioid and sedative-hypnotic poisoning. and tachyarrhythmias. Table e35-2). or a withdrawal syndrome. GABA. vital sign changes are secondary to depression of CNS cardiovascular and respiratory centers (or consequent hypoxemia) and significant abnormalities in these parameters do not occur until there is a marked decrease in the level of consciousness (grade 3 or 4 physiologic depression. The latter is distinguished from other depressant toxidromes by the presence of muscarinic and nicotinic signs and symptoms (Table e35-1). temperature. blood pressure. Pronounced cardiovascular depression in the absence of significant CNS depression suggests a direct or peripherally acting sympatholytic. hypotension.. bradycardia from selective α-adrenergic stimulants (e. For example..g. As noted below. lysergic acid di- ethylamide. A normal physiologic status and physical examination may be due to a nontoxic exposure.g. AGMA. GI. the lack of such abnormalities suggests an AGMA inducer. . and antipsychotics). opioids. γ-hydroxybutyric.g. MAO. β-adrenergic antagonists. Alternatively. and anion-gap metabolic acidosis (AGMA) inducers (Table e35-1). and seizures (due to cholinergic agents. Miosis is also common and most pronounced in opioid and cholinergic poisoning. nystagmus from phencyclidine and ketamine (the only physiologic stimulants that cause this finding). Seizures suggest a sympathetic etiology. Discordant or mixed vital sign and neuromuscular abnormalities are characteristic of poisoning by asphyxiants. CNS syndromes. decongestants). limb ischemia from ergot alkaloids. CNS. GHB.. propoxyphene. seizures. gastrointestinal. and marked neuromuscular dysfunction without significant vital sign abnormalities suggests a CNS syndrome. slowly distributed to Copyright © 2008 The McGraw-Hill Companies. GHB. AGMA inducer poisoning can be distinguished from other causes of AGMA by the serum lactate concentration. anion-gap metabolic alkalosis. and delayed cardiac conduction from high doses of cocaine and some anticholinergic agents (e. cyclic antidepressants). All rights reserved. angiotensin-converting enzyme. manifestations of physiologic stimulation and physiologic depression occur together or at different times during the clinical course. monoamine oxidase. central nervous system. digitalis glycosides. meperidine. In contrast. γ-hydroxybutyric. membrane-active agents can cause simultaneous coma. In these conditions.g. Drug Overdose. and sedative-hypnotic γ-aminobutyric acid (GABA)-ergic] agents (Tables e35-1 and e35-2). cyclic antidepressants. antihistamines. γ-aminobutyric acid. propoxyphene. respiratory rate. nystagmus (due to sedative-hypnotics). cholinergic (muscarinic and nicotinic) agents. and cyclic antidepressants). or poisoning by “toxic time-bombs. phenothiazines). and diphenoxylate-atropine (Lomotil)]. Early. hypotension from selective β-adrenergic stimulants (e.” agents that are slowly absorbed. and neuromuscular activity are indicative of physiologic depression caused by “functional” sympatholytics (agents that decrease cardiac function and vascular tone as well as symthathetic activity). LSD.. asthma therapeutics). Decreased pulse. vital signs may be normal but the patient has altered mental status or is obviously sick or clearly symptomatic. pronounced vital sign and mental status changes suggest asphyxiant or membrane-active agent poisoning. an anticholinergic agent with membrane-active properties (e. membrane-active agents.

and oxalate poisoning. Bradycardia and atrioventricular block may occur in patients poisoned by α-adrenergic agonists. an opioid. fluorescence polarization. Laboratory assessment may be helpful in the differential diagnosis (Fig. brainstem reflexes intact Unresponsive to pain. hyperthermia. or salicylates. unintelligible speech. diaphoresis.laboratory tests. magnesium. or N-3-pyridylmethyl-N′-pnitrophenylurea (PNU. enzyme-multiplied. mercury. Nitrate Absent Toluene lithium. e35-1). cardiovascular collapse Physiologic Depression Grade 1 Grade 2 Grade 3 Grade 4 Awake. Pulmonary edema (adult respiratory distress syndrome. a glycol (diethylene. a β-adrenergic blocker. The serum lactate concentration is low (less than the anion gap) in the former and high (nearly equal to the anion High Low Ketosis Iron Bromide Iodine gap) in the latter. tremulous. or shock. flushing or pallor. or high-performance liquid chromatography. uretics. Ventricular tachyarrhythmias may be seen in poisoning with cardiac glycosides. respirations. psychotherapeutic agents. sorbitol). hydrogen sulfide. An abnormally low anion gap can be Lithium due to elevated blood levels of bromide. Isopropanol Seizures Phosphates Valproic Severe Salicylates ethylene. propylene). and blood urea nitroAsphyxiants Propylene Formaldehyde Alcoholic Ethylene Ethanol Calcium gen of >10 mmol/L—suggests the presence of a low-moketoacidosis glycol Biguanides glycol Kidney failure Magnesium lecular-weight solute such as acetone. glycol). colorimetric and fluorometric assays. Psychogenic illness (fear of being poisoned. seizures. Diagnosing a nontoxic exposure requires that the identity of the exposure agent be known or that a toxic time-bomb exposure has been excluded and that the time since exposure exceeds the longest known or predicted interval between exposure and peak toxicity. isopropanol. ethylene glycol. QRS. beta blockers. Aspiration pneumonia is common in patients with coma. or sleeping but arousable by voice or tactile stimulation. and agents that cause hyperkalemia or potentiate the effects of endogenous catecholamines (e. spontaneous motor activity absent. chloral hydrate. by inhalation of irritant gases. irritable. illicit drug packets. vital signs mildly to moderately increased Delirious. cardiovascular vital signs decreased their sites of action. or toluene. flaccid paralysis. potassium salts. fluorides. magnesium) or sugar (glycerol. Toxicologic analysis of urine and blood (and occasionally of gastric contents and chemical samples) can sometimes confirm or rule out suspected poisoning. isopropyl alcohol. or an “unmeaacid agitation Sulfur/sulfate sured” cation (calcium. and temperature decreased Unresponsive to pain. or salicylate poisoning. cyanide. or tricyclic antidepressants. or disrupt metabolic processes (Table e35-1). phencyclidine. seizures. cholinergic agents (carbamate and organophosphate insecticides). a sedative-hypnotic. and petroleum distillate ingestion. can vocalize but not converse. Hypocalcemia may be seen in ethylene glycol. lithium. calcium channel Osmolal Gap blockers. Hypoglycemia may be due to poisoning with β-adrenergic blockers. methanol). fluoride. may be confused Responds to pain but not voice. caffeine. require metabolic activation.TABLE e35-2 SEVERITY OF PHYSIOLOGIC STIMULATION AND DEPRESSION IN POISONING AND DRUG WITHDRAWAL Physiologic Stimulation Grade 1 Grade 2 Grade 3 Grade 4 Anxious. An increased AGMA is charIncreased with metabolic acidosis Normal Decreased acteristic of advanced methanol. theophylline. and salicylate intoxication but can occur with other agents Lactate level (Table e35-1) and in any poisoning that results in hepatic. renal. The presence of radiopaque densities on abdominal x-rays suggests the ingestion of calcium salts. The electrocardiogram (ECG) can sometimes be useful for rapid diagnostic purposes. theophylline.g. or salicylate. An increased osmolal Present gap—a difference between the serum osmolality (measured by freezing point depression) and that calculated from the serum sodium. hyperkalemia suggests poisoning e283 with an α-adrenergic agonist. ammonia.and QT-interval prolongation may be caused by hyperkalemia and by membrane-active drugs (Table e35-1). or shock. enteric-coated tablets. heavy metals. Shock mannitol. “toxic time-bombs” are increasingly common. gas-liquid. Ketosis suggests acetone. Acetone Liver failure Paraldehyde Methanol ethanol. or ARDS) can be caused by poisoning with carbon monoxide. uncontrollable motor hyperactivity. polymers). chlorine. ethanol. or by prolonged anoxia. iron. caffeine. aldehydes. iodine. Copyright © 2008 The McGraw-Hill Companies. β-adrenergic agonists. lethargic. membrane-active drugs. mass hysteria) may also occur after a nontoxic exposure and should be considered when symptoms are inconsistent with the exposure history. Normal Increased insulin. cardiac glycosides. cardiac glycosides. Radiologic studies may also be useful. or nitrate. or fluoride. fumes. Anxiety reactions resulting from a nontoxic exposure can cause mild physiologic stimulation (Table e35-2) and be indistinguishable from toxicologic causes (Table e35-1) without ancillary testing or a suitable periAnion Gap od of observation. ether (ethyl. quinine. chlorinated hydrocarbons. aliphatic and halogenated hydrocarbons). metal oxides. whereas hyperglycemia can occur in poisoning with acetone. moderately to markedly increased vital signs. lithium. isocyanates. β-adrenergic agonists. seizures. sympathomimetics. and hyperreflexia may be present Agitated. motor tone. Interpretation of laboratory data requires knowledge of the tests used for screening and confirmation (thin-layer. Vacor). brainstem reflexes and respirations absent. may have confusion or hallucinations but is able to converse and follow commands. glucose. calcium channel blockers. di. spontaneous motor activity present. and radio- CHAPTER e35 Poisoning and Drug Overdosage . paraquat. Hypokalemia can be FIGURE e35-1 Differential diagnosis of poisoning based on the results of routine caused by barium. or respiratory failure. phosgene. and salicylates. antiarrhythmic agents. mydriasis. calcium. All rights reserved. phenothiazines. brainstem reflexes depressed. iodinated compounds. or vapors (acids and alkali. able to converse and follow commands. tachyarrhythmias possible Coma. chloral hydrate. oral hypoglycemic agents. methylxanthines. an alcohol (benzyl. vital signs normal. Because so many medications are now reformulated in a once-a-day form for patient convenience and adherance. magnesium..

salicylate. 299). the route and amount of exposure. blood levels may be greater than those in tissue and may not correlate with toxicity. or when the clinical picture is consistent with the reported history. Specific treatment depends on the identity of the poison. when the patient is asymptomatic. supportive care and monitoring should continue until clinical. When a metabolite is responsible for toxic effects. the preferred biologic specimen for analysis. and their use is associated with potential complications. In the latter case. During the resolution phase of poisoning. Diagnostic certainty (usually via laboratory confirmation) is generally a prerequisite. When an accurate history is not obtainable and a poison causing delayed toxicity or irreversible damage is suspected. Resuscitation and stabilization are the first priority. ECG. Since decontamination is more effective when accomplished soon after exposure. Extracorporeal elimination methods are effective for many poisons. comprehensive screening tests require 2–6 h for completion. All rights reserved. Baseline laboratory. bedsores. thromboembolic disease. blood levels are usually lower than tissue levels during this phase and again may not correlate with toxicity. A negative result may mean the substance is not detectable by the test used or that its concentration is too low for detection at the time of sampling. laboratory. SUPPORTIVE CARE The goal of supportive therapy is to maintain physiologic homeostasis until detoxification is accomplished and to prevent and treat secondary complications such as aspiration. the time of presentation relative to the time of exposure. dialysis). and prevention of reexposure (Table e35-3). agents that are slowly absorbed. Measures that enhance poison elimination may shorten the duration of toxicity and lessen its severity. Symptomatic patients should have an IV line. However. repeating the test at a later time may yield a positive result. administration of specific antidotes. rhabdomyolysis. and the severity of poisoning. or disrupt metabolic processes (Table e35-1). Redistribution from tissues may cause a rebound increase in the blood level after termination of these procedures. The prompt reversal of dystonic (extrapyramidal) signs and symptoms following an IV dose of benztropine or diphenhydramine confirms a drug etiology. pneumonia. narcotic poisoning. Quantitative analysis is useful for poisoning with acetaminophen (Chap. The maximum potential toxicity based on the greatest possible exposure should be assumed. management is based primarily on clinical and laboratory findings. and last longer than they do after a therapeutic dose. Copyright © 2008 The McGraw-Hill Companies. oxygen saturation determination. alcohols (including ethylene glycol and methanol). Effects after an overdose usually begin sooner. naloxone. decontamination is the highest priority. ethylene glycol. digoxin. cardiovascular instability. require metabolic activation. their sensitivity (limit of detection) and specificity. Intestinal (or “gut”) dialysis with repetitive doses of activated charcoal is usually safe and can enhance the elimination of selected poisons. Knowledge of the offending agents’ pharmacokinetics and pharmacodynamics is essential. peak later. The response to antidotes may be useful for diagnostic purposes. and benzodiazepine intoxication. particularly in patients with potentially serious ingestions or unclear histories. In addition. enhancement of poison elimination. and theophylline. for quantitative analysis. Longer observation will likely be necessary for patients who have ingested toxic time-bombs. the time between the onset of poisoning and the peak effects. sepsis. Thus. they are not without risk. Urinary alkalinization and chelation therapy enhance the elimination of a relatively small number of poisons. seizures. Most patients who remain or become asymptomatic 4–6 h after ingestion will not develop subsequent toxicity and can be discharged safely. slowly distributed to their sites of action. Decontamination should also be considered. During the toxic phase. naloxone. prior to the onset of poisoning. immediate management must often be based on the history. Since chemicals are eliminated sooner from the blood than from tissues. Intravenous glucose (unless the serum level is documented to be normal). Although complete reversal of both central and peripheral manifestations of anticholinergic poisoning by physostigmine is diagnostic of this condition. and xray evaluation may also be appropriate. Resolution of altered mental status and abnormal vital signs within minutes of IV administration of dextrose. Although rapid qualitative screening tests for a limited number of drugs of abuse are available. However. as well as for carboxyhemoglobin and methemoglobin. qualitative screening is neither clinically useful nor cost-effective. and the optimal time of specimen sampling. and routine bedside ancillary tests (e. mass spectrometry). lithium. which must be weighed against the potential benefit. antiarrhythmics. physostigmine may cause some arousal in patients with CNS depression of any etiology. cerebral and pulmonary edema. During the pretoxic phase. metabolic or respiratory acidosis. the initial history and physical examination should be focused and brief. renal failure. Results can often be available within an hour. TABLE e35-3 FUNDAMENTALS OF POISONING MANAGEMENT Supportive Care Airway protection Oxygenation/ventilation Treatment of arrhythmias Hemodynamic support Treatment of seizures Correction of temperature abnormalities Correction of metabolic derangements Prevention of secondary complications Prevention of Further Poison Absorption Gastrointestinal decontamination Syrup of ipecac–induced emesis Gastric lavage Activated charcoal Whole-bowel irrigation Catharsis Dilution Endoscopic/surgical removal Decontamination of other sites Eye decontamination Skin decontamination Body cavity evacuation PART 17 Poisoning. but their expense and risk make their use reasonable only in patients who would otherwise have an unfavorable outcome.e284 immunoassays. and continuous observation. respectively. and treatment is based solely on the history. It is of greatest value in patients with severe or unexplained toxicity such as coma.g. . and Envenomation Enhancement of Poison Elimination Multiple-dose activated charcoal Diuresis Alteration of urinary pH Chelation Extracorporeal removal Peritoneal dialysis Hemodialysis Hemoperfusion Hemofiltration Plasmapheresis Exchange transfusion Hyperbaric oxygenation Administration of Antidotes Neutralization by antibodies Neutralization by chemical binding Prevention of Reexposure Adult education Child-proofing Notification of regulatory agencies Psychiatric referral Metabolic antagonism Physiologic antagonism POISONING AND DRUG OVERDOSE GENERAL PRINCIPLES Treatment goals include support of vital signs. acetone. physical examination. if indicated. or methanol) may indicate the need for additional interventions (antidotes. but it is less likely to be effective during this phase than during the pretoxic one. and thiamine should be considered in patients with altered mental status. or flumazenil is virtually diagnostic of hypoglycemia. Drug Overdose. Personal communication with the laboratory is essential. During absorption and distribution. blood and urine should be sent for toxicologic screening and. anticonvulsants. This is particularly true when extracorporeal elimination procedures are used. high blood levels of agents whose metabolites are more toxic than the parent compound (acetaminophen. continued treatment might be necessary in the absence of clinical toxicity or abnormal laboratory studies. coagulopathy. and non-sinus cardiac rhythms. It is also advisable to establish IV access and initiate cardiac monitoring. ECG). cardiac monitoring. prevention of further poison absorption. and ECG abnormalities have resolved. A drug’s published pharmacokinetic profile in standard references like the Physician’s Desk Reference (PDR) is usually different from its toxicokinetic profile in over- dose. particularly those with coma or seizures. heavy metals. and generalized organ dysfunction due to hypoxia or shock. barbiturates.. gas chromatography.

the availability. in the management of overdose patients. although profound CNS depression and cardiac conduction abnormalities suggest the latter. severity. Electroencephalographic monitoring and continuing treatment of seizures are necessary to prevent permanent neurologic damage. or a combination of a beta blocker and a vasodilator (esmolol and nitroprusside) may be considered for cases refractory to high doses of benzodiazepines. 225. it is reasonable to simply observe them rather than to administer another potentially proarrhythmic agent. and rhabdomyolysis. Since clinical assessment of respiratory function can be inaccurate. Invasive (esophageal or intracardiac) ECG recording may be necessary to determine the origin (ventricular or supraventricular) of wide-complex tachycardias (Chap. For ventricular tachyarrhythmias due to tricyclic antidepressants and probably other membrane-active agents (Table e35-1). lithium. fluoride. Respiratory Care Endotracheal intubation for protection against the aspiration of gastrointestinal contents is of paramount importance in patients with CNS depression or seizures as this complication can increase morbidity and mortality. Magnesium sulfate and overdrive pacing (by isoproterenol or a pacemaker) may be useful in patients with torsades des pointes and pro- Central Nervous System Therapies Neuromuscular hyperactivity and seizures can lead to hyperthermia. however. and there are insufficient data to support or exclude a beneficial effect when they are used >1 h after ingestion. Extracorporeal measures (membrane oxygenation. hepatic and renal dysfunction. metabolic abnormalities. The average time from ingestion to presentation for treatment is >1 h for children and >3 h for adults. CHAPTER e35 Poisoning and Drug Overdosage PREVENTION OF POISON ABSORPTION Gastrointestinal Decontamination Whether or not to perform gastrointestinal decontamination. It is clearly unnecessary when predicted toxicity is minimal or the time of expected maximal toxicity has passed without significant effect. Drug-induced pulmonary edema is usually noncardiac rather than cardiac in origin. cardiopulmonary bypass) and partial liquid (perfluorocarbon) ventilation may be appropriate for severe but reversible respiratory failure. gastric lavage. a dopamine receptor antagonist. a calcium channel blocker (verapamil or diltiazem). Those who cannot respond to voice or who are unable to sit and drink fluids without assistance are best managed by prophylactic intubation. Activated charcoal has comparable or greater efficacy. alkalis. IC. The gag reflex is not a reliable indicator of the need for intubation. For poisons with central dopaminergic effects (phencyclidine) manifested by psychotic behavior. and other inorganic compounds are not well Copyright © 2008 The McGraw-Hill Companies. Patients who have attempted suicide require continuous observation and measures to prevent self-injury until they are no longer suicidal. seizures). iron. antidotes. and those with significant underlying medical problems. such as haloperidol. lactic acidosis. or enhanced elimination therapy. Treatment with an α-adrenergic antagonist (phentolamine) alone may sometimes be appropriate. Beta blockers can be hazardous if the arrhythmia is due to sympathetic hyperactivity. and syrup of ipecac decreases with time. Most patients will recover from poisoning uneventfully with good supportive care alone. allowing the charcoal-toxin complex to be evacuated with stool. All rights reserved. physostigmine is the treatment of choice. Since benzodiazepines and barbiturates act by slightly different mechanisms (the former increases the frequency and the latter increases the duration of chloride channel opening in response to GABA). and high-dose insulin with dextrose may be effective in both beta blocker and calcium channel blocker poisoning. and should be treated aggressively. Intraaortic balloon pump counterpulsation and venoarterial or cardiopulmonary perfusion techniques should be considered for severe but reversible cardiac failure. and contraindications of the procedure. and rhabdomyolysis associated with neuromuscular hyperactivity. treatment with a benzodiazepine should be prioritized. not routinely. Arrhythmias may be resistant to drug therapy until underlying acid-base. the existing and predicted toxicity of the ingestant. respiratory depression. and temperature derangements are corrected. the need for oxygenation and ventilation is best determined by continuous pulse oximetry or arterial blood-gas analysis. and which procedure to use. straw. The treatment of seizures secondary to cerebral ischemia or edema or to metabolic abnormalities should include correction of the underlying cause. and secondary complications should be treated by standard therapies. Seizures resulting from membrane destabilization (beta blocker or cyclic antidepressant poisoning) require GABA enhancers (benzodiazepines first. When the etiology is sympathetic hyperactivity. specific antidotal therapy may be necessary. 226). Seizures caused by isoniazid.Admission to an intensive care unit is indicated for the following: patients with severe poisoning (coma. therapy with both may be effective when neither is effective alone. fewer contraindications and complications. and risk of complications. whereas class IA. epinephrine. or high-dose dopamine may be necessary. particularly aspiration. Seizures caused by excessive stimulation of catecholamine receptors (sympathomimetic or hallucinogen poisoning and drug withdrawal) or decreased activity of GABA (isoniazid poisoning) or glycine (strychnine poisoning) receptors are best treated with agents that enhance GABA activity. Activated charcoal suspension (in water) is given orally via a cup. depends on the time since ingestion. chest pain. gastrointestinal decontamination should be performed selectively. especially in theophylline overdose. In vitro. and respiratory monitoring). longed QT intervals. The recommended dose is 1 g/kg body weight. which inhibits the synthesis of GABA at several steps by interfering with the cofactor pyridoxine (vitamin B6). intermediate care unit. depending on the anticipated duration and level of monitoring needed (intermittent clinical observation versus continuous clinical. cardiac. Charged (ionized) chemicals such as mineral acids. chocolate. Phenytoin is contraindicated in toxicologic seizures: animal and human data demonstrate worse outcomes after phenytoin loading. cardiac arrhythmias. but complications of gastrointestinal decontamination. or cola syrup) to the suspension. such as benzodiazepine or barbiturates. and III antiarrhythmic agents are contraindicated because of similar electrophysiologic effects. can prolong this process. acidosis. Palatability may be increased by adding a sweetener (sorbitol) or a flavoring agent (cherry. In anticholinergic and cyanide poisoning. efficacy. venoarterial perfusion. Hence. thus it is the preferred method of gastrointestinal decontamination in most situations. may require high doses of supplemental pyridoxine. oxygenation. Charcoal adsorbs ingested poisons within the gut lumen. Antibody therapy may be indicated for cardiac glycoside poisoning. specific therapy is indicated. or ECG evidence of ischemia. sodium bicarbonate should be considered first for any ventricular arrhythmia suspected to have a toxicologic etiology. In severe cases or those associated with hemodynamic instability. Neuromuscular paralysis is indicated in refractory cases. treatment with norepinephrine. Other Measures Temperature extremes. If the cause is anticholinergic poisoning. those needing close monitoring. Measurement of pulmonary artery pressure may be necessary to establish the cause and direct appropriate therapy. those showing progressive clinical deterioration. calcium. sodium bicarbonate is indicated. Serotonergic receptor overstimulation in serotonin syndrome may be treated with cyproheptadine. Supraventricular tachycardia associated with hypertension and CNS excitation is almost always due to agents that cause generalized physiologic excitation (Table e35-1). and highly dissociated salts of cyanide. A patient with CNS depression may maintain airway patency while being stimulated but not if left alone. with their attendant complications. cardiac conduction abnormalities. Glucagon. Magnesium and anti-digoxin antibodies should be e285 considered in patients with severe cardiac glycoside poisoning. Cardiovascular Therapy Maintenance of normal tissue perfusion is critical for complete recovery to occur once the offending agent has been eliminated. and is less aversive and invasive than ipecac or gastric lavage. . Further treatment with a combined alpha and beta blocker (labetalol). barbiturates second). Supraventricular tachycardia without hypertension is generally secondary to vasodilation or hypovolemia and responds to fluid administration. The efficacy of activated charcoal. hypotension. If hypotension is unresponsive to volume expansion. charcoal adsorbs ≥90% of most substances when given in an amount equal to 10 times the weight of the substance. Bradyarrhythmias associated with hypotension generally should be treated as described in Chap. Mechanical ventilation may be necessary for patients with respiratory depression or hypoxia and to facilitate therapeutic sedation or paralysis in order to prevent or treat hyperthermia. If the patient is hemodynamically stable. or small-bore nasogastric tube. Although lidocaine and phenytoin are historically safe for ventricular tachyarrhythmias of any etiology. Most cases are mild or moderate in severity and require only observation or nonspecific sedation with a benzodiazepine. hypothermia or hyperthermia. Patients with mild to moderate toxicity can be managed on a general medical service. electrolyte. or emergency department observation area. and the nature. may be useful.

Pharmacokinetic efficacy approaches that of hemodialysis for some agents (e. and exchange transfusion are capable of removing any toxin from the bloodstream. Colyte) orally or by gastric tube at a rate of 2.5–1 g/kg body weight every 2–4 h. lithium. Chronic ipecac use (by patients with anorexia nervosa or bulimia) may cause electrolyte and fluid abnormalities.e.. and agents that are poorly adsorbed by charcoal (e. Complications include intestinal obstruction. pseudoobstruction. and diarrhea or constipation. and electrolyte parameters should be monitored carefully. the pharmacokinetic efficacy (removal of drug at a rate greater than that accomplished by intrinsic elimination) and clinical benefit (shortened duration of toxicity or improved outcome) of such interventions are often more theoretical than proven. whole-bowel irrigation appears to be as effective as other decontamination procedures. Even the American Academy of Pediatrics (AAP). Serious complications (esophageal and gastric perforation. water solubility. and nonocclusive intestinal infarction in patients with decreased gut motility. traditionally the strongest proponent of ipecac. and in those who have ingested corrosives or rapidly acting CNS poisons (camphor. For this reason. more effective decontamination procedures. Its efficacy is similar to that of ipecac. or agents that have coalesced into gastric concretions or bezoars (barbiturates. Their primary use is to prevent constipation following a single dose of charcoal. glutethimide. Hence. Decontamination of Other Sites Immediate. are generally recommended. 51% when given at 30 min. mercury. nausea. salicylates. issued a policy statement in 2003 recommending that ipecac should no longer be used in poisoning treatment. Whole-bowel irrigation is performed by administering a bowel-cleansing solution containing electrolytes and polyethylene glycol (Golytely. Lavage decreases ingestant absorption by an average of 52% if performed within 5 min of ingestion administration. whereas basic ones become ionized and trapped in acid urine. Alone. Gastric lavage is performed by sequentially administering and aspirating ~5 mL fluid per kilogram of body weight through a no.e286 adsorbed by charcoal. Endoscopic or surgical removal of poisons may be useful in rare situations. methotrexate. cost. It may increase the dissolution rate (and hence absorption) of capsules. preferably under direct visualization. Since membranes are more permeable to nonionized molecules than to their ionized counterparts. and the patient must be cooperative or adequately restrained (with pharmacologic sedation if necessary) during the procedure. While making theoretical sense for some overdoses (amphetamines). reliable histories. Although data are limited. cathartics do not prevent ingestant absorption and should not be used as a method of gut decontamination. phosphorus). Charcoal is not recommended for patients who have ingested corrosives because it obscures endoscopy. Cathartics are contraindicated in patients who have ingested corrosives and in those with preexisting diarrhea. It is most appropriate for those who have ingested foreign bodies. fluid. slow-release or enteric-coated medications. vomiting. Contraindications include congestive heart failure. tube misplacement in the trachea) occur in ~1% of patients. soap. Drug Overdose. drinkable liquid is the initial treatment for topical exposures (exceptions include alkali metals. All rights reserved. thallium). packets of illicit drugs. 28 French tube for children). or another available clear. and salicylates. Abdominal cramps. Multiple-Dose Activated Charcoal Repetitive oral dosing with charcoal can enhance the elimination of previously absorbed substances by binding them within the gut as they are excreted in the bile. gastric lavage is absolutely contraindicated in combative patients or those who refuse. phenobarbital. A triple wash (water. Complications include mechanical obstruction of the airway. Nausea and vomiting from ipecac may prevent use of other. copious flushing with water. Ipecac irritates the stomach and stimulates the central chemoreceptor trigger zone. serious complications (e. Multiple-dose therapy should be considered only for selected agents (theophylline. and bowel obstruction and infarction caused by inspissated charcoal. plasmapheresis. Vomiting usually occurs about 20 min after administration. In animal and human volunteer studies. and cerebral edema. hemodialysis. and 36% at 60 min. CNS depression. acidic (low-pKa) poisons are ionized and trapped in alkaline urine. high water solubility.5 L/h in children) until rectal effluent is clear.. drinking 5 mL/kg of body weight of water or another clear liquid) is recommended only after the ingestion of corrosives (acids. or seizures. hemodynamic instability. especially when lavage is perfomed improperly. Aspiration is a common complication (occurring in up to 10% of patients). meprobamate.g. heavy metals. phenobarbital. fluoride. theophylline). chlorpropamide. The patient should be placed in Trendelenburg and left lateral decubitus positions to prevent aspiration (even if an endotracheal tube is in place). tobramycin. and 16% if performed at 60 min. pills) should be removed manually. renal failure. tablets. magnesium citrate and sulfate. as most published complications involve patient resistance to the procedure. charcoal or resin hemoperfusion. sorbitol) that promote the rectal evacuation of gastrointestinal contents. saline. phenobarbital. Except for infants. It is also contraindicated in those with a compromised unprotected airway and those at risk for hemorrhage or perforation due to esophageal or gastric pathology or recent surgery. sodium sulfate) or saccharides (mannitol. and compromised unprotected airways. the decision to use such measures should be based on the actual or predicted toxicity and the potential efficacy. ENHANCEMENT OF POISON ELIMINATION Although the elimination of most poisons can be accelerated by therapeutic interventions. The patient must be in a sitting position. Sorbitol and other cathartics are absolutely contraindicated when administering multiple doses of activated charcoal because of electrolyte and fluid shifts.. Some argue it can still be considered for the home management of patients with unintentional ingestions. Extracorporeal Removal Peritoneal dialysis. Acid-base. the physician should personally insert the lavage tube and confirm its placement. hemofiltration. or passively diffuse into the gut lumen (reverse absorption or enterocapillary exsorption). and Envenomation Urinary Alkalinization Ion trapping via alteration of urine pH may prevent the renal reabsorption of poisons that undergo excretion by glomerular filtration and active tubular secretion. Gastric lavage is contraindicated in corrosive or petroleum distillate ingestions because of the respective risks of gastroesophageal perforation and aspiration pneumonitis.0 L/h (0. has no role in the hospital setting. PART 17 Poisoning. Patients who become toxic from cocaine due to its leakage from ingested drug packets require immediate surgical intervention. vomiting. alkali). low protein binding. and other solid ingestants and should not be used in these circumstances. and myopathy. heavy metals). dapsone. The removal of liquids from body cavities such as the vagina or rectum is best accomplished by irrigation. Urinary alkalinization (producing a urine pH ≥7. quinine) and is not effective in accelerating elimination of chlorpropamide.g. where normal saline is recommended. Magnesium-containing cathartics should not be used in patients with renal failure.g. Finally. iron. strychnine). Except for aspiration. Doses of 0. adjusted downward to avoid regurgitation in patients with decreased gastrointestinal motility. small volumes of distribution (<1 L/kg body weight). gastric or esophageal tears and perforations) are rare. Copyright © 2008 The McGraw-Hill Companies. tap water is acceptable. diflunisal. Inhalational exposures should be treated initially with fresh air or oxygen. 40 French orogastric tube (no. secreted by gastrointestinal cells. or agents that adsorb poorly to charcoal. charcoal decreases the absorption of ingestants by an average of 73% when given within 5 min of ingestant administration. The most effective cathartic is sorbitol in a dose of 1–2 g/kg of body weight.5 and a urine output of 3–6 mL/kg body weight per hour by adding sodium bicarbonate to an IV solution) enhances the excretion of chlorphenoxyacetic acid herbicides. once the most commonly used decontamination procedure. propoxyphene. tricyclic antidepressants. acid diuresis is never indicated and is potentially harmful. Charcoal may also prevent the absorption of orally administered therapeutic agents. and occasional vomiting are side effects. sulfonamides. Significant amounts of ingested drug are recovered in ~10% of patients. prolonged elimination (long halflife). Side effects of charcoal include nausea. Complications of repeated dosing include hypermagnesemia (from magnesium salts) and excessive diarrhea. ileus. a potentially lethal amount of a heavy metal (arsenic. It is contraindicated in patients with bowel obstruction. carbamazepine. aspiration. Cathartics are salts (disodium phosphate. or protein binding do not limit the efficacy of the other forms of extracorporeal removal. calcium oxide. cardiac toxicity. Molecular weight. and high dialysis clearance relative to total-body clearance. Solids (drug packets. 26% if performed at 30 min. sustained-release preparations). such as ingestion of a potentially toxic foreign body that fails to transit the gastrointestinal tract. .. and risks of therapy. Dilution (i. Ipecac is contraindicated in patients with recent gastrointestinal surgery. Agents most amenable to enhanced elimination by dialysis have low molecular mass (<500 Da). and mild predicted toxicity when transport to a hospital site is prolonged. water) may be best for dermal decontamination. cyanide. Saline is preferred for eye irrigation. Syrup of ipecac.

and cyproheptidene (a serotonin receptor antagonist) for mild to moderate limb ischemia. or fatal toxicity. salicylates. pronounced gastrointestinal symptoms and β agonist effects (see above). and involuntary movements can also occur. cyanide. if used alone. anticoagulants. and metal-chelate complexes. ethylene glycol. paraquat. a nonselective β blocker. contraindicated. Candidates for extracorporeal removal therapies include patients with severe toxicity who deteriorate despite aggressive supportive therapy.g. provision of competitive metabolic or receptor substrate). Both techniques require central venous access and systemic anticoagulation and often result in transient hypotension. inhibition of phosphodiesterase resulting in increased intracellular cyclic adenosine and quanosine monophosphate Physiologic stimulation (Table e35-2). in infants). Physiologic stimulation (Table e35-2). phenylpropanolamine β2-Adrenergic agonists (bronchodilators): albuterol. Although hemofiltration can enhance elimination of aminoglycosides. and valproate. those who lack the capacity for selfdetoxification because of liver or renal failure. cocaine. drug-induced dystonic reactions. bradycardia. vasospasm with limb (isolated or generalized). benzodiazepines. indications for hemoperfusion or hemodialysis include unstable vital signs. Phentolamine. beta blockers. hypnotic-sedatives (barbiturates. Causes Stimulated Sympathetics (see also Chap. CHAPTER e35 Poisoning and Drug Overdosage TABLE e35-4 PATHOPHYSIOLOGIC FEATURES AND TREATMENT OF SPECIFIC TOXIC SYNDROMES AND POISONINGS Physiologic Condition. disopyramide. ethanol. and sulfhemogloginemia. bromocriptine. All rights reserved. isopropyl alcohol. isoniazid. membrane-active agents. myocardial. hemoperfusion. or other cardioselective β blocker for hypertension with tachycardia due to nonselective agents (β blockers. Toxicity occurs at lower drug levels in chronic poisoning than in acute poisoning. stimulation of dopamine receptors Methylxanthines Caffeine. β agonists can cause hypotension and hypokalemia. Peritoneal dialysis and exchange transfusion are less effective but may be used when other procedures are either not available. antibody-antigen reactions. chemical binding) or by antagonizing their physiologic effects (e.. hypocalcemia. carbamazepine. those with potentially prolonged. meprobamate.or sodium chlorate– induced hemolysis. procainamide. and thrombocytopenia. seizures. a β blocker with α-blocking activity. Copyright © 2008 The McGraw-Hill Companies. hypotension. theophylline. Other Techniques The elimination of heavy metals can be enhanced by chelation. and most hospitals no longer have hemoperfusion cartridges readily available.g. metoprolol. propofol. or technically difficult (e. elimination enhanced by multiple-dose charcoal. . dopamine receptor antagonists (antipsychotics) for hallucinations and movement disorders Propranolol. captopril. labetalol. the roles of hemofiltration and plasmapheresis in the treatment of poisoning are not yet defined. recent advances in hemodialysis technology make it useful for removing poisons such as caffeine. Fortunately. theophylline Inhibition of adenosine synthesis and adenosine receptor antagonism. cholinergic agents. sympathomimetics. mushrooms (amatoxin-containing). methotrexate. ethylene glycol. benzodiazepines. it does not correct associated acid-base and electrolyte abnormalities. anticholinergic agents. vancomycin. dapsone. Although hemoperfusion may be more effective in removing some of these poisons.Dialysis should be considered in cases of severe poisoning due to acetone. ephedrine Stimulation of central and peripheral sympathetic receptors directly or indirectly (by promoting the release or inhibiting the reuptake of norepinephrine and sometimes dopamine) Physiologic stimulation (Table e35-2). methemoglobinemia.. carbon tetrachloride. hypoglycemic agents. pergolide Stimulation and inhibition of serotonergic and α-adrenergic receptors. ADMINISTRATION OF ANTIDOTES Antidotes counteract the effects of poisons by neutralizing them (e. chelation. heavy metals. for hypotension and tachycardia due to β2 agonists. reflex bradycardia can occur with selective α1 agonists.g. glutethimide. calcium channel blockers. carbon monoxide. for severe hypertension due to α1-adrenergic agonists. hydrogen sulfide. irreversible. carbamazepine. Hemoperfusion may also cause hemolysis. for tachycardia with hypotension. a nonselective β blocker. bromide. chloral hydrate. stimulation of epinephrine and norepinephrine release. Poisons or conditions with specific antidotes include acetaminophen. ethchlorvynol. propranolol. Nitroprusside or nitroglycerine for severe vasospasm.. and valproate. a nonselective α1adrenergic receptor antagonist. methysergide. and hemodialysis. and cerebral ischemia progressing to gangrene or infarction. chloramphenicol. Since their safe use requires correct identification of a specific poisoning or syndrome. barbiturates. formication. details of antidotal therapy are discussed with the conditions for which they are indicated (Table e35-4). Antidotes can significantly reduce morbidity and mortality but are potentially toxic if used for inappropriate reasons. fluoride. methemoglobinemia. methanol. can exacerbate hypertension and vasospasm due to unopposed α stimulation). or phentolamine with esmolol. activation of opposing nervous system activity. prazocin (an α1 blocker). (continued) Examples Mechanism of Action Clinical Features Specific Treatments Ergot alkaloids Ergotamine. nifedipine. lithium. and a theophylline level of 80−100 μg/mL after acute overdose and 40−60 μg/mL with chronic exposure. and a variety of envenomations. phenytoin. terbutaline Nonspecific adrenergic agonists: amphetamines. those with e287 dangerous blood levels of toxins. and the removal of carbon monoxide can be increased by hyperbaric oxygenation. Exchange transfusion may be indicated in the treatment of severe arsine. any β blocker for supraventricular or ventricular tachycardia without hypotension. procainamide. theophylline. methaqualone). 389) Sympathomimetics α1-Adrenergic agonists (decongestants): phenylephrine. and those with a serious underlying illness or complication that will adversely affect recovery. opioids. cardiac glycosides.

dicyclomine Atropine. dry skin and mucous membranes. thioridazine Antipsychotics Stimulation of α2-adrenergic receptors leading to inhibition of CNS sympathetic outflow. dobutamine. atrioventricular block. hyperkalemia. and mechanical cardiovascular support for refractory cases. direct-acting sympathomimetics (e. epinephrine. myoclonus and picking activity.. pindolol α1 Antagonists: carvedilol. propranolol. norepinephrine. hypoglycemia. Onset may be delayed for ≥12 h after overdose of sustained-release formulations. verapamil Inhibition of β-adrenergic receptors (class II antiarrhythmic effect). atrioventricular block. . flushing. Drug Overdose. Contraindications include nonanticholinergic cardiovascular toxicity (e. potassium. hyperglycemia. scopolamine Amitriptyline. Physiologic depression (Table e35-2). terminal hypotension and bradycardia in severe cases. phenothiazines. Inhibition of slow (type L) cardiovascular calcium channels (class IV antiarrhythmic effect). muscarinic. miosis. All rights reserved. Sotalol can cause increased QT interval and ventricular tachydysrhythmias. Physiologic depression (Table e35-2).g. electrical pacing. organ ischemia and infarction. Physiologic depression (Table e35-2). timolol Partial β agonists: acebutolol. and norepinephrine may sometimes be effective. Anticholinergics Antihistamines Antiparkinsonian agents Antipsychotics Antispasmotics Belladonna alkaloids Cyclic antidepressants Muscle relaxants Mushrooms and plants Depressed Sympatholytics α2-Adrenergic agonists Diphenhydramine. β-Adrenergic blockers Calcium channel blockers Cardioselective (β1) blockers: atenolol. jimson weed. diphenhydramine. Atropine. Glucagon and calcium for hypotension and symptomatic bradycardia.e288 TABLE e35-4 PATHOPHYSIOLOGIC FEATURES AND TREATMENT OF SPECIFIC TOXIC SYNDROMES AND POISONINGS (CONTINUED) Physiologic Condition. PART 17 Poisoning. epinephrine. high-dose insulin (with glucose and potassium to maintain euglycemia and normokalemia).g. and III antiarrhythmics. hallucinations. dopamine. Dopamine and norepinephrine for hypotension. hyoscyamine. amrinone. Magnesium. Some agents also inhibit sodium. Clinical Features Delayed or slowly progressive physiologic stimulation (Table e35-2). an acetylcholinesterase inhibitor (see below) for delirium. olanzapine. and ventricular arrhythmias). decreased bowel sounds. dopaminergic. Calcium and glucagon for hypotension and symptomatic bradycardia. Onset may be delayed after sotalol and sustained-release formulation overdose. Avoid class IA. IC. and overdrive pacing for torsades de pointes. Hypotension is usually due to decreased vascular resistance rather than to decreased cardiac output. seizures. activity at nonadrenergic imidazoline binding sites also contributes to CNS effects. esmolol. imipramine Cyclobenzaprine. Sodium bicarbonate and lidocaine for ventricular tachydysrhythmias associated with QRS prolongation. esmolol) for severe hypertension and tachycardia. and neuromuscular hyperactivity. isoproterenol. propranolol. nightshade Physiologic stimulation (Table e35-2). and urinary retention. doxylamine. High-dose insulin (with glucose and potassium to maintain euglycemia and normokalemia). Physiologic depression (Table e35-2). and tricyclic antidepressants have additional nonanticholinergic activity (see below). Some agents have activity at additional receptors or have membrane effects (see below). Central effects may occur without significant autonomic dysfunction. anticholinergic effects (see above). Causes Monoamine oxidase inhibitors Examples Phenelzine. and calcium channels. Partial agonists can cause hypertension and tachycardia. sotalol Diltiazem. tetrahydrozoline and other imidazoline decongestants. Atropine for symptomatic bradycardia. electrical pacing. histaminergic. doxepin. pyrilamine Amantidine. Transient initial hypertension may be seen. Dopamine. Inhibition of α-adrenergic. Specific Treatments Short-acting agents (e. haloperidol. and isoproterenol are less often effective but can be used adjunctively. (continued) Copyright © 2008 The McGraw-Hill Companies. selegiline Mechanism of Action Inhibition of monoamine oxidase resulting in impaired metabolism of endogenous catecholamines and exogenous sympathomimetic agents Inhibition of central and postganglionic parasympathetic muscarinic cholinergic receptors. QRS. trihexiphenydyl Chlorpromazine. Naloxone for CNS depression (inconsistently effective). seizures. quetiapine. Amrinone. norepinephrine.. including torsades des pointes. isoproterenol. miosis. pantherina. clozapine. thioridazine Clinidium. atropine. guanabenz. and QT intervals) with ventricular tachydysrhythmias.g. hypotension. tachycardia. nifedipine and other dihydropyridine derivatives.. and serotonergic receptors. Cardiac conduction delays (increased PR. labetalol Membrane-active agents: acebutolol. epinephrine) for hypotension and bradycardia Physostigmine. and mechanical cardiovascular support for refractory cases. At high doses. cardiac conduction abnormalities. amantidine. henbane. tizanidine and other imidazoline muscle relaxants Chlorpromazine. nitroprusside. risperidone. orphenadrine Amanita muscaria and A. tranylcypromine. orphenadrine. extrapyramidal reactions (see below). JT. can sometimes develop. and Envenomation Clonidine. metoprolol Nonselective (β1 and β2) blockers: nadolol.

Avoid class IA. gabapentin. gastrointestinal. All rights reserved. temazapam. cardiac conduction delays (increased PR. its metabolite carisoprodol. phenytoin. to some extent. seizures.TABLE e35-4 PATHOPHYSIOLOGIC FEATURES AND TREATMENT OF SPECIFIC TOXIC SYNDROMES AND POISONINGS (CONTINUED) Physiologic Condition. JT. Baclofen and. and QT intervals. lamotrigine. muscle cramps. tiagabine. hypernatremia. triazolam Short-acting: alprazolam. Cholinesterase activity in plasma and red cells <50% of normal in acetylcholinesterase inhibitor poisoning. imipramine Inhibition of α-adrenergic dopaminergic. levetiracetam. (continued) Copyright © 2008 The McGraw-Hill Companies. ethosuximide. nicotine (tobacco) Atropine for muscarinic signs and symptoms. propoxur) and medicinals (neostigmine.5 meq/L. oxazepam Long-acting: chlordiazepoxide. nystagmus. fasciculations. valproate. tacrine). nerve gases (sarin. epinephrine. . seizures. midazolam. soman. and increased bowel and bladder activity with nausea. K+ATPase membrane pump. and hypoglycemia can be seen in valproate poisoning. and orphenidrine antagonize N-methyl-D-aspartate (NDMA) excitatory receptors. CHAPTER e35 Poisoning and Drug Overdosage Cyclic antidepressants Amitriptyline. weakness. GABA-ergic. foxglove and other plants. tachycardia. abdominal cramps. excessive secretions (lacrimation. malathion) Bethanecol. Delayed absorption can occur with carbamazepine. Inhibition of acetylcholinesterase leading to increased synaptic acetylcholine at muscarinic and nicotinic cholinergic receptor sites Physiologic depression (Table e35-2). Physiologic depression (Table e35-2). He modialysis and hemoperfusion may be indicated for severe poisoning by some agents (see Extracorporeal Removal. and zonisamide decrease conduction through T-type calcium channels. Hypertonic sodium bicarbonate (or hypertonic saline) and lidocaine for ventricular tachydysrhythmias associated with QRS prolongation. Nicotinic signs and symptoms: hypertension. inhibition of norepinephrine and serotonin reuptake. topiramate. Elimination of phenobarbital and possibly other long-acting agents enhanced by multiple-dose charcoal. vomiting. Death is usually due to respiratory failure.) Mechanism of Action Inhibition of cardiac Na+. Hyperkalemia in acute poisoning. phenytoin. psychiatric. valproate Flumazenil for benzodiazepine and zolpidem poisoning. pentobarbital. chlopyriphos. tachycardia. Anticholinergic toxidrome (see above). and external cardiac pacing for bradydysrhythmias and magnesium. and incontinence of feces and urine. salivation. and tachyarrhythmias can occur with baclofen. diarrhea. secobarbital Long-acting: phenobarbital. Mobitz II or third-degree atrioventricular block. Inocybe sp. hypertension. inhibition of sodium channels (see membraneactive agents). chemical hepatitis. Internal cardiac pacing and cardioversion can increase ventricular irritability and should be reserved for refractory cases. hyperkalemia (>5. and III antiarrhythmics. Carbamazepine and oxcarbazepine may produce hyponatremia from SIADH. and serotonergic receptors. Muscarinic signs and symptoms: seizures. physostigmine. toad skin secretions (Bufonidae sp. valproate. doxepin. Clinical Features Physiologic depression (Table e35-2). Benzodiazepines and barbiturates for seizures. oxcarbazepine. Causes Cardiac glycosides e289 Examples Digoxin. nerve gases. Physiologic depression (Table e35-2). felbamate. See above and below for treatment of anticholinergic and sodium channel (membrane) blocking effects. zonisamide Barbiturates Short-acting: butabarbital. AGMA. Cholinergics Acetylcholinesterase inhibitors Muscarinic agonists Carbamate insecticides (aldicarb. atrioventricular block with or without concomitant supraventricular tachyarrhythmia. ventricular tachyarrhythmias. in acute poisoning only). clonazepam. lorazepam. and valproate. diazepam. pilocarpine Lobeline. and orphenadrine. bronchorrhea and wheezing. phenytoin. in text). mushrooms (Boletus. felbamate. QRS.). Temporizing measures include atropine. VX) organophosphate insecticides (diazinon. or an unknown anticholinesterase. meprobamate. Clitocybe. endogenous cardioactive steroids. and visual symptoms. flurazepam Pharmacologically related agents: zaleplon. terminal QRS right axis deviation) with aberrancy and ventricular tachydysrhythmias. Tachyarrhythias can also occur with chloral hydrate. Toxicity occurs at lower drug levels in chronic poisoning than in acute poisoning. IC. histaminergic. Myoclonus. tabun. diaphoresis). 388) Anticonvulsants Carbamazepine. Specific Treatments Digoxin-specific antibody fragments for hemodyamically compromising dysrhythmias. a cholinesterase reactivator. Use of phenytoin is controversial. carbamazepine. lidocaine. phenytoin. ethosuximide. hyperammonemia. Nicotinic agonists Stimulation of CNS and postganglionic parasympathetic cholinergic (muscarinic) receptors Stimulation of preganglionic sympathetic and parasympathetic and striated muscle (neuromuscular junction) cholinergic (nicotine) receptors Sedative-hypnotics (see also Chap. and bretylium for ventricular tachydysrhythmias. hyperosmolality. zolpidem Potentiation of the inhibitory effects of GABA by binding to the neuronal GABA-A chloride channel receptor complex and increasing the frequency or duration of chloride channel opening in response to GABA stimulation. for nicotinic signs and symptoms due to organophosphates. primadone Benzodiazepines Ultrashort-acting: estazolam. dopamine. flunitrazepam. carbaryl. and paralysis. muscarinic. Pralidoxime (2PAM). GHB act at the GABA-B rector complex.

transport. ethclorvynol. glutethimide. Carbon monoxide also binds to hemoglobin and myoglobin and prevents oxygen binding. lack of clinical improvement. High-dose oxygen. nitrogen oxides. carisoprodol. and for ethanol-like intoxication or increased osmolal gap if level not readily obtainable. phenytoin. meprobamate. A bitter almond breath odor may be noted with cyanide ingestion. nitrates. Initial ethanol-like intoxication. cyanide. thereby blocking electron transport and oxidative metabolism. Amyl and sodium nitrite (without thiosulfate) for similar toxicity in hydrogen sulfide poisoning. . Signs and symptoms of hypoxia with initial physiologic stimulation and subsequent depression (Table e35-2). Precipitation of oxalic acid metabolite as calcium salt in tissues and urine results in hypocalcemia. and cardiovascular dysfunction in cyanide poisoning. Coma. Specific Treatments Muscle relaxants PART 17 Poisoning. Exchange transfusion and hyperbaric oxygen for severe or refractory cases. folinic acid. Hyperbaric oxygen for moderate to severe carbon monoxide poisoning and for cyanide or hydrogen sulfide poisoning unresponsive to other measures. and sodium channel blocking activity (see above and below). or ischemia (contraindicated in G6PD deficiency). and renal failure. normal PO2 and calculated oxygen saturation but decreased oxygen saturation and increased methehemoglobin fraction by co-oximetry (oxygen saturation by pulse oximetry may be falsely increased or decreased but is less than normal and less than the calculated value). lactic acidosis. Oxidation of hemoglobin protein causes hemoglobin precipitation and hemolytic anemia (manifest as Heinz bodies and “bite cells” on peripheral blood smear).and nitrosohydrocarbons. and tiagabine blocks GABA reuptake. orphenadrine. hydrogen sulfide Inhibition of mitochrondrial cytochrome oxidase. calcium oxylate crystalluria. Drug Overdose. Gastric aspiration for recent ingestions. Thiamine. oxcarbazepine. Intravenous methylene blue for methemoglobin fraction > 30%. Sodium bicarbonate to correct acidemia. All rights reserved. Causes GABA precursors Examples γ-Hydroxybutyrate (sodium oxybate. nitrites. and zonisamide slow the rate of recovery of inactivated sodium channels. normal PO2 and calculated oxygen saturation but decreased oxygen saturation by co-oximetry (that measured by pulse oximetry is falsely elevated but is less than normal and less than the calculated value). phenazopyridine. Some agents also have α2 agonist. Hemodialysis for persistent AGMA. anticholinergic. Signs and symptoms of hypoxia with initial physiologic stimulation and subsequent depression (Table e35-2). AGMA inducers Ethylene glycol Ethylene glycol causes CNS depression and increased serum osmolality. hypotension. γbutyrolactone (GBL). gray-brown cyanosis unresponsive to oxygen at methemoglobin fractions > 15–20%. methaqualone. and Envenomation Other agents Discordant Asphyxiants Cytochrome oxidase inhibitors Carbon monoxide. Chloral hydrate. seizures. Metabolites (primarily glycolic acid) cause AGMA.e290 TABLE e35-4 PATHOPHYSIOLOGIC FEATURES AND TREATMENT OF SPECIFIC TOXIC SYNDROMES AND POISONINGS (CONTINUED) Physiologic Condition. methocarbamol. Sudden collapse may occur with cyanide and hydrogen sulfide exposure. Baclofen. tizanidine and other imidazoline muscle relaxants. topiramate. crystalluria or renal dysfunction. (continued) Copyright © 2008 The McGraw-Hill Companies. ethylene glycol level > 3 mmol/L (20 mg/dL). symptomatic hypoxia. transport. valproate.4butanediol. Inhaled amyl nitrite and IV sodium nitrite and sodium thiosulfate (Lilly cyanide antidote kit) for coma. Headache and nausea are common with carbon monoxide. etomidate. and high-dose pyridoxine to facilitate metabolism. and tissue uptake (binding to hemoglobin shifts the oxygen dissociation curve to the left). nausea. GHB). Oxidation of hemoglobin iron from ferrous (Fe2+) to ferric (Fe3+) state prevents oxygen binding. methyprylon Mechanism of Action decreases GABA degradation. lamotrigine. Clinical Features Some agents can cause anticholinergic and sodium channel (membrane) blocking effects (see above and below). 1. vomiting. and renal dysfunction. back pain. lactic acidosis (at methemoglobin fractions > 45%). cyclobenzaprine. headache. metaxalone. dapsone. Delayed AGMA. and tissue uptake (methemoglobinemia shifts oxygen dissociation curve to the left). carbamazepine. metabolic acidosis. Hemodialysis also useful for enhancing ethylene glycol elimination and shortening duration of treatment when ethylene glycol level > 8 mmol/L (50 mg/dL). increased osmolar gap. primaquine-type antimalarials. ARDS in severe cases. Methemoglobin inducers Aniline derivatives. local anesthetics. and crystalluria. nitro. tissue edema. propafol. magnesium. and hydrogen sulfide smells like rotten eggs. High-dose oxygen. renal failure. sulfonamides. Ethanol or fomepizole for AGMA. CNS depression.

vomiting. Hypoglycemia. methanol level > 6 mmol/L (20 mg/dL). Sodium bicarbonate to correct acidemia. alkalemia. Non-transferrin-bound iron catalyzes formation of free radicals that cause mitochondrial injury. cardiovascular and CNS depression. IV hydration and supplemental glucose. Specific Treatments Whole-bowel irrigation for large ingestions. visual symptoms. increased capillary permeability. lack of clinical improvement. and for ethanol-like intoxication or increased osmolal gap if level not readily obtainable. some cyclic antidepressants and antihistamines. Endoscopy and gastrostomy if clinical toxicity and large number of tablets still visible on x-ray. Diazepam or barbiturates for seizures. Hemodialysis for coma. Methanol causes ethanollike CNS depression and increased serum osmolality. a cofactor for glutamic acid decarboxylase. dystonia. Subsequent alkalemia with both respiratory alkalosis and AGMA. and renal dysfunction. cardiovascular depression in severe cases. hypokalemia. and paradoxical aciduria. coma. salicylate level > 7 mmol/L (100 mg/dL) following acute overdose. IV hydration. (continued) Copyright © 2008 The McGraw-Hill Companies. visual (clouding. AGMA. inhibition of nicotine-adenine dinucleotide dependent lactate and hydroxybutyrate dehydrogenases resulting in substrate accumulation. Hemodialysis also useful for enhancing methanol elimination and shortening duration of treatment when methanol level > 15 mmol/L (50 mg/dL). Gastric aspiration for recent ingestions. pulmonary edema. Initial nausea. All rights reserved. Decreased CNS dopaminergic activity with relative excess of cholinergic activity. CHAPTER e35 Poisoning and Drug Overdosage Methanol Salicylate Increased sensitivity of CNS respiratory center to changes in PO2 and PCO2 stimulates respiration. and seizures can occur. hepatitis. High-dose folinic acid or folate to facilitate metabolism. IV deferoxamine for systemic toxicity. vasodilation. Formic acid metabolite causes AGMA and retinal toxicity. Ethanol or fomepizole for AGMA. and seizures. confusion. alkaluria. lactic and ketoacidosis in severe cases. progressive acid-base disturbances or clinical toxicity. which converts glutamic acid to GABA. agitation. Sodium bicarbonate for acidemia. diarrhea. blindness) and retinal (edema. Coma. Hemodialysis for persistent AGMA. and organ toxicity. Late acidemia with CNS and respiratory depression. Possible pancreatitis. spots. Interference with activation and supply of pyridoxal-5phosphate. vomiting. hyperemia) abnormalities. and seizures in severe cases. Alkaline diuresis for systemic toxicity. and stimulation of carbohydrate and lipid metabolism generate unmeasured endogenous anions and cause AGMA. seizures. coma. Sodium bicarbonate to correct acidemia. renal failure. coagulopathy. nausea. confusion. complexation with and depletion of pyridoxine itself. Akathisia. iron level > 90 μmol/L (500 μg/dL). seizures. vomiting.TABLE e35-4 PATHOPHYSIOLOGIC FEATURES AND TREATMENT OF SPECIFIC TOXIC SYNDROMES AND POISONINGS (CONTINUED) Physiologic Condition. parkinsonism Nausea. . Cerebral and pulmonary edema in severe cases. vomiting. abdominal pain. hyperventilation. lipid peroxidation. increased osmolar gap. CNS syndromes Extrapyramidal reactions Isoniazid Antipsychotics (see above). High-dose intravenous pyridoxine (vitamin B6 ) for agitation. Initial ethanol-like intoxication. Radiopaque iron tablets may be seen on abdominal x-ray. respiratory depression. Causes AGMA inducers e291 Examples Iron Mechanism of Action Hydration of ferric (Fe3+) ion generates H+. hypocalcemia. results in decreased levels of this inhibitory CNS neurotransmitter. Clinical Features Initial nausea. Uncoupling of oxidative phosphorylation. Oral or parenteral anticholinergic agent such as benztropine or diphenhydramine. inhibition of Kreb’s cycle enzymes. cerebral edema. seizures. Delayed AGMA.

Note: AGMA. tryptophan. myoclonus. which prolongs the QRS duration and promotes reentrant (monomorphic) ventricular tachycardia. flushing. carbamazepine. hyperthermia. Blockade of fast sodium membrane channels prolongs phase 0 (depolarization) of the cardiac action potential. and neurotransmitter release. central nervous system. opioids (meperidine. Consider endoscopic removal if high and rising drug level with progressive clinical toxicity. GABA. G6PD. adenylate cyclase and Na+. SIADH. syndrome of inappropriate antidiuretic hormone. fever. or persistent encephalopathy or neuromuscular dysfunction. Altered mental status (agitation. PREVENTION OF REEXPOSURE Poisoning is a preventable illness. Ic. diaphoresis. or direct stimulation of CNS and peripheral serotonin receptors (primarily 5HT-1a and 5HT-2). nausea. lactic acidosis. IV hydration. rigidity. Anticholinergic effects with amantidine. confusion. myoclonus. tinnitus. some β blockers). local anesthetics (including cocaine). falsely elevated serum chloride with low anion gap. diarrhea. Toxicity occurs at lower drug levels in chronic poisoning than in acute poisoning. ARDS. Promotion of serotonin release. coma. Causes Lithium Examples Mechanism of Action Interference with cell membrane ion transport. tremors). MAO inhibitors. dehydrogenase. tachycardia). Similar effects on neuronal membrane channels cause CNS dysfunction. orphenadrine. Patients should be advised to avoid circumstances that result Copyright © 2008 The McGraw-Hill Companies. Physostigmine for anticholinergic effects (see above). Clinical Features Nausea. peak lithium level > 8 meq/L (mmol/L) following acute overdose. Drug Overdose. severe. MAO. ventricular tachyarrhythmias. and overdrive pacing for polymorphic ventricular tachycardia. and Envenomation Serotonin syndrome Amphetamines. Extracorporeal removal for some agents (see text). seizures). nephrogenic diabetes insipidus. antipsychotics (see above). seizures. K+-ATPase activity. and prolonged or permanent encephalopathy and movement disorders in severe cases. arrhythmias. Unfortunately. diaphoresis) and blindness with quinoline antimalarials. meperidine. Delayed onset after acute overdose. ataxia. Lidocaine for monomorphic ventricular tachycardia (except when due to class Ib antiarrhythmics). inhibition of serotonin reuptake. glucose-6-phosphate Serotonin receptor antagonist such as cyproheptadine or chlorpromazine. seizures. nystagmus. antihistamines (particularly diphenhydramine). quinine). particularly with delayed-release formations. headache. Adults with unintentional exposures should be instructed regarding the safe use of medications and chemicals (according to labeling instructions). quinoline antimalarials (chloroquine. 388). Cinchonism (hearing loss. anion-gap metabolic acidosis. disopyramide. propoxyphene). ataxia. salivation. hydroxychloroquine. adult respiratory distress syndrome. dextromethorphan. monoamine oxidase. cyclic antidepressants (see above). Coma. hyperreflexia. prolonging the JT interval and promoting early afterdepolarizations and polymorphic (torsades des pointes) ventricular tachycardia. γ-aminobutyric acid. and recurrences are common. Opioid effects with meperidine and propoxyphene (see Chap. isoproterenol. alone or in combination. Errors in dosing by health care providers may require educational efforts. carbamazepine. PART 17 Poisoning. tachycardia. Confused patients may need assistance with the administration of their medications. seizures. mutism. and multisystem organ failure.e292 TABLE e35-4 PATHOPHYSIOLOGIC FEATURES AND TREATMENT OF SPECIFIC TOXIC SYNDROMES AND POISONINGS (CONTINUED) Physiologic Condition. Magnesium. tramadol. Membrane-active agents Amantidine. 388). Naloxone for opioid effects (see Chap. tearing. Complications include hyperthermia. QRS and JT prolongation (or both) with hypotension. . triptans. antihistamines. neuromuscular hyperactivity (hyperreflexia. vomiting. cocaine. flushing. Specific Treatments Whole-bowel irrigation for large ingestions. tricyclic antidepressants. selective serotonin (5HT) reuptake inhibitors. labile hypertension. choreoathetosis. Some agents also block α-adrenergic and cholinergic receptors or have opioid effects (see above and Chap. vertigo. Hypertonic sodium bicarbonate (or hypertonic saline) for cardiac conduction delays and monomorphic ventricular tachycardia. All rights reserved. 388). and cyclic antidepressants (see above). Hemodialysis for coma. and autonomic dysfunction (abdominal pain. vomiting. rhabdomyolysis. mydriasis. CNS depression. diarrhea. antiarrhythmics (class I and III agents. and III antiarrhythmics also block potassium channels during phases 2 and 3 (repolarization) of the action potential. CNS. progressive. Class Ia. encephalopathy. some adults and children are poison-prone. antipsychotics. Unintentional polypharmacy poisoning has become especially common among adults with developmental delays and among the growing population of geriatric patients who are prescribed a large number of medi- cations.

and vitamins should be kept out of reach or in locked or child-proof cabinets. 3d ed. nonedible plants. CURRY SC: Poisoning by sodium channel blocking agents. Philadelphia. Crit Care Clin 13:829. treatment should include attending to the general principles discussed above. 1975 FURTHER READINGS AMERICAN ACADEMY OF CLINICAL TOXICOLOGY/EUROPEAN ASSOCIATION OF POISONS CENTERS AND CLINICAL TOXICOLOGISTS: Position Statements on Gastrointestinal Decontamination: Introduction. Mosby. 2003 HADDAD LM et al (eds): Clinical Management of Poisoning and Drug Overdose. 1987 BURGESS JL et al: Emergency department hazardous materials protocol for contaminated patients. and follow-up. HENDERSON A et al: Experience with 732 acute overdose patients admit. Lippincott Williams & Wilkins. medications. 8th ed. 1983 LE BLAYE I et al: Acute overdosage with thioridazine: A review of the available clinical experience. KRIEGER GR: Clinical Environmental Health and Toxic Exposures 2d ed. Gastric lavage. household products (automotive. 1987 RUMACK BH (eds): Poisindex Information System (updated quarterly). . Arch Intern Med 147:133. 2006 SZTAJNKRYCER MD et al: Development and implementation of an emergency department observation unit protocol for deliberate drug ingestion in adults—preliminary results. Saunders. JAMA 249:762. KENNEDY HL: Torsades de pointes associated with drugs and toxins: Recognition and management. produce life-threatening toxicity. Am J Dis Child 138:737. Calif Med 118:1. PALMER BF: Simultaneous in series hemodialysis and hemoperfusion in the management of valproic acid overdose. 1993 OLSON KR et al: Physical assessment and differential diagnosis of the poisoned patient. Appropriate agencies and health departments should be notified in cases of environmental or workplace exposure. 2001 BARRY D et al: Phenothiazine poisoning: A review of 48 cases. cleaning. 1998 HARBISON RD (ed): Hamilton and Hardy’s Industrial Toxicology. clinical features. alcoholic beverages. Med Toxicol 2:52. 1993 LEE A: Treatment of drug-induced dystonic reactions. All rights reserved. and treatment of toxidromes and poisonings that are common. Clin Toxicol 44(6-7):803. Am J Ther 13(6):485. 2001 GOLDFRANK LR et al (eds): Goldfrank’s Toxicologic Emergencies. Drug Safety 8:81. the neuroleptic malignant syndrome is discussed in Chap. particularly supportive care. and heavy metal poisoning is discussed in Chap. Philadelphia. 743. Depressed or psychotic patients should receive psychiatric assessment. acetaminophen poisoning is discussed in Chap. Industrial. 2003 DART RC et al: Combined evidence-based literature analysis and consensus guidelines for stocking emergency antidotes in the United States. Louis. 1993 Antidotes BAILEY B: Are there teratogenic risks associated with antidotes used in the acute management of poisoned pregnant women? Birth Defect Res A Clin Mol Teratol 67(2):133. Antiarrhythmics KOLECKI PF. toiletry products). New York: Lippincott Williams & Wilkins. 1993 Barbiturates MATTHEW H: Barbiturates. Micromedex SULLIVAN JB. Whole bowel irrigation. 1983 MURPHY JM et al: Phenytoin intoxication. St. MATYUNAS NJ: Delayed toxidromes. Single-dose activated charcoal. e34. J Am Coll Emerg Phys 8:453. 1998 Copyright © 2008 The McGraw-Hill Companies. hallucinogen. 2007 BIBLIOGRAPHY REFERENCE TEXTS AND GENERAL PRINCIPLES BASELT RC: Disposition of Toxic Drugs and Chemicals in Man. In households where children live or visit. Am Heart J 113:1470. McGraw-Hill. 387 to 390. 699. Med Clin North Am 89(6):1379. CA. Int J Clin Pharmacol Ther Toxicol 18:523. South Med J 84:1199. They should be given prescriptions for a limited supply of drugs and with a limited number of refills and be monitored for compliance and response to therapy. Denver. New York. ODERDA GM: Jimsonweed intoxication in adolescents and young adults. Alcohol. The best approach with young children and patients with intentional overdose (deliberate self-harm or suicide) is to limit their access to poisons. Ann Emerg Med 35:374. 2000 MYCYK MB et al: Compliance with poison center fomepizole recommendations is suboptimal in cases of toxic alcohol poisoning. 1980 KLEIN-SCHWARTZ W. 753. Ann Emerg Med 36(2):126. 7th ed. VANCE MV: Massive diphenhydramine poisoning resulting in wide-complex tachycardia: Successful treatment with sodium bicarbonate. 1984 Anticonvulsants DUPUIS R et al: Acute valproic acid overdose. disposition. 721. 711. 5th ed. Ann Emerg Med 34:205. 1999 DART RC et al (eds): Ellenhorn’s Medical Toxicology 3d ed. Foster City. J Emerg Med 17:679. New York. In all cases.e293 ted to an intensive care unit over 6 years. Clin Toxicol 8(5):495. 2003 FORD MD et al (eds): Clinical Toxicology. 1987 Anticholinergics BURNS MJ et al: A comparison of physostigmine and benzodiazepines for the treatment of anticholinergic poisoning. Med J Aust 158:28. 1993 TANK JE. Am J Kidney Dis 22:431. 2007 GREENBERG MI et al (eds): Occupational. 2005 KLAASSEN CD (ed): Casarett and Doull’s Toxicology: The Basic Science of Poisons. pathogenesis. 1997 BOSSE GM. 2000 CLARK RF. 2005 Antipsychotics BURNS M: The pharmacology and toxicology of atypical antipsychotic agents. Louis. and management of drug-induced seizures. Clin Toxicol 35:695. St. 2006 RIES NL et al: New developments in antidotes. 366. or require unique therapeutic interventions. pet-care. 1979 WILT JL et al: Torsades de pointes associated with the use of intravenous haloperidol.in chemical exposure or poisoning. Vet Hum Toxicol 35:147. 2004 BRETT AS et al: Predicting the clinical course of intentional drug overdose: Implications for utilization of the intensive care unit. Chemical Toxicity Institute. Drug Safety 5:65. McGraw-Hill. 6th ed. 1999 BRUNTON L et al (eds): Goodman and Gilman’s The Pharmacologic Basis of Therapeutics. Mosby. Cathartics. cocaine. 1990 EARNEST M et al: Complications of intravenous phenytoin for acute treatment of seizures. and opioid poisoning and alcohol and opioid withdrawal are discussed in Chaps. Ipecac syrup. fuel. J Toxicol Clin Toxicol 39(1):1. 1991 SEYMOUR JF: Carbamazepine overdose. 1990 SPECIFIC POISONINGS AND TREATMENTS CHAPTER e35 Poisoning and Drug Overdosage SPECIFIC TOXIC SYNDROMES AND POISONINGS Table e35-4 summarizes the pathophysiology. Ann Intern Med 119:391. Saunders. 1997 STRATMAN HG. Poisonings not covered in this chapter are discussed in the referenced texts. 11th ed. Clin Toxicol (Phila) 45(5):499. New York. 299.com. Philadelphia. 2001 ZACCARA G et al: Clinical features. Details regarding specific therapies can be found in the references cited here and at harrisonsonline. McGraw-Hill. Ann Emerg Med 21:318. 2001 LAI MW et al: 2005 Annual Report of the American Association of Poison Control Centers National Poisoning and Exposure Database. Drug Safety 5:109. 1992 DAUNDERER M: Physostigmine salicylate as an antidote. and Environmental Toxicology.

1994 PEARIGEN PD. Circulation 81:1744. 1990 SMITH TW et al: Digitalis glycosides: Mechanisms and manifestations of toxicity. 1986 YEN D et al: The clinical experience of acute cyanide poisoning. Am J Emerg Med 21(4):333. Med Tox Adverse Drug Exp 4:32. 1995 WEAVER LK et al: Hyperbaric oxygen for acute carbon monoxide poisoning. 2004 SHANNON MW: Comparative efficacy of hemodialysis and hemoperfusion in severe theophylline intoxication. Ann Emerg Med 39(3):273. Clin Toxicol 44(S):1. 1984 KERNS W et al: β-blocker and calcium channel blocker toxicity. Ann Intern Med 37:290. N Engl J Med 339:1603. Emerg Med Clin North Am 12:365. N Engl J Med 340:832. J Toxicol Clin Toxicol 35(7):753. J Toxicol Clin Toxicol 32(3):233. ZIBRAK JD: Carbon monoxide poisoning. TROMMER L: Cyclic antidepressant overdoses: A review. Ann Emerg Med 20:536. 1990 PROUDFOOT AT: Position paper on urinary alkalinization. 2003 BOND GR: The role of activated charcoal and gastric emptying in gastric decontamination: A state-of-the-art review. Acad Emerg Med 4(7):674. 1999 THOM SR et al: Delayed neurological sequelae following carbon monoxide poisoning.e294 MCCARRON MM et al: Short-acting barbiturate overdosage: Correlation of intoxication score with serum barbiturate concentration. Ann Intern Med 119:273. new results from the prehospital emergency setting. 1993 Cyanide DART RC: Hydroxocobalamin for acute cyanide poisoning: New data from preclinical and clinical studies. Hum Exp Toxicol 13:161. 1994 Decontamination AMERICAN ACADEMY OF CLINICAL TOXICOLOGY AND THE EUROPEAN ASSOCIATION OF POISON CENTRES AND CLINICAL TOXICOLOGISTS: Position statement: Whole bowel irrigation. Ann Emerg Med 15:1067. Emerg Med Clin North Am 12:365. 2003 Industrial Exposures BOSSE GM: Nebulized sodium bicarbonate in the treatment of chlorine gas inhalation. 1977 HALL AH. J Toxicol Clin Toxicol 37(6):381. 1999 GARRETTSON LK. Ann Emerg Med 15:826. 1995 Cyclic Antidepressants BOEHNERT MT. 1984 Calcium Channel Blockers HOWARTH DM et al: Calcium channel blocking drug overdose: An Australian series. VIOLENCE. 2006 GRAHAM DL et al: Acute cyanide poisoning complicated by lactic acidosis and pulmonary edema. 1994 HOIDAL CR et al: Hydrogen sulfide poisoning from toxic inhalations of roofing fumes. BMJ 301:1308. 1986 MYCYK MB et al: A visual schematic for clarifying the temporal relationship between the anion and osmol gaps in toxic alcohol poisoning. Ann Emerg Med 13:1123. or…an antidote in search of an overdose. J Toxicol Clin Toxicol 42(1):1. 1992 THE FLUMAZENIL IN BENZODIAZEPINE INTOXICATION STUDY GROUP (Bayer MJ et al): Treatment of benzodiazepine overdose with flumazenil. and Envenomation Copyright © 2008 The McGraw-Hill Companies. 1984 (part II). 26:495. RUMACK BH: Clinical toxicology of cyanide. All rights reserved. Am J Emerg Med 2:518. Drug Overdose. MCMARTIN KE: Methanol and ethylene glycol poisonings: Mechanism of toxicity. Clin Ther 14:978. 2002 KULIG KW et al: Management of acutely poisoned patients without gastric emptying. Ann Emerg Med 26:195. 1984 (part I). Prog Cardiovasc Disc 26:413. diagnosis and treatment. 1986 JACOBSEN D. Ann Emerg Med 25:474. 1999 Carbon Monoxide ERNST A. Am J Emerg Med 13:524. JAMA 248:55. . GELLER RJ: Acid and alkaline diuresis: When are they of value in the treatment of poisoning? Drug Safety 5:220. 1995 PIMENTEL L. 1992 Beta Blockers CRITCHLEY JA. 1990 SPIVEY WH: Flumazenil and seizures: Analysis of 43 cases. randomized controlled study. Ann Intern Med 105:16. Med J Aust 170:203. N Engl J Med 347(14):1057. Drug Safety 6:408. 1992 LIEBELT EL et al: ECG lead aVR versus QRS in predicting seizures and arrhythmias in acute tricyclic antidepressant toxicity. 1997 SMITH SW et al: Whole-bowel irrigation as a treatment for acute lithium overdose. 1997 AMERICAN ACADEMY OF PEDIATRICS COMMITTEE ON INJURY. 1985 BORYS DJ et al: Acute fluoxetine overdose: A report of 234 cases. AND POISON PREVENTION: Poison treatment in the home. Am J Emerg Med 10:115. 1982 REED CE et al: Acute barbiturate intoxication: A study of 300 cases based on a physiologic classification of severity of the intoxication. 1998 SCHEINKESTEL CD et al: Hyperbaric or normobaric oxygen for acute carbon monoxide poisoning: A randomised controlled clinical trial. LOVEJOY FH JR: Value of the QRS duration versus serum drug level in predicting seizures and ventricular arrhythmias after an acute overdose of tricyclic antidepressants. 1991 YUAN TH et al: Insulin-glucose as adjunctive therapy for severe calcium channel antagonist poisoning. Arch Intern Med 137:1051. 1986 PART 17 Poisoning. 1989 HEATH A: α-Adrenoreceptor blocker toxicity: Clinical features and therapy. N Engl J Med 313(8):474. UNGAR A: The management of acute poisoning due to betaadrenoreceptor antagonists. 2002 Cardiac Glycosides ANTMAN EM et al: Treatment of 150 cases of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragments. Med Toxicol 1:309. 1994 WEINSTEIN RS: Recognition and management of poisoning with betaadrenergic blocking agents. Emerg Med Clin North Am 12:533. BENOWITZ NL: Poisoning due to calcium antagonists. 2000 HOJER J et al: Diagnostic utility of flumazenil in coma with suspected poisoning: A double-blind. clinical course. 1985 Enhanced Elimination AMERICAN ACADEMY OF CLINICAL TOXICOLOGY AND THE EUROPEAN ASSOCIATION OF POISON CENTRES AND CLINICAL TOXICOLOGISTS: Position statement: multi-dose activated charcoal in the treatment of acute poisoning. 27:26. 1952 Benzodiazepines GOLDFRANK LR: Flumazenil: a pharmacologic antidote with limited medical toxicology utility. 1984 (part III) UJHELYI MR et al: Influence of digoxin immune Fab therapy and renal function on the disposition of total and free digoxin. 1999 GABOW PA et al: Organic acids in ethylene glycol intoxication. 1991 Ethylene Glycol BRENT J et al: Fomepizole for the treatment of ethylene glycol poisoning. Ann Emerg Med 14(6):562. Acad Emerg Med 36(2):126. Clin Ther 14:292. Pediatrics 112(5):1182. 1996 KERNS W et al: β-blocker and calcium channel blocker toxicity. 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1994 Serotonin Syndrome BOYER EW: The serotonin syndrome. Drug Safety 5:195. 2002 PERRY HE et al: Baclofen overdose: Drug experimentation in a group of adolescents. 1999 Iron MILLS KC. All rights reserved. Emerg Med Clin North Am 12:397. 1983 MASON PE. N Engl J Med 348(18):1786. Emerg Med Clin North Am 12:351. 1994 BRYANT SM et al: Pretreating rats with parenteral ophthalmic anti. 1994 Isoniazid HOLDINESS MR: Neurological manifestations and toxicities of antituberculosis drugs—a review. Med Toxicol 1:253. 1998 SING K et al: Chloral hydrate toxicity from oral and intravenous administration. Pediatrics 101(6):1045.e295 muscarinic agents decreases mortality from lethal organophosphate poisoning. Acad Emerg Med 14(4):370. Pharmacol Ther 58:51. 2003 CHAPTER e35 Poisoning and Drug Overdosage Copyright © 2008 The McGraw-Hill Companies. 1988 PARK GD et al: Use of hemoperfusion for treatment of theophylline intoxication. Ann Emerg Med 37(2):147. 1993 SIVILOTTI ML et al: Multiple centrally acting antidotes protect against severe organophosphate toxicity. RODVOLD KA: Evaluation of theophylline overdoses and toxicities. Crit Care Clin 13:923. 2007 HOLSTEGE CP et al: Chemical warfare: Nerve agent poisoning. Ann Emerg Med 11:214. 1996 Organophosphate and Carbamate Insecticides BARDIN PG et al: Organophosphate and carbamate poisoning. 1987 TEMPLE AR: Acute and chronic effects of aspirin toxicity and their treatment. Ann Emerg Med 34(1):35. 2003 Sympathomimetics AARON CK: Sympathomimetics. 1981 Methemoglobinemia CURRY S: Methemoglobinemia. 1990 Methanol BURNS MJ et al: Treatment of methanol poisoning with intravenous 4methylpyrazole. Ann Pharmacother 30:527. 1988 WIJETUNGA M et al: Acute coronary syndrome and crystal methamphetamine use: A case series. 2003 SWARTZ RD et al: Epidemic methanol poisoning: Clinical and biochemical analysis of a recent episode. 1997 JACOBSEN D. N Engl J Med 319(11):673. Am J Med 74:961. Clin Toxicol 20:281. Emerg Med Clin North Am 12:511. 2006 Pharmacogenomics ENSOM MH et al: Pharmacogenetics: The therapeutic drug monitoring of the future? Clin Pharmacokinet 40(11):783. 2001. MCMARTIN KE: Methanol and ethylene glycol poisoning: Mechanism of toxicity. Clin Toxicol 34:101. J Adolesc Health 40(1):76. 2006 TRAUB SJ et al: Body-packing—the internal concealment of drugs. O’CONNOR PG: Management of drug and alcohol withdrawal. 1994 LINDEN CH et al: Cyclobenzaprine overdose. Clin Toxicol 32:391. Arch Intern Med 154:1433. 2003 Lithium BAILEY B. 1986 MYCYK MB et al: A visual schematic for clarifying the temporal relationship between the anion and osmol gaps in toxic alcohol poisoning. Ann Emerg Med 17(2):135. clinical course. . 2005 MCCABE SE et al: Medical and non-medical use of prescription drugs among secondary school students. N Engl J Med 352(11):1112. diagnosis and treatment. 1986 Muscle Relaxants and Sedative-Hypnotics GARNIER R: Acute zolpidem poisoning: Analysis of 344 cases. 1981 YIP L et al: Concepts and controversies in salicylate toxicity. 1987 ORLOWSKI JP et al: Treatment of potentially lethal dose isoniazid ingestion. JAMA 252:1898. 1981 PENTEL P: Toxicity of over-the-counter stimulants. 2003 WARNER EA: Should informed consent be required for laboratory testing for drugs of abuse in medical settings? Am J Med 115(1):54. Emerg Med Clin North Am 8:513. 1997 MARRS TC: Organophosphate poisoning. N Engl J Med 349(26):2519. Acad Emerg Med 13(4):359. J Emerg Med 16:615. MCGUIGAN ML: Comparison of patients hemodialyzed for lithium poisoning and those for whom dialysis was recommended by PCC but not done: What lesson can we learn? Clin Nephrol 54(5):388. CURRY SC: Acute iron poisoning. Med Toxicol 1:309. SIMON RR: Management of salicylate intoxication. 1999 BOYER EW et al: Which drug tests in medical emergencies? Clin Chem 49(3):353. Am J Emerg Med 21(4):333. Ann Emerg Med 17:73. 1998 Substance Abuse BOYER EW et al: The internet and psychoactive substance use among innovative drug users. Pharmacotherapy 26(1):1501. Arch Intern Med 141:364. 1990 CATRAVS JD. J Pharmacol Exp Ther 217(2):350. 1982 HALL AH et al: Drug. 1984 ROTH D et al: Acute rhabdomyolysis associated with cocaine intoxication.and chemical-induced methaemoglobinaemia. WATERS IW: Acute cocaine intoxication in the conscious dog: Studies on the mechanism of lethality. Acad Emerg Med 9(7):730. Hawaii Med J 63(1):8. 2000 GROLEAU G: Lithium toxicity. 1988 Laboratory Evaluation BELSON MG et al: The utility of toxicologic analysis in children with suspected ingestions. Pediatr Emerg Care 15(6):383. 1983 Withdrawal DYER JE et al: Gamma hydroxybutyrate withdrawal syndrome. KOSTEN TR. KERNS WP 2ND: Gamma hydroxybutyric acid (GHB) intoxication. 2005 BROWN TM et al: Pathophysiology and management of the serotonin syndrome. 2001 GASCHE Y et al: Codeine intoxication associated with ultra-rapid CYP2D6 metabolism.KAO WF et al: Ingestion of low concentration hydrofluoric acid: An insidious and potentially fatal poisoning. 1994 MAO Inhibitors LIPPMAN SB. Ann Emerg Med 30:829. Pediatrics 115(2):302. Medicine 60:373. 2004 Salicylates BRENNER BE. Med Toxicol 2:33. 2007 TETER CJ et al: Illicit use of specific prescription stimulants among college students. 2004 Theophylline PALOUCEK FP. NASH K: Monoamine oxidase inhibitor update: Potential adverse food and drug interactions. 1996 GRAUDINS A et al: Treatment of the serotonin syndrome with cyproheptadine. N Engl J Med 351(27):2827. Drugs 24:335.

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many novel biomarkers may be identified by genomic and proteomic analyses of COPD samples in the future. on occasion. or a single biopsy at the end of active treatment with a biopsy in a parallel group of patients taking placebo therapy. these lymphocytes express chemokine receptors associated with a type 1 response.e36 Pulmonary Biomarkers in COPD Peter J. inhaled glucocorticoids seem to have little effect on the airway inflammation typical of COPD. New assays may have greater sensitivity and assay reproducibility. there is increased activation of the transcription factor nuclear factor-κB (NF-κB) in bronchial epithelial cells of COPD patients. IL-5. vessels. All rights reserved. Several studies have assessed the potential anti-inflammatory effects of treatments in bronchial biopsies of patients with COPD. and the pattern of inflammation differs substantially from that described in asthma (Table e36-1). Bronchial biopsies are useful for documenting the structural changes. it is not observed at the tissue level. sputum. there is a pressing need to identify reliable biomarkers that may indicate whether an anti-inflammatory therapy is likely to have clinical benefit. With the development of many new drugs that target inflammation in COPD. CC chemokine receptor. The biopsy of proximal airways may not closely reflect all the pathologic changes present in peripheral airways and lung parenchyma. For example. further studies are required to establish whether the airway inflammation in COPD can be successfully suppressed (as with glucocorticoids in asthma) and whether this would result in significant clinical improvement. apoptosis or uncontrolled proliferation. which is associated with upregulation of specific chemoattractants. ease of assay. tissue) that reflects the disease process. Unfortunately. basement membrane. however. thus allowing investigation of interactions between inflammatory and resident cells. chemokines. interferon. it may be difficult to recruit patients. in addition. Moreover. In COPD. Unlike sputum and BAL.6 These changes in bronchial biopsies reflect the changes in NF-κB and HDAC found in lung parenchyma. A major barrier is the lack of any “gold standard” antiinflammatory therapy that is effective in COPD.2 A meta-analysis of biomarker measurements in 150. There is also a reduction in T cells expressing CCR5 in COPD. and exhaled breath are considered. as a yardstick to compare potential therapies. bronchoalveolar lavage (BAL). mediators. such as epithelium. CCR.and posttreatment). CXCL10. Here. particularly of CD8+ T lymphocytes. IL-13. During exacerbations of the disease. and expression of inflammatory proteins in patients with COPD. This means that biomarkers of structural modification. mast cells CD4+ T lymphocytes Eosinophils and neutrophils during exacerbations Neutrophils in severe disease IL-4. bronchial biopsies appear to reflect at least some of the cellular abnormalities described in peripheral lung tissue. cellular patterns. connective tissue. such as CCL5 (RANTES) and CXCL5 (ENA-78). especially in multicenter studies involving large numbers of patients. but these changes have not been related to functional or clinical improvements. an increased recruitment of eosinophils and neutrophils has been described.3 More research in this area is now needed with repeated measurements in carefully phenotyped patients. Overall. as a result. and IL-9. the primary sites responsible for airflow limitation in COPD. IL-9. serum tumor necrosis factor (TNF) α. as are inhaled glucocorticoids in asthma. CXCL. It is likely that some biomarkers will prove to be much more useful than others in terms of reproducibility of measurement. and predictability for assessing therapeutic efficacy. interleukin. Problems There are. and C-reactive protein (CRP) showed any trend towards separating different stages of COPD. except in patients with severe airflow limitation. TABLE e36-1 MORPHOLOGIC CHANGES IN BRONCHIAL BIOPSIES OF PATIENTS WITH COPD AND ASTHMA COPD Reticular basement membrane thickness Inflammatory cell infiltrate Within normal range Macrophages CD8+ T lymphocytes Eosinophils and neutrophils during exacerbations Neutrophils in severe disease IFN-γ. there are many possible biomarkers to study with a high degree of redundancy. Since this is an invasive procedure. BRONCHIAL BIOPSIES Although the inflammation in COPD involves predominantly lung parenchyma and small airways. bronchial biopsies provide an assessment of structural components of the airway wall. which express interferon (IFN) γ. biomarkers in bronchial biopsies.1 Pulmonary inflammation in COPD appears to increase with disease progression and increases during exacerbations. several types of biomarker have been measured that are related to disease pathobiology and the inflammatory and destructive process in the lung. with increased production of multiple inflammatory mediators. These studies usually involve either a baseline biopsy and then a second biopsy after a defined period of treatment. maintaining the spatial relationships of structural components that may be important for functional changes. IL-9. it may not be possible to apply this procedure to pa- CHAPTER e36 Pulmonary Biomarkers in COPD Copyright © 2008 The McGraw-Hill Companies. While a prominent neutrophilia is present in the airway lumen of stable patients with COPD. few of these biomarkers have been validated. and enzymes are involved in the complex pathobiology of COPD. CXCL10 (IP-10). such as CXCR3. The main advantage of endobronchial biopsies is that they directly sample airway tissue. Moreover.5 There is also a reduction in histone deacetylase (HDAC) activity and HDAC2 expression in bronchial biopsies of COPD patients compared to normal smokers and nonsmokers. CXCR3 e297 Asthma Increased Eosinophils. CXC chemokine ligand. which increases with disease severity. Bronchial biopsies may give some insights into disease pathogenesis. especially in studies investigating treatment effects that require two biopsies (pre. COPD involves a specific pattern of inflammation in the respiratory tract and lung parenchyma. IL.1 A biomarker refers to the measurement of any molecule or material (cells. the different inflammatory cell subtypes can be identified by immunohistochemistry in their microenvironment. However. although they are able to reduce mast cells. Some biomarkers are more easily measurable and reliable than others and are more easily applied in clinical studies. and. there is increased infiltration of macrophages and activated T lymphocytes.4 In stable COPD. which express chemokine receptors typical of a type 2 response (chemokine receptor CCR4). in contrast to lymphocytes in asthma. Greater anti-inflammatory effects have been obtained after treatment with either a phosphodiesterase (PDE) 4 inhibitor or with the combination of a glucocorticoid and a longacting β2-agonist. and. CCR4 Cytokines.000 patients with COPD revealed the poor sensitivity of current biomarkers to define clinical status and quantify the effect of treatment. interleukin (IL) 8. and there is little information about their reproducibility and the relationship to disease severity or progression. individual structural components can be dissected from the biopsies and studied in isolation using techniques recently developed. . Many inflammatory cells. such as laser microdissection. several limitations to analysis of bronchial biopsies to assess outcome in COPD. smooth muscle and submucosal glands. can be measured. relationship to disease severity. and receptors Abbreviations: IFN. Barnes INTRODUCTION There has been increasing interest in using pulmonary biomarkers to understand and monitor the inflammation in the respiratory tracts of patients with chronic obstructive pulmonary disease (COPD). an effect associated with a reduction in the frequency of exacerbations. Moreover. and this change is correlated with a reduction in NFκB activity and increased expression of inflammatory genes. Finally. Only sputum neutrophils.

airflow obstruction is often observed and cannot be prevented by premedication with β2-agonists. eosinophils (the latter predicting a greater likelihood of response to glucocorticoids).7 BAL may be performed in the same patients as bronchial biopsy. Proteases and antiproteases are also detectable in BAL fluid: there is an increase in total elastase activity and a decrease in antielastase activity in COPD patients compared to normal smokers. Quantification of biomarkers in supernatant is a problem as there is no satisfactory marker to account for the dilutional effect of the saline lavage. in a healthy population. for various periods of treatment on inflammatory cell counts and mediators in BAL. some studies have shown that patients with COPD have higher eosinophil percentages than healthy smokers. Effects of Therapy There are few published studies of the effects of treatments on cellular and mediator components of BAL. Alveolar macrophages. higher levels of neutrophil elastase-α1 protease inhibitor complexes in BAL fluid have been significantly associated with accelerated decline in FEV1. including TNF-α and CRP. such as TNF-α.9 Neutrophils have been studied most extensively and are increased in number in COPD patients compared to those in matched smokers with normal lung function. however. few have been related to disease severity or progression. Higher concentrations of inflammatory cytokines. No other studies have compared smokers and ex-smokers with COPD. The reduction in HDAC2 is associated with increased activation of the NF-κB. these studies suggest that there may be a reduction in percentages of neutrophils and lymphocytes with inhaled glucocorticoid treatment. Levels of eosinophil cationic protein (ECP). but there appears to be a reasonably good reproducibility of cells and mediators in long-term repeatability studies. Numbers of lymphocytes are generally higher in ex-smokers than in smokers. are reported in patients with more severe compared to less severe COPD. In general. BRONCHOALVEOLAR LAVAGE BAL has the advantage. myeloperoxidase (MPO). Moreover.8 It should be recognized that “sputum” obtained after inhaling nebulized hypertonic saline may have a different composition than mucus and may be more similar to proximal airway washings. Problems BAL is an invasive procedure and may cause more discomfort to the patients than bronchial biopsy. however. Studies investigating individuals with COPD. is increased in COPD patients compared to smokers. Only one study has investigated the association between the severity of COPD and BAL inflammation. from COPD patients behave abnormally in tissue culture. Mediators Many mediators have been reported to be increased in the sputum supernatant of COPD patients. but that the activation state of these cells with accompanying mediator release may be important. with a further increase during exacerbations. This inflammation seems to be the result of macrophage and neutrophil activation. Effect of Smoking and Disease Severity In one study. longterm studies in larger populations are needed. Studies investigating other mediators have not been replicated and are not discussed here. Sputum concentrations are unaffected by glucocorticoids but are reduced by theophylline. suggesting that smoking induces the changes. Some studies have investigated the effects of smoking cessation on BAL composition. Finally. with progressive reduction with disease severity. It may be possible in the future to study the effects of treatment in patients on cellular behavior in vitro. one open label and two double-blind. including TNF-α. This is one of the factors that may contribute to the variability in measurements and the necessity for relatively large numbers of patients. provided careful assessment is performed and guidelines are followed.e298 tients with more severe disease. For this reason. Mediators and Proteases Several inflammatory mediators can be measured in BAL fluid. CD8+ T cells are increased in the induced sputum of COPD patients. SPUTUM Many COPD patients produce suitable sputum spontaneously. with an increase in the number of total inflammatory cells and in the percentage of neutrophils. There is also a relatively high variability in baseline measurements of inflammatory cells. and. This also suggests that the number or percentage of cells is not a prerequisite for development or progression of emphysema.2 Sputum IL-8 has been studied most extensively. the number of inflammatory cells did not correlate with lung function decline over a 4-year follow-up. however. All rights reserved. and exsmokers show that smoking is generally associated with increased numbers of neutrophils. Alveolar macrophages also show a reduction in expression and activity of HDAC2. thus providing additional and complementary information. and matrix metalloproteinase (MMP) 9. ex-smokers with COPD had lower mast cell numbers in BAL than ex-smokers without COPD. Cells There is an abnormal pattern of inflammatory cells in COPD patients. assessed the effect of different types of inhaled glucocorticoids. The recovery of fluid is often reduced in COPD patients. There is little information about the reproducibility of differential cell counts in induced sputum of COPD patients. with some neutrophils and T lymphocytes. precluding firm conclusions. which necessitates multiple biopsies. with or without COPD. and may be further increased with exacerbations. and showed that healthy smoking men with a near normal FEV1 show signs of inflammation in the lower airways that are related to a decrease in lung diffusion (DLCO) and to emphysematous lesions on high-resolution CT. complicated by cardiac comorbid conditions and often associated with significant oxygen desaturation and hypercapnia. resulting in samples that are inadequate for analysis. The procedure is tolerated by patients with FEV1 >30% predicted. and IL-6. The percentages of macrophages and neutrophils are usually higher than in healthy nonsmokers and healthy smokers. is related to disease severity (FEV1 % predicted). Three studies. fluid recovery is greater in patients with less extensive emphysema as assessed by diffusion capacity. and some patients having increased numbers of eosinophils. which may be separated by adhesion and cultured in vitro for functional studies. In contrast. in some patients. . with increased expression of inflammatory proteins. An increased number of eosinophils may indicate concomitant asthma and appears to predict the patients who show a larger bronchodilator response and improvement with glucocorticoids. compared to healthy nonsmokers. Leptin is detectable in the induced sputum of COPD patients and is correlated with other inflammatory markers. BAL can generally be safely performed. and most show a greater increase in COPD than in smokers without COPD. as assessed by mediators measured in BAL. Cellular Composition The cellular composition in individuals with COPD is predominantly (>80%) alveolar macrophages. PART 18 e-Chapters from International Advisory Editors Copyright © 2008 The McGraw-Hill Companies. IL-8. since studies evaluating the effect of treatment should be designed to provide a power of at least 80%.2 Although the numbers of patients involved were small. it may also cause transient fever. induced sputum has usually been the procedure of choice. Most studies have shown no change in inflammatory cells with inhaled or oral glucocorticoids. but spontaneously produced sputum may contain a high proportion of dead cells. particularly macrophages. A significant reduction in neutrophils with low-dose oral theophylline has been reported. a large number of patients for each treatment group is usually required. showing inconsistent decreases in cell numbers. which potentially give misleading cell counts and mediator measurements. unlike bronchial biopsies. confirming the imbalance between proteases and antiproteases. and IL-8 are increased in COPD patients and in healthy smokers. Several studies have reported the effects of drugs on sputum neutrophils. Increased concentrations of TNF-α and soluble TNF receptors are found in sputum of COPD patients compared to that in normal smokers. rather than COPD itself. healthy smokers. IL-8. of sampling inflammation in the lung periphery. which modulates the expression of inflammatory genes.

A recent study reported increases in the concentrations of proinflammatory cytokines. Assays are usually performed using enzyme-linked immunosorbent assay. but only malondialdehyde is increased in COPD patients compared to smokers without COPD. are related to disease severity. this suggests increased degradation of extracellular matrix in COPD. The isoprostanes represent a family of isomers that are derived from the nonoxidative metabolism of arachidonic acid and are stable biomarkers of oxidative stress. there are important issues about reproducibility and sensitivity that need to be addressed before this approach can be recommended as a routine outcome measurement. and is related to disease severity. CHAPTER e36 Pulmonary Biomarkers in COPD EXHALED GASES Measuring biomarkers in the breath is a very attractive approach to monitoring inflammation in COPD as it is noninvasive and makes repeated sampling possible. conventionally measured FENO is less useful as the levels are usually normal or only slightly elevated. Hyaluronan. so that it is possible to partition airwayderived NO. however. a component of extracellular matrix. Solubilization of sputum with dithiothreitol (DTT). including neutrophil elastase. which disrupts sulfhydryl bonds. EXHALED BREATH CONDENSATE Many mediators have now been detected in exhaled breath condensate (EBC). is found in higher concentration in the sputum of COPD patients than in the sputum of smokers without COPD and nonsmokers. and these assays have been validated using gas chromatography–mass spectrometry for some mediators. 8-Isoprostane is a stable marker of oxidative stress and is also increased in EBC of COPD patients. and (2) the low concentrations that may be near to the detection limits of the assays used. repeated sampling within this period is not possible. Concentrations of ethane are elevated in patients with COPD and correlate with disease severity. and steroid responsiveness. and there is a decrease in pH in EBC of COPD patients. An increase in FENO in COPD patients is correlated with increased numbers of eosinophils. this is likely to be due to the increase in oxidative stress. from peripheral NO derived from endothelium via the alveoli and probably from small airways. and TNF-α. and the effects of treatment are now needed. relationship to disease severity. IL-6. there is an increase in peripheral NO that is related to disease severity. the signal is low and the measurement is also confounded by highly variable environmental CO levels and the effects of passive smoking. may alter proteins so that they are not recognized by antibodies. including IL-1β. including cytokines and enzymes. All rights reserved. Increased nitrative stress in COPD is indicated by increased concentrations of nitrite and S-nitrosothiols in EBC. and MMP-12. although there was a reduction in tachykinins noted during exacerbations of COPD in one study.11 Several factors affect the measurement. especially in patients with the lowest FEV1 values. Chemokines cannot be reliably measured in EBC. Measurement of ethane by gas chromatography–mass spectrometry offline is difficult and thus unlikely to be useful in clinical trials. Sputum induction with hypertonic saline promotes neutrophilic inflammation that persists for 24 h and. and this may relate (1) to the extensive variable dilution that occurs from water vapor during condensation. Nitric Oxide Exhaled nitric oxide (FENO) has been extensively investigated in asthma and shown to correlate with airway inflammation and to be reduced by glucocorticoid therapy. particularly in COPD. Copyright © 2008 The McGraw-Hill Companies. There is considerable variability in exhaled pH in COPD patients. smaller and more sensitive detectors for hydrocarbons are now in development. Using this technique it is possible to show that while airway NO is low or normal in COPD. Hydrocarbons Volatile hydrocarbons. No differences in the concentrations of the tachykinins substance P and neurokinin A were found in COPD patients compared with smokers without COPD and nonsmokers. Increased prostaglandin E2 and IL-6 have also been reported in COPD patients. Recent studies using dialysis to remove DTT and protease inhibitors show that it is possible to increase markedly the concentrations of several cytokines in induced sputum of COPD patients. Recently. MMP-9. Induced sputum samples predominantly derive from large airways and may not reflect the peripheral inflammation that may be important for clinical outcomes in COPD. MMP-9 is increased more in COPD patients with CT evidence of emphysema than in patients of similar respiratory functional severity without evidence of emphysema. More work is needed on long-term reproducibility in COPD patients. MMP8.Increased concentrations of proteases have been reported in the sputum of patients with COPD. and recommendations have recently been formulated by an ERS/ATS task force. Oxidative/Nitrative Stress Hydrogen peroxide (H2O2) is increased in EBC of COPD patients. Peripheral NO may prove to be a useful noninvasive biomarker of COPD inflammation. Most proteins. . cannot reliably be measured in EBC. an increased bronchodilator response. during exacerbations of COPD. Importantly. however. studying the effect and duration of exacerbations and correlating individual biomarkers with disease severity and progression. thus. The measurement is highly reproducible in normal and asthmatic subjects if careful attention is paid to technique. but reproducibility was not reported. this is a particular problem with several cytokines and chemokines. Certain aldehydes resulting from lipid peroxidation are also increased in COPD patients. This observation also explains why FENO is reduced in normal smokers.10 Sputum markers of structural changes in the airways have been difficult to identify. and it remains elevated in sustained ex-smokers. the measurement of FENO has been extended by making measurements of exhaled NO at different flows. except during exacerbations. Problems Although induced sputum samples are relatively easy to obtain in COPD patients and give a lot of information about inflammatory cells and mediators. A limitation of the technique is the variability of the measurement and the low concentrations of mediators (often close to the limits of detection). but it is also elevated in normal smokers owing to the high CO content in cigarette smoke. Exhaled H2O2 is reported to be reproducible in repeated measurements over 3 days. there are several problems that need to be addressed. which is further increased during exacerbations. Correction for the variable dilution is one approach. which is flow-independent. There is an increase in the concentration of leukotriene (LT) B4 in COPD patients.11 However. which is greater than in normal subjects. proteases in sputum. have been detected in exhaled breath and are biomarkers of lipid peroxidation as a result of oxidative stress.12 This may reflect the increase in inducible NO synthase in the lung periphery of patients with COPD. Carbon Monoxide Although it is easy to measure carbon monoxide e299 (CO) in the breath this has not turned out to be as useful a measurement as FENO. which has the advantage that it is easy to perform and completely noninvasive. is further increased during exacerbations. In COPD. exhaled CO is elevated to a greater extent in COPD patients than in matched smokers without COPD. and are further increased during exacerbations. and the lower pH has been ascribed to increased acidity of salivary contaminants. and thus may be useful in detecting associated asthma. may degrade certain protein mediators. Mediators Inflammation is associated with tissue acidification. It is not yet clear how most of these biomarkers relate to disease severity. such as ethane and pentane.13 Concentrations of 8-isoprostane are greater in COPD patients than in smokers without COPD. Furthermore. Problems There is a relative high variability in repeated measurements of EBC biomarkers. Further work is needed to optimize these measurements and to determine the causes of variability. resulting in formation of peroxynitrite and nitrate so that NO is removed from the gaseous phase. but further studies on reproducibility. Exhaled CO is elevated in patients with COPD.

George’s respiratory questionnaire (SGRQ). and further studies addressing several of the issues raised in this chapter are already in progress. BAL may provide more information about peripheral inflammation. as these patients do not respond well to glucocorticoids. Bronchial biopsies provide valuable information about inflammatory cells and mediators. e. with or without a patient-centered clinically meaningful endpoint. However. it is important to identify biomarkers that indicate the efficacy of the drug on components of the inflammatory process before proceeding to large and prolonged clinical trials. There are several types of drugs that can be developed for COPD based on whether the drug is intended to improve airflow obstruction. functional capacity. based on which a rational decision can be made on further development of the drug. With the possible exception of a drug that is intended to improve airflow obstruction.or physician-reported symptom severity. or for predicting response to therapy. provide symptom relief. scores based on patient. and this further underscores the need of development of biomarkers.. often extending to many years. Bronchial biopsies and BAL provide important information about cellular composition but cannot be repeated.g. and its invasiveness precludes repeated measurements. their clinical relevance is far from certain. there is a relative lack of information about how they relate to disease severity. there is little information at present about how they relate to other outcome measurements in COPD. What is of critical importance is to ensure that there are carefully matched control groups (smokers and nonsmokers) and that the COPD patients are phenotypes in as much detail as possible. test of exercise capacity. such as rate of decline in FEV1. measurement of sputum eosinophils and FENO may be very useful in clinical practice in identifying the patients with COPD who have concomitant asthma and who may respond better to bronchodilators and inhaled glucocorticoids. and noninfective mechanisms. drugs of other types will likely require prolonged studies. or modify lung structure. ideally with detailed lung function assessments (including lung volumes and gas transfer). For assessment of anti-inflammatory treatments. e. identifying populations that are more likely to benefit from a drug. can be used in early phase studies. Biomarkers can facilitate drug development in a number of ways. For all of these biomarkers. providing “go/no-go” decisions at early stages of the drug development process. Because no effective anti-inflammatory treatments for COPD currently exist. The recent demonstration by CT scan that MMP-9 is some ninefold higher in COPD patients with emphysema than in those without indicates that sputum biomarkers may be useful in the future in discriminating parenchymal disease from small-airway involvement. It is not yet clear whether pulmonary biomarkers will be able to discriminate these two pathophysiologic processes. treadmill or cycle ergometry. which may be difficult using physiologic parameters that are likely to improve only very slowly. progress is now being made in asthma. assessment of an anti-inflammatory drug will require the measurement of inflammatory cells and specific inflammatory mediators. The effect of smoking itself is rarely documented. modify or prevent exacerbations. biomarkers. This uncertainty makes it important to develop reliable biomarkers to quantify inflammation in COPD patients and to validate these against some other measure of disease activity and progression. Medical Research Council dyspnea score.g. The technique probably samples more proximal airways and thus may not reflect the inflammatory process in the lung periphery. Clinical Perspective Although many pulmonary biomarkers have been described in COPD patients. Mahler baseline dyspnea index (BDI)/transitional dyspnea index (TDI). Similar studies have not been done in COPD patients. and mortality. these biomarkers are reflective of the disease and have potential use for regulatory purposes. whereas assessment of an antioxidant may require measurements of oxidative stress and an antiprotease will require measurement of protease activity. they may not reflect all pathologic changes in the periphery of the lung that appear to be more important in COPD. However. how reproducible they are. The biomarkers selected for measurement will depend on the nature of the study. for predicting disease progression.g. viral. such as proof-of-action or proof-of-concept studies. Exhaled biomarkers are noninvasive and may be repeated but are technique-dependent and have a relatively high variability. alter disease progression. Examples of such endpoints include pulmonary function tests. These studies become rather risky expensive endeavors. it is not certain how much and how rapidly clinical parameters will change in patients. Biomarkers can also be used in either early phase studies or phase 3 studies to support the drug’s putative mode of action. health-related quality-of-life (QOL) instruments. such as improvement of symptoms. Patients with mixed asthma and COPD and patients who have COPD without smoking also need to be characterized.. or even help elevate a biomarker to a surrogate endpoint status. it is possible that inflammatory cells in sputum may be used to monitor the response to treatment. . In addition. In the future it is possible that patterns of pulmonary biomarkers may predict exacerbations. but there are problems of quantification of mediators because of variable dilution and the same problems as with biopsies in reproducibility. discriminating between bacterial.. Nevertheless. and high-resolution CT scanning. All rights reserved. There is a need for comparison of all pulmonary biomarkers in COPD patients with those in smokers without airflow limitation but matched for smoke exposure (pack-years) and also with those in age-matched nonsmoking control subjects. and may reflect different mechanisms of exacerbations. None of the approaches described in this chapter are in routine use for the diagnosis of COPD. and how they may be affected by concurrent therapies. St. In addition.10 How other biomarkers relate to the phenotype of COPD deserves further investigation. whereas induced sputum and exhaled markers are repeatable. exacerbation frequency. e. However. COPD involves small airway inflammation and fibrosis as well as alveolar destruction. where monitoring sputum eosinophils and FENO appears to improve control of asthma and at the same time reduce steroid requirements. For example. chronic respiratory disease questionnaire (CRQ). Which Biomarker? The choice of which pulmonary biomarker is measured will depend on the research question posed or the clinical problem that is being addressed. Induced sputum is a valuable procedure giving information about cells. and ex-smokers may have a different profile of biomarkers than active smokers. and predicting safety problems. This is an active research area. identifying criteria for dose selection for phase 2 and phase 3 studies. Carefully selected biomarkers. activity scales. Borg scale. use of the biomarkers in phase 3 studies in conjunction with clinically meaningful endpoints may help validate the use of the biomarker. and markers of oxidative/nitrative stress. or survival.e300 USE OF BIOMARKERS TO ASSESS RESPONSE TO THERAPY Many drugs are now in development as potential anti-inflammatory therapies for COPD. such as providing evidence that a drug can reach its target and modify that target in some positive way. as they do in asthma. as well as the spatial relationships between the inflammatory process in the airway wall. The biomarkers described elsewhere in this chapter are not sufficiently validated to date for use as evidence of efficacy in phase 3 studies or for supporting specific labeling claims. whose efficacy can be relatively easily assessed by measuring FEV1 in short-term studies. but standardization of the technique is important to reduce the high variability in the Copyright © 2008 The McGraw-Hill Companies. measurement of free fat mass. and death. When more effective anti-inflammatory treatments become available for COPD patients. Prediction of steroid responsiveness may be given by increased FENO and sputum eosinophils. Correlation of PART 18 e-Chapters from International Advisory Editors OVERVIEW Many biomarkers of inflammation and oxidative/nitrative stress have now been measured in the airways of patients with COPD using a variety of techniques of differing invasiveness. mediators. exercise performance. The efficacy endpoints that are currently used in phase 3 studies to support registration of a drug for COPD are based on measures that translate to direct benefit of some aspects of the disease that is clinically meaningful to patients.

Franciosi LG et al: Markers of disease severity in chronic obstructive pulmonary disease. Eur Respir J 26:52. Eur Respir J 22:672. Brindicci C et al: Exhaled nitric oxide from lung periphery is increased in COPD.pulmonary biomarkers with other outcome measures is essential for the future assessment of the inflammatory destructive process and for measuring the effects of the new anti-inflammatory drugs that are now in development for the treatment of COP. Am J Respir Crit Care Med 168:S1. 2006 12. REFERENCES 1. . Am J Respir Crit Care Med 174:6. Boschetto P et al: Association between markers of emphysema and more severe chronic obstructive pulmonary disease. 2006 3. Montuschi P et al: Isoprostanes: Markers and mediators of oxidative stress. FASEB J 18:1791. Kharitonov SA. Barnes PJ: Exacerbations of chronic obstructive pulmonary disease. Chest 130:1541. 2005 13. 2003 9. Barnes PJ et al: Chronic obstructive pulmonary disease: Molecular and cellular mechanisms. Eur Resp J 20:556. moderately severe COPD. Di Stefano A et al: Increased expression of NF-κB in bronchial biopsies from smokers and patients with COPD. All rights reserved. Application to studies of pathogenesis and the effects of treatment. Tsoumakidou M et al: Induced sputum in the investigation of airway inflammation of COPD. Barnes PJ et al: Pulmonary biomarkers in chronic obstructive pulmonary disease. 2003 10. 2003 2. Eur Resp J 29:1224. Pulm Pharmacol Ther 19:189. Lofdahl JM et al: Bronchoalveolar lavage in COPD: Fluid recovery correlates with the degree of emphysema. Celli BR. Barnes PJ: Exhaled biomarkers. Beeh KM et al: Long-term repeatability of induced sputum cells and inflammatory markers in stable. 2005 7.e301 structive pulmonary disease. as well as for understanding how disease mechanisms relate to clinical outcomes. 2003 5. Eur Respir J 25:275. Jeffery PK et al: Methods for the assessment of endobronchial biopsies in clinical research. N Engl J Med 352:1967. 2005 8. 2006 4. 2007 CHAPTER e36 Pulmonary Biomarkers in COPD Copyright © 2008 The McGraw-Hill Companies. Respir Med 97:863. Ito K et al: Decreased histone deacetylase activity in chronic ob. Chest 123:778. 2004 14. Thorax 61:1037. 2006 11. 2002 6.

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Figure e37-1 shows the typical apex lesion with severe myocardial fibrosis in a heart examined at autopsy. MRI was more accurate due to the higher spatial resolution. or purified antigens have been developed to increase specificity and reduce cross-reactivity with other infections and with autoimmune diseases. delayed enhanced MRI can detect even traces of myocardial fibrosis in individuals in the indeterminate phase. Copyright © 2008 The McGraw-Hill Companies. immunofluorescence. . Once established. conventional tests have elevated sensitivity. endothelium-dependent and -independent impairment in coronary vasodilation have been observed in patients with Chagas’ disease. In parallel with PCR for detecting T. Recently.e37 Chagas’ Disease: Advances in Diagnosis and Management Andrei C. cruzi DNA target sequences by polymerase chain reaction (PCR) has become a preferred method for the detection of parasites in blood and tissues. 222 e303 CHAPTER e37 Chagas’ Disease: Advances in Diagnosis and Management LABORATORY DIAGNOSIS Parasitemia During the acute phase of the disease. According to the World Health Organization Technical Report. Myocardial delayed enhancement by MRI has been proved to be efficient in detecting myocardial fibrosis in ischemic and nonischemic myocardial disease. cruzi and extends from the Southern United States11 and Mexico to the south of Argentina. procedures for parasite concentration or indirect methods (xenodiagnosis and hemoculture) can be used instead. noninvasive methods have been developed to explore potential clinical benefits from assessing the degree of myocardial inflammation and fibrosis in patients with Chagas’ disease. such a finding is rare in the chronic phase of the disease. intrinsic risk of the procedure and the lack of evidence-based parameters that may guide clinical decisions. novel research on the diagnosis and management of Chagas’ disease. mechanical factors. occurring in up to 30% of individuals who have a positive specific serology. Artificial xenodiagnosis is preferred to avoid inconveniences from direct contact between the triatomines and patients’ skin. cruzi infection is related to the close proximity between humans and triatomines carrying T. Figure e37-2 shows myocardial denervation and ischemia by scintigraphic imaging. among individuals living in Latin American countries. In patients with Chagas’ disease who undergo heart transplantation. synthetic peptides. Moreover. constituting a classic sign of the disease. In such patients. Such PCR techniques are especially helpful for the follow-up of chemotherapy for T.4 With scintigraphic perfusion imaging using thallium-201. However. parasites can easily be found by microscopic observation of fresh blood. When parasitemia is low. From a pathophysiologic standpoint. rangeli can also be determined by staining the blood smears. cruzi allowing the indirect diagnosis of Chagas’ disease. In the Strout method. cruzi can be easily detected in muscle cells and interstitial histiocytes of individuals in the acute phase of Chagas’ disease. thromboembolism. transforming myofibers into fibrous tissue and featuring the changes in heart structure and function. Myocardial Perfusion Myocardial ischemia has been frequently reported in patients with Chagas’ disease and normal coronary angiograms. All rights reserved. However. 5–6 million are infected and 25 million are at risk of contracting the infection (Chap. Immunodiagnosis Infected individuals soon develop antibodies. vascular dysautonomia due to denervation and inflammatory damage of the microcirculation is considered the leading cause of myocardial ischemia in these patients. blood cells are first eliminated by precipitation and centrifugation. Despite both noninvasive techniques detecting Chagas’ myocarditis. the signs of heart failure result in life expectancy being reduced to ≤5 years. In general. myocardial fibrosis is found particularly at the apex and inferolateral regions of the left ventricle. Ramires INTRODUCTION Chagasic cardiomyopathy is the major complication resulting from infection by Trypanosoma cruzi. gallium-67 myocardial uptake scintigraphy and MRI. blood is centrifuged and the buffy coat examined by microscopy to visualize trypomastigote movements. and a positive result in two conventional tests is sufficient to diagnose the infection.3 Such refined accuracy would potentially be helpful for characterization and treatment of arrhythmogenic foci in patients with Chagas’ disease. Therefore. In these affected regions. the use of endomyocardial biopsy has been limited by the mild. myocardial fibrosis caused by Chagas’ disease is a strong marker of clinical impairment and ventricular dysfunction. however. against several epitopes of T. ventricular wall aneurysms would develop in a later stage of Chagas’ cardiomyopathy. In this chapter. these patients have chest pain associated with electrocardiographic signs of ischemia simulating obstructive coronary artery disease. The histopathologic evaluation of myocardial fibrosis and inflammation can be obtained through a percutaneous and transvenous endomyocardial biopsy of the right ventricle. 206). Sposito. we discuss the results from recent. initially IgM and later IgG. In the microhematocrit. the severity of myocardial fibrosis detected by MRI is proportional to the severity of myocardial dysfunction and clinical symptoms. In fact. endomyocardial biopsy is considered the “gold standard” technique in the differentiation between allograft rejection and reactivation of the disease. and parasympathetic nerve cell destruction are considered among potential underlying mechanisms for these lesions. inflammation. the main finding in the hearts of patients with chronic Chagas’ disease is the presence of inflammatory infiltrates. Conventional immunodiagnostic tests are available worldwide and are based on three main techniques: hemagglutination. The T. that is. Hence. Accordingly. transient and permanent myocardial perfusion abnormalities have been described in patients with the disease (Chaps. conventional serologic tests could also be used for the follow-up of patients undergoing chemotherapy. despite being more sensitive than xenodiagnosis and hemoculture. the histopathologic findings of myocardial inflammation via endomyocardial biopsy were compared with two noninvasive techniques. suggesting that denervation is the initiating event. In angiographic studies. and ELISA. In our group. cruzi. cardiac arrhythmias. cruzi parasitemia. but is much larger. F. this sensitivity is equally dependent on the magnitude of the parasitemia. In patients in the chronic phase of the disease. albeit significant. Chagas’ myocarditis lesions are spread out over both ventricles and in a large spectrum of severity. Parasite concentration could be obtained either by microhematocrit or by the Strout method. This diagnostic procedure has been proved to be a powerful tool for both the prediction of clinical outcome and estimation of the severity of myocardial damage in Chagas’ disease and in other primary and secondary cardiac diseases. Ischemia. strategies to identify the disease in the early phase and characterize predictive signs and potential therapeutic targets have been intensely pursued. The xenodiagnostic method consists of feeding uninfected triatominae with blood from the patient under examination and then investigating the intestinal contents of the insects some days later to search for metacyclic trypomastigotes. amplification of T. Jose A. Morphologic characteristics of the parasite and differentiation from T. Consequently. It usually takes 10–20 years for the infection to manifest the disease in a broad range of clinical presentations including heart failure. Nonconventional tests using recombinant chimeric proteins. ANATOMIC DIAGNOSIS Myocardial Fibrosis and Inflammation T. In Chagas’ disease. the denervation demonstrated by the reduced cardiac uptake of 123I-metaiodobenzylguanidine (MIBG) is concordant with the perfusion deficit. The supernatant is then submitted to a second centrifugation and the precipitate is examined as fresh blood. the period before presentation of cardiac electrical or mechanical abnormalities. and sudden death.

the systolic dysfunction may be apparent only under pharmacologic stress by dobutamine or phenylephrine. These studies demonstrate an elevated topographic correlation between perfusion and wall motion abnormalities. the development of heart failure is typically manifested with a predominance of systemic over pulmonary congestion. indicating the impairment of left ventricular relaxation. In this case. diastolic dysfunction occurs in an early phase of the disease. the activity of treatment with both compounds is evident in terms of parasite load reduction and serologic conversion to negative in the acute phase of Chagas’ disease and in congenital Copyright © 2008 The McGraw-Hill Companies. Frequently. From the clinical point of view. Above. The segmental thinning of the ventricular wall. Normally. pericardial effusion and occasionally myocardial wall motion abnormalities have been described. Myocardial Wall Motion In the acute phase of the disease. As the disease progresses. thinning. FIGURE e37-1 Photo of a heart from a patient with chronic chagasic cardiac disease. scintigraphic. aneurysm formation. These patients have impairment of the vasodilator responses to both metabolic and pharmacologic stimuli and an increased sensitivity to vasoconstrictors. Actually. it is plausible to consider that such perfusion defects would represent an early sign of Chagas’ cardiomyopathy. and the global systolic function of the left and right ventricles deteriorates. which may increase mechanical tension and contribute to aneurysm formation in this area. Whether such perfusion disturbances also contribute to the detriment of ventricular wall motion is presently unknown. akinetic. Initially. radionuclide angiography or MRI is preferred for evaluation of this chamber. In addition. In the chronic phase. Nevertheless. A permanent perfusion deficit with smaller size as compared with the denervation is demonstrated by scintigraphic perfusion with 99mTc-sestamibi (MIBI). the appearance of an abnormality of the ventricular wall reflects progression of the disease and must be considered. e37-3. By definition. characterizing the reduction of systolic reserve. the early flow velocity (E) is higher than the late flow velocity (A). The denervation is demonstrated by the reduced cardiac uptake of 123l-metaiodobenzylguanidine (MIBG) (arrows). in the indeterminate phase. as shown in Fig. abnormalities of other left ventricular segments can also be found.e304 FIGURE e37-3 Echocardiographic analysis of mitral inflow by pulse-wave Doppler showing diastolic function in a patient with Chagas’ disease. there is an inverted E/A relation. The thinning of the apex becomes an aneurysm. in these patients. Even though prospective cohorts demonstrating a temporal association between perfusion defects and the development of wall motion dysfunction are lacking. In keeping with necropsy. Accordingly. these radionuclide studies also indicate that the perfusion defects are predominantly in the apex and inferolateral regions. These compounds seem to exert their trypanosomicidal action by the generation of superoxide radicals causing oxidative stress and cell death in susceptible parasites. Such evidence indicates that the segmental microvascular dysfunction observed in patients with Chagas’ disease is unlikely to be pathogen-dependent but rather an early sign of ventricular wall disease. and wall motion dysfunction are the most frequent findings detected on echocardiography. which are those most affected by the inflammatory damage and the autonomic denervation. ETIOLOGIC TREATMENT Nitrofurans and nitroimidazole derivatives (nifurtimox and benznidazole respectively) have been the cornerstones of trypanosomicidal treatment in recent decades. Echocardiography or MRI can accurately detect these characteristics. and e20). The right ventricle is first and predominantly affected in the majority of patients with Chagas’ disease. or even dyskinetic. accordingly. promotes remodeling of the left ventricle. All rights reserved. caution must be taken to interpret the presence of perfusion defects detected by either scintigraphy or MRI as an indication of epicardial coronary disease in patients with Chagas’ disease. and MRI studies. both the endothelium-dependent and -independent vasodilatory responses of coronary resistance vessels are also affected in patients with idiopathic dilated cardiomyopathy and angiographically normal coronary arteries. chronically infected individuals remain a parasite reservoir without being affected by the disease and consequently have a normal life expectancy. which is related to atrial contraction. as the onset of the chronic phase of Chagas’ disease. PART 18 e-Chapters from International Advisory Editors CHAGAS’ DISEASE FIGURE e37-2 Myocardial denervation and ischemia detected by scintigraphic imaging. From a clinical perspective. Because echocardiography has a low accuracy for detecting right ventricular dysfunction. Below. Hence. these echocardiographic findings are mostly observed in the apex and inferobasal regions of the left ventricle. particularly at the apex. . This may occur even in the absence of any detectable abnormality in the left ventricle. the affected segments of the ventricular wall become hypokinetic. exhibiting a typical lesion at the left ventricle.

infection. In the indeterminate phase, new promising findings have been reported particularly in children and young adults, showing long-lasting disappearance of specific antibodies in 58–98% of treated individuals together with a 10–20% rate reduction of side effects. In general, treatment with nitroimidazole derivatives, especially benznidazole, has been shown to be effective more frequently in reducing parasitemia and specific antibody titers in individuals in the indeterminate phase. Whether this treatment will prevent the development of cardiac or digestive complications of the disease is still unclear. Large randomized controlled trials are required to define this issue. The effect of trypanosomicidal therapies on parasite load or disease progression in patients in the chronic symptomatic phase of Chagas’ disease is even less clear. The disappearance of specific antibodies is uncommon in the chronic phase and may take up to 10–20 years. Parasite DNA is present in several tissues and may induce immune response and perhaps disease progression. Hence, the ideal therapeutic schema or duration for such chronic patients is unknown. In addition, several adverse reactions, such as peripheral neuropathy and skin disorders, have been reported in a large proportion of patients treated with both nifurtimox and benznidazole. Thus, there is insufficient evidence to demonstrate the clinical benefit for trypanosomicidal treatment in patients in the chronic phase of Chagas’ disease. Novel potential targets for trypanosomicidal treatment have been investigated to reduce side effects and increase treatment efficacy. Sterol biosynthesis inhibitors, protein prenylation inhibitors, protease inhibitors, and phospholipid analogues are among potential chemotherapeutic agents for this purpose. Although some of these compounds have already demonstrated potent inhibitory activity in vitro against T. cruzi, clinical benefits have not been proved thus far.

eurysmatic zone or in focal areas of fibrosis in the inferolateral region of the e305 left ventricle. Surgical treatment consists of conventional aneurysmectomy associated with endocardial or myocardial resection and/or isolation of critical sites of reentry by endocardiectomy or cryoablation guided by electrophysiologic mapping. Alternatively, interpapillary endomyocardial cryoablation without electrophysiologic mapping has been attempted in patients with sustained ventricular tachycardia and akinesia or dyskinesia of the inferolateral region of the left ventricle, with efficacy in nearly 60%. Because the mortality of the procedure is high, surgical ablation should be considered only when systolic dysfunction is not severe, the overall surgical risk is low, and when other surgical procedures, such as aneurysmectomy, are not indicated. Nonsurgical simultaneous epicardial and endocardial catheter ablation has been introduced recently as an alternative approach in the treatment of patients with Chagas’ disease and recurrent ventricular tachycardia.10 Because critical sites of reentry may be endocardial, intramural, or epicardial, this combined approach provides a higher efficacy for treating recurrent ventricular tachycardia. For patients with severe systolic dysfunction, however, the insertion of an ICD is the treatment of choice, particularly in those with left ventricular ejection fractions <30%. Symptomatic or highrisk bradyarrhythmia is frequently manifested in these patients. Thus, implantation of an ICD with pacing capability is often indicated. ICDs are effective in preventing death due to ventricular tachyarrhythmias, but frequent shocks triggered by tachycardias, life-threatening or not, can lead to a reduced quality of life. Therefore, a combination of ICD, antiarrhythmic therapy, and catheter ablation appears to be ideal in these patients.

CHAPTER e37 Chagas’ Disease: Advances in Diagnosis and Management

COMPLEMENTARY TREATMENT In the acute phase, symptoms disappear in up to 2 months. In rare cases of severe acute myocarditis, an empirical combination of corticoid and trypanosomicidal treatments has been attempted. In animal models, immunosuppressive therapy in combination with benznidazole has been demonstrated to be effective in attenuating the inflammatory response. However, insufficient studies in humans have been done to define the ideal approach in these cases. The aim of treatment in the chronic phase of Chagas’ disease is to attenuate symptoms and prevent complications. The most relevant cardiac complications in the late chronic phase are heart failure and life-threatening arrhythmias. The mortality attributable to Chagas’ disease is fundamentally related to these two disorders. Even though few studies have compared the efficacy of the treatment for heart failure in patients with and without Chagas’ disease, the standards of clinical treatment are mostly the same. Heart failure in both classes of patients responds equally to digitalis, diuretic, and vasodilator therapy (Chaps. 227 and 231). The use of angiotensin-converting enzyme (ACE) inhibitors has been reported to reduce neurohormonal activation, improving heart failure symptoms and nonlethal arrhythmias. In an animal model, there is evidence that aldosterone blockade with spironolactone attenuates myocardial remodeling and inflammatory infiltration and may reduce mortality in Chagas cardiomyopathy.8 As is the case for nonchagasic heart failure, the use of beta blockers is also believed to be beneficial in patients with Chagas’ disease. In addition, beta blockers may reduce the transmyocardial pressure gradient and attenuate subendocardial ischemia, which is supposed to participate in the deterioration of ventricular function in Chagas’ disease. The blockade of sympathetic activity, which is typically augmented in these patients, may help to attenuate ventricular remodeling and arrhythmias. Thus, despite the lack of specific trials to verify this assumption, beta blocker use in patients with Chagas’ disease who also have heart failure is indicated. There is some evidence that amiodarone can prevent complex arrhythmias in patients with heart failure irrespective of the cause. In small studies in patients with Chagas’ disease with sustained ventricular tachyarrhythmias, amiodarone provided longer intervals free of arrhythmic events compared with other antiarrhythmic drugs. The efficacy of amiodarone in preventing ventricular tachyarrhythmias seems to be reduced in patients with severe systolic dysfunction. In these patients, percutaneous catheter ablation, implantation of implanted cardioverter/defibrillators (ICD) or surgical procedures may be attempted. Reentry is considered to be the major arrhythmogenic mechanism of ventricular tachyarrhythmias in Chagas’ disease, it is usually in the perian-

ACKNOWLEDGMENTS The authors are indebted to Dr. Carlos E. Rochitte, Dr. Maria de Lurdes Higuchi, Dr. Wilson Mathias, and Dr. Claudio Meneghetti for kindly providing the figures for this chapter.

REFERENCES
1. Higuchi ML et al: The role of active myocarditis in the development of heart failure in chronic Chagas’ disease: A study based on endomyocardial biopsies. Clin Cardiol 10:665, 1987 2. Bocchi EA et al: Magnetic resonance imaging in chronic Chagas’ disease: Correlation with endomyocardial biopsy findings and Gallium-67 cardiac uptake. Echocardiography 15:279, 1998 3. Rochitte CE et al: Myocardial delayed enhancement by magnetic resonance imaging in patients with Chagas’ disease: A marker of disease severity. J Am Coll Cardiol 46:1553, 2005 4. Torres FW et al: Coronary vascular reactivity is abnormal in patients with Chagas’ heart disease. Am Heart J 129:995, 1995 5. Marin-Neto JA et al: Pathogenesis of chronic Chagas’ heart disease. Circulation 115:1109, 2007 6. Acquatella H et al: Limited myocardial contractile reserve and chronotropic incompetence in patients with chronic Chagas’ disease: Assessment by dobutamine stress echocardiography. J Am Coll Cardiol 33:522, 1999 7. Villar JC et al: Trypanocidal drugs for chronic asymptomatic Trypanosoma cruzi infection. Cochrane Database Syst Rev 2002(1):CD003463 8. Ramires FJ et al: Aldosterone antagonism in an inflammatory state: Evidence for myocardial protection. J Renin Angiotensin Aldosterone Syst 7:162, 2006 9. d’Avila A et al: New perspectives on catheter-based ablation of ventricular tachycardia complicating Chagas’ disease: Experimental evidence of the efficacy of near infrared lasers for catheter ablation of Chagas’ VT. J Interv Cardiol Electrophysiol 7:23, 2002 10. Sosa E et al: Radiofrequency catheter ablation of ventricular tachycardia guided by nonsurgical epicardial mapping in chronic Chagasic heart disease. Pacing Clin Electrophysiol 22(1 Pt 1):128, 1999 11. Bern C et al: Evaluation and treatment of Chagas disease in the United States. JAMA 298(18):2171, 2007

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e38 The Polypill

K. Srinath Reddy, Nitish Naik, Ambuj Roy

Cardiovascular diseases (CVDs) are leading contributors to the global burden of disease, accounting for nearly 30% of global deaths and nearly 20% of disability-adjusted life years (DALYs) lost. Identification of multiple risk factors as well as interventions that alter risk by modifying one or more of them provide opportunities for reducing the risk of CVD through actions that impact on populations or directly on individuals. Major goals of preventive cardiology and clinical medicine are to identify individuals at a high risk of future CVD events and to intervene in order to substantially reduce their risk. The decision to modify a risk factor has traditionally depended on the measured level of the risk factor, the risk of future CVD associated with that level, and the potential benefit of reducing it to a lower level through interventions that are cost-effective and safe. Evidence from observational studies, especially from large and long-term cohorts, has defined the prevention norms by indicating a continuous relationship between risk factor levels and CVD risk. Evidence from clinical trials has set the thresholds at which interventions are considered beneficial. Over the past two decades, prevention norms and clinical norms have converged because of accumulating new knowledge. For example, in the seventh U.S. Joint National Committee report on hypertension, the definition of normal blood pressure was lowered to <120/80 mmHg from <130/85 mmHg in the sixth report. Similarly, the target goals of lowdensity lipoprotein (LDL) cholesterol have been lowered progressively in patients with established coronary artery disease (CAD). However, clinical outcome data are scarce in patients when multiple risk factors are simultaneously targeted or when borderline abnormal values are treated. Hence, much interest was generated when Wald and Law proposed a polypill to target multiple risk factors, regardless of their levels, as a potentially effective intervention to reduce the risk of CVD. This chapter reviews the possible benefits and shortcomings of the polypill.

CARDIOVASCULAR DISEASE—MULTIFACTORIAL CAUSATION

Major risk factors related to CVD include behavioral factors, such as smoking, unhealthy diet, physical inactivity, and biologic factors, such as high blood pressure, elevated blood lipids, and diabetes. According to the INTERHEART study, nine risk factors [smoking; higher-than-normal ratio of apolipoprotein (apo) B to apoA; a history of hypertension and diabetes; abdominal obesity; psychological factors; and lack of daily consumption of fruits and vegetables, regular alcohol intake, and regular physical activity] account for ~90% of CVD risk globally, cutting across all major ethnic populations. Interventions, directed toward lowering many of 1 Four elements these risk factors, have been shown to lower the risk of subsequent CVD events. Three elements Drugs that act on critical steps in the 0.9 Two elements pathogenesis of atherothrombotic events, either by reducing risk factors (e.g., statOne element ins) or preventing pathologic processes 0.8 (e.g., aspirin), have been shown to reduce vascular events. Both lifestyle measures and pharmacotherapy have been demonNo element 0.7 strated to prevent or delay the onset of CVD-related clinical events in persons with high levels of one or more risk facp-logrank < .0001 0.6 tors (primary prevention). They have also 0 2 4 6 8 10 12 been shown to reduce the risk of recurrent events and to extend survival in perMonths after discharge sons who have manifest CVD (secondary prevention). Optimal drug therapy for FIGURE e38-1 Post-MI survival in German hospitals is significantly improved in patients who resecondary prevention of CVD currently ceive four medications (aspirin, beta blocker, ACE inhibitor, and statin) when compared with those includes aspirin, beta blockers, angioten- who receive zero, one, or two ( p-logrank < .0001). (Unpublished results from the MITRA registry. Reprosin-converting enzyme (ACE) inhibitors, duced from Sleight et al.)
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and statins. These drugs have been shown to significantly reduce overall e307 coronary and overall CVD event rates in patients with manifest CAD (Fig. e38-1). Some of them have also been demonstrated to be effective in reducing the risk of recurrent cerebrovascular events in persons who have earlier experienced a stroke or transient ischemic attack. Statins have now become a cornerstone of secondary prevention strategies. They have been shown to improve survival, lower the risk of recurrent myocardial infarction (MI), and reduce the need for revascularization in patients with acute and chronic CAD. These benefits accrue regardless of measured blood cholesterol levels in patients with CAD. There is, however, a threshold of benefit, with little apparent clinical benefit in patients who achieved a <30% reduction in LDL cholesterol levels. In several randomized trials, patients receiving highdose statin therapy (such as atorvastatin, 80 mg) benefited from a greater reduction in combined endpoints of cardiovascular mortality, MI, stroke, and need for revascularization when compared to patients receiving moderate-dose therapy (such as atorvastatin, 10 mg, pravastatin, 40 mg, or simvastatin, 20 mg/d). β-Adrenergic blockers have clearly been shown to significantly reduce mortality after MI. In a meta-analysis of 25 trials, beta blockers were shown to reduce relative risk for overall death by 23% and reinfarction by 26%. While these benefits persist for many years on continuing therapy, they disappear on discontinuing therapy. Despite these proven benefits, many patients do not receive the benefit of these drugs for secondary prevention. The EUROASPIRE and WHO-PREMISE studies have shown suboptimal prescribing practices for CVD risk reduction among physicians in Europe and the developing countries, respectively. In a U.S. national survey on prescription patterns after MI, it was observed that beta blockers were not prescribed to nearly two-thirds of eligible patients in some regions. It has been estimated that if all post-MI patients received beta blockers over 20 years, then adverse outcomes of nearly one-fifth could be prevented, with a decrease in sudden death by 32% and a decrease in recurrent MI and revascularization by 27%. The benefits of ACE inhibitors in patients with acute MI with left ventricular systolic dysfunction, as well as in those with chronic systolic heart failure, are well proven. Benefits of this class of drugs in patients at high risk for cardiovascular events, even without left ventricular dysfunction, have also been demonstrated. The HOPE study, which included patients with CVD or diabetes and at least one cardiovascular risk factor but the absence of left ventricular dysfunction, demonstrated a 26% reduction in cardiovascular death rates and a 16% reduction in overall mortality with ramipril. These benefits were observed even in the presence of other known therapies to lower CVD related events such as aspirin, beta blockers, and lipid-lowering drugs. In patients with acute MI, aspirin has been shown to effect a 23% risk reduction in vascular mortality and a 10–40% risk reduction in

CHAPTER e38 The Polypill

Survival after STEMI

e308 the composite endpoint of recurrent MI, stroke, or vascular death.
However, it is also associated with an increased risk of gastrointestinal bleed and hemorrhagic stroke. Lowering cardiovascular mortality by combinations of these drugs, when administered together, has been shown in some studies. In the ASCOT BPLA trial, calcium channel blockers and ACE inhibitors were observed to be more effective in controlling blood pressure than the traditional thiazide diuretics and beta blockers. Moreover, adding statins to the treatment led to a highly significant 36% reduction in the combined endpoint of nonfatal MI and fatal coronary heart disease. Analysis from the MITRA study demonstrated improved survival in post-MI patients who received these four medications (aspirin, beta blockers, ACE inhibitors, and statins) as opposed to those who received none to two drugs. However, the protective role of combinations of these drugs for primary prevention of CVD has not been proved clearly. While statins and aspirin have been shown to reduce events in certain population subsets at high risk for CAD, actual data from clinical trials specifically designed to test the utility of this multidrug combination pharmacotherapy are lacking.

POLYPILL STUDY MODELS

Two studies have attempted to define the possible benefits of pharmacologic treatment of multiple risk factors in reducing cardiovascular events by modeling potentially achievable risk reduction with the use of multiple drugs. Wald and Law, in 2003, combined six drugs to model reduction of four cardiovascular risk factors—LDL cholesterol, blood pressure, serum homocysteine, and platelet function. The combined formulation included a statin (atorvastatin, 10 mg, or simvastat- LIMITATIONS OF THE POLYPILL in, 40 mg), three blood pressure–lowering drugs (a thiazide diuretic, a Despite the perceived advantages associated with the delivery of multibeta blocker, and an ACE inhibitor, all at half the standard dose), folic ple drugs in a single pill, including convenience of delivery, ensuring inacid (0.8 mg), and aspirin (75 mg). The authors suggested that the pill clusion of all drugs considered essential for primary or secondary be used in all persons above the age of 55 years (as 96% of CVD events prevention, and possible improvements in compliance, several factors occur beyond this age in western populations) and in adult patients of need to be accounted for before a polypill can actually be recommended. any age with manifest CVD, regardless of their risk factors. In their The strongest objection to the concept of combination pharmacomodel, the six drugs were used irrespective of the pretreatment risk therapy is the absence of any clinical trial to substantiate its merits. factor levels, as the authors asserted that arbitrary thresholds of indi- While several trials have documented the benefits of some of these vidual risk factors were poor predictors of future CVD events. classes of drugs administered separately in different patient subsets, The concept of a continuum of risk was preferred to predefined cut- such as post-MI survivors, those with CAD and left ventricular dysoff levels that attempt to separate “normal” from “abnormal” levels. function, and other high-risk subsets, there is still paucity of data on Published meta-analyses of multiple randomized trials were used to the benefit of some of these drugs in certain patient subsets, e.g., ACE quantify the estimated benefit from this combination of drugs. The inhibitors in low-risk stable patients of CAD without left ventricular model factored a reduction of ischemic heart disease events at 2 years dysfunction. In the PEACE trial, which examined the efficacy of ACE by 61% due to statins, by 46% due to anti-hypertensive drugs, by 16% inhibitors in lowering CVD events, no significant benefits were found due to folic acid, and by 32% due to aspirin. By multiplying the rela- with the use of trandolapril. Similarly, there is a lack of evidence to tive risk reduction from each class of drugs, the authors estimated that support the use of beta blockers in all patients with stable CAD. Aspithe combined effect of the four drugs would be an 88% reduction in rin also does not have a well-established role in preventing cardiovasischemic heart disease events and an 80% reduction in stroke events cular disease events in all women >55 years. Even the addition of a (Table e38-1). Even if folic acid were omitted from the formulation, statin to aspirin does not significantly improve cost-effectiveness in the authors estimate that 86% of ischemic heart disease events could primary prevention models, unless absolute risks are high. still be averted. Similarly, absence of aspirin reduces the advantage of the TABLE e38-1 EFFECT OF POLYPILL ON RISK OF ISCHEMIC HEART DISEASE (IHD) AND STROKE, AS polypill by only 5 percentage points to ESTIMATED BY WALD AND LAW, AFTER 2 YEARS OF TREATMENT AT THE AGE 55–64 YEARS 83%. These benefits accrued with a low incidence of projected side effects. It % Reduction in Risk (95% CI) Reduction in was estimated that only 15% of patients Risk Factor Risk Factor Agent IHD Event Stroke would be expected to have adverse efa b fects due to the formulation, mostly as61 (51–71) 17 (9–25) LDL cholesterol Statin 1.8 mmol/L (70 mg/ dL) reduction cribable to aspirin. If all people >55 Blood pressure Three classes of drugs 11 mmHg diastolic 46 (39–53) 63 (55–70) years used the pill, it was estimated that at half standard dose one in three people would benefit diSerum homocysteine Folic acid (0.8 mg/d) 3 μmol/L 16 (11–20) 24 (15–33) rectly, gaining an additional 12–20 years Platelet function Aspirin (75 mg/d) Not quantified 32 (23–40) 16 (7–25) of life-years without a coronary heart Combined effect All 88 (84–91) 80 (71–87) disease event or stroke. aLDL, Low-density lipoprotein. Gaziano et al. further quantified bAtorvastatin, 10 mg/d, or simvastatin or lovastatin, 40 mg/d taken in the evening or 80 mg/d taken in the morning. these assertions in a subsequent study Source: Adapted from Wald and Law. that examined cost-effectiveness of comCopyright © 2008 The McGraw-Hill Companies. All rights reserved.

bination pharmacotherapy in reducing CVD in low-income and middle-income countries. Using a Markov model to assess cost-effectiveness, the authors used a combination of four drugs—aspirin, a calcium channel blocker, an ACE inhibitor, and a statin—for primary prevention. For secondary prevention, the authors substituted a beta blocker for the calcium channel blocker while retaining the other three constituents. For primary prevention, the authors included patients with a 10-year absolute risk of CVD of between 5% and 35%. This strategy thus required an additional hospital visit to assess CVD risk factors such as blood pressure, diabetes, serum cholesterol, and smoking status. The authors estimated that a nearly 50–60% reduction in CVD-related events could be expected if all patients with a 10-year absolute risk >5% were treated. This would lead to at least a 2-year increase in life expectancy in those above the age of 35 years. Using the secondary prevention strategy, the authors predicted a 10–15% reduction in lifetime risk of death due to CVD. Using this model, the authors reported that the incremental cost-effectiveness of the primary prevention strategy was US$746–890 per quality-adjusted life year (QALY) for patients with a 10-year absolute CVD risk >25%, across six developing regions, as defined by the World Bank. The cost was higher in patients with lower levels of absolute 10-year cardiovascular risk, as more patients needed to be treated to achieve a similar reduction in CVD events, leading to higher expenditure and lower cost-effectiveness. However, incremental cost-effectiveness was still favorable for all primary prevention strategies, except for the strategy of treating all patients >55 years. For secondary prevention, incremental cost-effectiveness of the polypill was most favorable, at US$306–388 per QALY gained.

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The projected benefits of these combinations of drugs have been assumed using mathematical multiplication of relative risks. For some drugs, the authors have included the best-case scenario figures for risk reduction. For example, Wald and Law assumed a relative risk reduction of 61% of CVD events with the use of statins. However, data from many large randomized trials of statins have estimated the relative risk reduction to be at a more conservative level of 35%. These assumptions therefore need to be verified by an actual clinical trial. This is especially important in the case of primary prevention. In secondary prevention trials, the sequential evaluation of cardioprotective drugs has seen each new drug being tested for incremental benefit when added to previously tested drugs and only then becoming standard therapy. Thus the value of combination therapy of multiple drugs (given separately and not as a single pill) is well proven. However, multiple drugs have not been used in such an incremental manner in primary prevention trials. It is essential that trial evidence, using major event-related endpoints, be generated for such multidrug combinations when used for primary prevention. In the case of secondary prevention, evidence on bioavailability, pharmacokinetics, and intermediate variables (risk factor levels) may suffice. Even in secondary prevention, some questions remain: Are beta blockers useful for secondary prevention of stroke? Are diuretics needed for secondary prevention of CAD? The actual incidence of adverse events or other side effects associated with the use of the polypill is also unknown. Beta blockers, ACE inhibitors, calcium channel blockers, statins, and aspirin are all known to produce side effects requiring discontinuation of therapy. Although Wald and Law estimated that 15% of patients would be expected to discontinue therapy due to side effects, the actual incidence may be higher. Polypills would need to be available in different formulations to avoid anticipated side effects due to one or more components in susceptible persons. The dilemma of primary prevention becomes more obvious when an attempt is made to treat all patients alike, regardless of their absolute risk with one fixed combination of drugs. On the one hand, many asymptomatic persons with low absolute risk of events would be treated with little or no expected benefit; however, they would be exposed to the adverse effects of combination multidrug therapy. On the other hand, there would be high-risk patients who would be undertreated and might not reach the desired therapeutic goals. Without appropriate risk profiling, the latter patients would be diligently taking drugs but not accruing the maximum benefits. Although the population risk would still be lowered by such an approach, the individual at risk would not derive optimum benefit in spite of drug therapy. Whether the polypill will necessarily improve compliance is not known. Although a low daily pill count does improve compliance, it is also affected by many other social and behavioral factors that are not necessarily overcome with the convenience associated with a polypill. Patient motivation and counselling, educational status, health education campaigns, and economic considerations are among the many factors that impact adherence positively and are unaffected by combination pharmacotherapy. Patients with overt clinical heart disease are more receptive to information regarding personal health behavior and its modification and are also more compliant with drug therapy. Longterm adherence to advice about behavior and drugs is lower when it is used for primary prevention in “real-world” settings. This can have a significant negative impact on the projected benefits. An important assumption made by Wald and Law in targeting multiple risk factors simultaneously is that there are no clear demarcations between “normal” and “abnormal” levels of risk factors. They proposed, after appraising data from many observational and randomized trials, that there is a continuum of risk, with no specific risk factor thresholds that need to be targeted. It was recommended that interventions to modify risk factors should be guided by a person’s level of absolute cardiovascular risk rather than the level of individual risk factors. Thus, patients with what is currently considered borderline elevation of multiple risk factors would derive benefit from interventions designed to modify those risk factors. However, data from the Framingham study suggest that 90% of CVD events occur in individuals with at least one preexisting major cardiovascular risk factor. Clus-

tering of these risk factors is frequently observed in individuals and e309 contributes to high level of absolute risk of CVD. Therefore, it is important to screen the population for these risk factors and then treat individuals at a high absolute risk with the combination pharmacotherapy, rather than treat the entire population >55 years with a blanket therapy. The ideal approach would be to assess an individual’s global (absolute) cardiovascular risk, based on available algorithms for different populations, to maximize the benefits of the polypill and thus make it cost-effective, as shown in the study by Gaziano. Another concern with use of a widespread pharmacologic intervention at the population level is the likely sense of complacency among both users and health care providers. Critics have expressed a fear that emphasis on healthy diet, physical activity, smoking cessation, and other lifestyle changes, which are essential elements in the management of these chronic diseases, may not be treated with the seriousness that they deserve. The polypill will not reduce the number of individuals acquiring a high-risk status in any population—it can only avert their future risk, if detected and treated. On the other hand, population-wide changes in diet, physical activity, and tobacco use are likely to reduce the number of individuals who enter this high-risk zone. Many other factors such as physician attitudes, cost-effectiveness, and long-term affordability have to be addressed before the promise of the polypill can be realized. These concerns would be best addressed by clinical trials that examine the benefits in the setting of both primary and secondary prevention.

CHAPTER e38 The Polypill

IMPACT ON DEVELOPING COUNTRIES
CAD is an emerging epidemic in low- and middle-income countries. By 2020, >80% of all CVD-related deaths worldwide are expected to occur in the developing world. Moreover, even as age-adjusted cardiovascular disease rates are declining in the developed world, rates of CVD are rising rapidly in these low- and middle-income countries. The same risk factors responsible for CAD in the western population are operative in these countries, as shown by the INTERHEART study. In the absence of well-resourced CVD prevention programs and limited public awareness of risk factors, the polypill appears attractive for such populations, especially for secondary prevention and highrisk primary preventions. It overcomes the problems of inadvertent drug omission by under-informed physician and provides the opportunity to include generic drugs such as lovastatin or simvastatin, enalapril, and propranolol to lower the cost of pharmacotherapy. The presence of a strong pharmaceutical industry in countries such as India offers the opportunity to lower the costs of drug production significantly, making the therapy more affordable and applicable. A World Health Organization report on chronic diseases suggests that a polypill could be made available for a little over US$1 per patient per month, using these generic products. Moreover, with the expected low side-effect profile of these pills, it may be possible to shift identification and treatment of high-risk individuals to non-physician health workers in these resource-poor countries, thereby lowering the cost and widening the access for effective risk reduction. However, the developing countries would need to place even greater emphasis on policies and educational interventions that protect their populations from the risk of CVD, while judiciously applying interventions such as the polypill.

CONCLUSIONS
The concept of a polypill to reduce the burden of CVD is attractive and seems to have great potential, especially in secondary and highrisk primary prevention. However, its role is presently speculative and needs to be assessed in randomized trials. It should not distract clinicians from the importance of managing risk factor levels; rather, it should enable persons at high risk of CVD to access affordable and easy-to-consume therapy for reducing that risk. It is also important that the polypill should not lull the patient and the physician into a false sense of security—continued emphasis on targeting modifiable risk behaviors such as smoking, sedentary lifestyle, and unhealthy diet

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e310 would continue to yield equal dividends. They would also be applicable to the wider population, with greater safety.

FURTHER READINGS
COMBINATION PHARMACOTHERAPY AND PUBLIC HEALTH RESEARCH WORKING GROUP: Combination pharmacotherapy for cardiovascular disease. Ann Intern Med 143:593, 2005 CONSTANTINO G et al: Prevention of cardiovascular disease with a polypill. Lancet 369:185, 2007 GAZIANO TA et al: Cardiovascular disease prevention with a multidrug regimen in the developing world: A cost-effectiveness analysis. Lancet 368:679, 2006

REDDY KS: The preventive polypill—much promise, insufficient evidence. N Engl J Med 356:212, 2007 SLEIGHT P et al: Benefits, challenges, and registerability of the polypill. Eur Heart J 27:1651, 2006 VASAN RS et al: Relative importance of borderline and elevated levels of coronary heart disease risk factors. Ann Intern Med 142:393, 2005 WALD NJ, LAW MR: A strategy to reduce cardiovascular disease by more than 80%. BMJ 326:1419, 2003 YUSUF S et al, on behalf of the INTERHEART Study Investigators: Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): Casecontrol study. Lancet 364:937, 2004

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Mitochondrial e39 Heritable TraitsDNA and and Diseases
Karl Skorecki, Hanna Mandel
Mitochondria are cytoplasmic organelles whose major function is to generate ATP by the process of oxidative phosphorylation under aerobic conditions. This process is mediated by the respiratory electron transport chain (ETC) multiprotein enzyme complexes I–V, and the two electron carriers, coenzyme Q (CoQ) and cytochrome-c. Other cellular processes to which mitochondria make a major contribution include apoptosis (programmed cell death), as well as additional celltype specific functions (Table e39-1). The efficiency of the mitochondrial ETC in ATP production is a major determinant of overall body energy balance and thermogenesis. In addition, mitochondria serve as the predominant source for the generation of reactive oxygen species (ROS), whose rate of production also relates to the coupling of ATP production to oxygen consumption. Given the centrality of oxidative phosphorylation to the normal activities of almost all cells, it is not surprising that mitochondrial dysfunction can affect almost any organ system (Fig. e39-1). Thus, physicians in many specialties might encounter patients with mitochondrial diseases and should be aware of their existence and characteristics. The integrated activity of several hundred proteins is required for normal mitochondrial biogenesis, function, and integrity. Most of these are encoded by nuclear genes and thus follow the rules and patterns of nuclear genomic inheritance (see Part 3, Genetics and Disease). These nuclear-encoded proteins are synthesized in the cell cytoplasm and imported to their location of activity in mitochondria through a complex biochemical process. In addition, the mitochondria themselves have their own genome consisting of numerous copies (polyploidy) per mitochondrion of a circular, double-strand mitochondrial DNA (mtDNA) molecule consisting of a 16,569-nucleotide sequence. This mtDNA sequence contains a total of 37 genes, of which 13 encode mitochondrial protein components of the ETC (Fig. e39-2). The remaining 22 tRNAand 2 rRNA-encoding genes are dedicated to Skeletal muscle Weakness the process of translation of the 13 mtDNA-enFatigue coded proteins. This dual genetic control of miMyopathy tochondrial function can result in fascinating Neuropathy patterns of inheritance, which may be challenging to unravel. The current chapter focuses on diseases and heritable traits related to the mtDNA component of the dual genetic control of mitochondrial function. The reader is reBrain ferred elsewhere for consideration of mitochonSeizures drial disease originating from mutations in the Myoclonus nuclear genome. The latter include (1) nuclear Ataxia genomic mutations that disrupt the integrity of Stroke Dementia the mitochondrial genome itself (mtDNA deleMigraine tion and depletion states), (2) disorders due to mutations in nuclear genes encoding structural components or assembly factors of the oxidative Nuclear DNA phosphorylation complexes, and (3) mitochondrial disorders due to mutations in nuclear genes encoding proteins indirectly related to oxidative phosphorylation.

TABLE e39-1 FUNCTIONS OF MITOCHONDRIA
All cells and tissues Oxidative phosphorylation Apoptosis (programmed cell death) Tissue- or cell-specific Cholesterol metabolism Amino and organic acid metabolism Fatty acid beta oxidation Sex steroid synthesis Heme synthesis Hepatic ammonia detoxification Neurotransmitter metabolism

e311

mechanisms of mtDNA differ from the corresponding mechanisms in the nuclear genome, whose nucleosomal packaging and structure is more complex. In terms of mtDNA replication, at least two major models have been proposed, which differ principally in whether the two strands of the mtDNA double helix replicate simultaneously or consecutively. Since each mitochondrion contains many copies of mtDNA, and because the number of mitochondrion per cell can vary during the lifetime of a cell through the processes of fission, fusion, and mitochondrial biogenesis, mtDNA copy number per mitochondrion and per cell can also vary within the lifetime of a cell, and it is not directly coordinated with the cell cycle. Thus, it is not surprising that vast differences in mtDNA copy number are observed between different cell types and tissues and during the lifetime of a cell. Another important feature of the mtDNA replication process is a greatly reduced stringency of proofreading and replication error correction, leading to a much greater degree of sequence variation compared to the nuclear genome. Some of these sequence variants are silent polymorphisms that do not

CHAPTER e39 Mitochondrial DNA and Heritable Traits and Diseases

Heart Conduction disorder Wolff-Parkinson-White syndrome Cardiomyopathy

Eye Optic neuropathy Ophthalmoplegia Retinopathy

Liver Hepatopathy

ATP

Nuclear DNA

Subunits

Oxidative phosphorylation

Kidney Fanconi's syndrome Glomerulopathy

Mitochondrial DNA

Pancreas Diabetes mellitus

Blood Pearson's syndrome Inner ear Sensorineural hearing loss

MITOCHONDRIAL DNA (mtDNA) STRUCTURE AND FUNCTION
As a result of its circular structure and extranuclear location, the replication and transcription

Colon Pseudo-obstruction

FIGURE e39-1 Dual genetic control and multiple organ system manifestations of mitochondrial disease. (Reproduced with permission from DR Johns: Mitochondrial DNA and disease. N Engl J Med 333:638, 1995.)

Copyright © 2008 The McGraw-Hill Companies. All rights reserved.

succinate dehydrogenase subunits. ND4 ND4L. COX15 SCO1. protons (H+) are pumped from the matrix to the intermembrane space through complexes I. NDUFS2 NDUFS4. MELAS. B. BCS1L. The 37 mtDNA genes comprise fully 93% of the 16. aminoaciduria. amyotrophic lateral sclerosis. growth retardation. SDHC.569 nucleotides of the mtDNA in what is known as the coding region. The mutation rate is considerably higher in the control region. ATPase 6 denotes ATP synthase 6.) kilobases (kb) of noncoding DNA. (Reproduced with permission from DiMauro and Schon. Cyt b COX III Sporadic myopathy Encephalomyopathy Sporadic anemia Septo-optic dysplasia Sporadic myopathy Encephalomyopathy Cardiomyopathy ALS-like syndrome H+ H+ Fumarate Cyt b O2 COXI COXII COXIII Cyt c H2O ADP Inner mitochondrial membrane Intermembrane space e− e− CoQ e− Complex I NDUFS1. lactic acidosis. three subunits of cytochrome-c oxidase (COX). loop. or D. ND5. cytochrome b–c complex assembly protein (complex III). and stroke-like episodes. III. of mtDNAencoded subunits No.e312 A 16S Leu (UUR) 12S Phe Val D-loop region Pro Thr Cyt b ND1 IIe Gln Met Glu ND6 ND2 Trp Ala Asn Cys Tyf ND5 Leu (CUN) Ser (AGY) His COXI Ser (UCN) Asp Arg Lys Gly ND4 ND4L COXII ND3 A8 A6 COXIII ATPase 6 NARP MILS FBSN H+ ATP A8 A6 PART 18 e-Chapters from International Advisory Editors B ND1. the cytochrome-b subunit of complex III (Cyt b). . SDHB. MILS. initiation can occur on both strands and proceeds through the production of an intronless polycistronic precursor RNA that is then processed to produce the 13 individual mRNA and 24 individual tRNA and rRNA products. and SDHD. LHON. The subunits of the respiratory chain encoded by nuclear DNA (nDNA) are shown in blue and the subunits encoded by mtDNA are shown in red. thought to have a major role in replication and transcription initiation. ataxia. SURF1. and ALS. SDHA. Indeed mtDNA sequence variants at both the coding and control regions are more highly partitioned across geographically defined populations than sequence variants in other parts of the ge- Copyright © 2008 The McGraw-Hill Companies. of nDNAencoded subunits 7 -39 Complex II SDHA. ND6 LHON MELAS LHON and dystonia Sporadic myopathy H+ Matrix Succinate ND1 ND2 ND3 ND6 ND4L ND5 ND4 COXI. With respect to transcription. whereas others may be considered pathogenic mutations. which contains a displacement. synthesis of cytochrome oxidase. ND3. SCO2. mitochondrial encephalomyopathy. COXII. As electrons (e–) flow along the electron-transport chain. A. GRACILE. Genes responsible for the indicated respiratory-chain disorders are also shown. SCO. SDHD Leigh’s syndrome Paraganglioma Pheochromocytoma 0 4 Complex III BCS1L Leigh’s syndrome GRACILE syndrome 1 10 Complex IV Complex V COX10. NARP. SURF1 Leigh’s syndrome Hepatopathy Cardioencephalomyopathy Leukodystrophy and tubulopathy 3 10 2 14 FIGURE e39-2 Mitochondrial DNA (mtDNA) and the mitochondrial respiratory chain. The map of the human mitochondrial genome. NDUF. NDUFS7 NDUFS8. FBSN. The D-loop region controls the initiation of replication and transcription of mtDNA. and retinitis pigmentosa.1 through complex V. lactic acidosis. The protein-synthesis genes—the 12S and 16S ribosomal RNAs and the 22 transfer RNAs (three-letter amino acid symbols)—are shown in blue. surfeit gene 1. The control region consists of ~1. Coenzyme Q (CoQ) and cytochrome-c (Cyt c) are electron-transfer carriers. ND2. NDUFV1 Leigh’s syndrome Leukodystrophy No. Leber hereditary optic neuropathy. maternally inherited Leigh’s syndrome. The protein-coding genes—seven subunits of complex I (ND). NADH dehydrogenase–ubiquinone oxidoreductase. SDHB SDHC. to produce ATP. and early death. neuropathy. familial bilateral striatal necrosis. and two subunits of adenosine triphosphate (ATP) synthase (A6 and A8)—are shown in red. and IV and then back into the matrix have the potential for a phenotypic or pathogenic effect. in turn containing two adjacent hypervariable regions (HVR-I and HVR-II) that give rise to large interindividual variability within the human population. All rights reserved.

As will be noted below. mtDNA sequence variation and associated phenotypic traits and diseases are inherited exclusively along maternal lines. will be considered in greater detail below. Mitochondria that contain mutated mtDNA are shown in red. During the production of primary oocytes. AND HIGH MUTATION RATE Each aerobic cell in the body has multiple mitochondria. Therefore. According to this formulation. including oocytes in females. (Reproduced with permission from Taylor and Turnbull. the somatic mutations in mtDNA are not carried forward to the next generation. indeed. . together with mutation. Thus. it is impor- e313 I II III FIGURE e39-3 Maternal inheritance of mtDNA disorders and heritable traits.nome. and combinations of these sequence variants define phylogeographic mtDNA haplogroups and haplotypes. For each oocyte.) Copyright © 2008 The McGraw-Hill Companies. MATERNAL INHERITANCE AND LACK OF RECOMBINATION The nuclear genome is characterized by homologous pairs of chromosomes of biparental origin. The fertilized oocyte degrades mtDNA carried from the sperm in a complex process involving the ubiquitin proteasome system. Furthermore. the heteroplasmic state is carried forward to the zygote and then. In turn. All rights reserved. this means coexistence within the oocyte of both the wildtype and mutant versions. However. In contrast. This restriction-amplification event can lead to a random shift of mtDNA mutational load between generations and is responsible for the variable levels of mutated mtDNA observed in affected offspring from mothers with pathogenic mtDNA mutations. the number of copies of mtDNA within each mitochondrion varies from several to hundreds. evidence of paternal transmission can almost certainly rule out an mtDNA genetic origin of phenotypic variation or disease. such that mutational events represent the only source of mtDNA genetic diversification. The particular mtDNA sequence variant may be entirely silent in terms of phenotype or disease predisposition Oocyte maturation and mtDNA amplification Mutant mitochondrion Normal mitochondrion Nucleus CHAPTER e39 Mitochondrial DNA and Heritable Traits and Diseases Fertilization High level of mutation (affected offspring) Intermediate level of mutation (mildly affected offspring) Primordial germ cell containing mutant mtDNA Primary oocytes Mature oocytes Low level of mutation (unaffected offspring) FIGURE e39-4 Heteroplasmy and the mitochondrial genetic bottleneck. A major active research question is whether or not differences in these haplotypes are of medical significance in terms of disease predisposition. numerous different mutations may accumulate with the aging of the organism. a selected number of mitochondrial DNA (mtDNA) molecules are transferred into each oocyte. With the exception of the nonrecombining region of the Y chromosome in males. cancer. serves as the source of universal genetic diversity. too. Affected men (filled square) do not transmit the trait to any of their offspring. it is only the maternal DNA that is transmitted to the offspring. tant to focus on the consequence of mtDNA polyploidy within the germ cells of the female reproductive system. Intensive research during the past two decades has confirmed that this is. sometimes this maternal inheritance is difficult to recognize at the clinical or pedigree level. Accordingly. to varying degrees. newly acquired somatic mutation is likely to be very small in terms of total cellular or organ system function. these homologous pairs undergo meiotic recombination during gametogenesis. the high somatic mtDNA mutation rate and the global effect on mitochondrial function counterbalance the reduced impact of the multiple copy number of each individual mtDNA mutation. e39-4). Affected women (filled circles) transmit the trait to their children. during organ system development and maintenance. Moreover. often numbering many hundreds or more in cells with extensive energy production requirements. Thus. a disease affecting both sexes without evidence of paternal transmission strongly suggests a heritable mtDNA disorder (Fig. In the case of somatic cells. It has been proposed that the total cumulative burden of acquired somatic mtDNA mutations with age may result in an overall perturbation of mitochondrial function. depending on mitotic segregation of mtDNA molecules. in terms of heritable traits and disease. Oocyte maturation is associated with the rapid replication of this mtDNA population. such as metabolic syndrome and diabetes. e39-3). In the case of pathogenic mutations. The foregoing structural and functional features of mtDNA lead to the expectation that phenotypic inheritance and disease patterns for disorders related to mtDNA sequence variation and mutation should be quite different from the more familiar inheritance and disease patterns attributed to variation and mutation of nuclear DNA. the case. The multiple mtDNA copy number within the maternal germ cells result in the phenomenon of heteroplasmy of inherited mtDNA mutations. this is true of both somatic as well as germ cells. while mothers transmit their mtDNA to both their sons and daughters. mtDNA molecules do not undergo recombination. however. MULTIPLE COPY NUMBER (POLYPLOIDY). and those with normal mtDNA are shown in green. The potential contribution of such acquired somatic mtDNA mutations to aging and to common age-related disturbances. contributing to age-related reduction in the efficiency of oxidative phosphorylation and increased production of damaging ROS. neurodegenerative. so. with very rare exceptions. One interesting consequence of uniparental inheritance and lack of recombination is the utility of mtDNA marker and sequence analysis in tracing matrilineal ancestry in phylogenetic research. It is evident that just as in the case of acquired somatic mutations in the nuclear genome. oocytes differ from each other in the degree of heteroplasmy for that sequence variant or mutation. and cardiovascular disease. because of the complex relationship between mtDNA mutations and disease expression. this means that the impact of each individual. only the daughters are able to transmit the inherited mtDNA to future generations. because of the manyfold higher mutation rate during mtDNA replication. Heteroplasmy for a given mtDNA sequence variant or mutation arises as a result of the coexistence within the oocyte of mtDNA molecules bearing both versions of the sequence variant (Fig. conversely. the percentage of mtDNA molecules bearing each version of the polymorphic sequence variant or mutation depends on stochastic events related to partitioning of mtDNA molecules during the process of oogenesis itself. Mitotic segregation refers to the unequal distribution of wild-type and mutant versions of the mtDNA molecules during all cell divisions that occur during prenatal development and subsequently throughout the lifetime of an individual. MITOTIC SEGREGATION. which.

Disease-causing mtDNA coding region mutations can affect either one of the 13 protein encoding genes. rendering genotype-phenotype correlation challenging. Very rough estimates suggest that heteroplasmic germ-line pathogenic mtDNA mutations may affect up to approximately 1 in 5000 individuals. Clinically. though these are more frequently involved in infants and children. Heteroplasmy can sometimes be elegantly demonstrated at the tissue level using histochemical staining for enzymes in the oxidative phosphorylation pathway. it is not surprising that mtDNA mutations can affect numerous tissues with pleiotropic effects. version of the mtDNA for that particular nucleotide site. III. pigment retinopathy. there is tremendous heterogeneity in disease penetrance and severity. see below) can show a mosaic pattern of reduced histochemical staining in comparison with histochemical staining for the complex II enzyme.. this enzyme has the lowest threshold for dysfunction when a threshold of mutated mtDNA is reached. Histochemical staining for cytochrome-c oxidase activity in tissues of patients affected with heteroplasmic inherited mtDNA mutations (or with the somatic accumulation of mtDNA mutations. this process establishes a new mtDNA haplotype in the human population. hepatic. and eventually exclusive. Thus. This may create difficulty in recognizing a maternal pattern of inheritance and making the diagnosis of an mtDNA genetic cause of disease. Consequently. renal. cardiac and skeletal muscle (including extraocular muscles). during certain stages of oogenesis. This heterogeneity arises from differences in the degree of heteroplasmy among oocytes and with subsequent mitotic segregation of the pathogenic mutation during tissue and organ development. such that the particular mtDNA species bearing the novel or derived sequence variant may become the increasingly predominant. the mtDNA sequence variant may affect one or more aspects of mitochondrial function in a manner that gives rise to a phenotypic effect or predisposes to a disease. Considerations of reproductive fitness limit the evolutionary or population emergence of homoplasmic mutations that are lethal or cause severe disease in infancy or childhood. with a number of notable exceptions (e. and. reflecting the accumulation of abnormal mitochondria under the muscle sarcolemmal membrane). IV. see below). and the female offspring will transmit it forward in subsequent generations. . and cytochrome-c are exclusively encoded by nuclear DNA. This leads to the notion of a “threshold” effect. Only when the ability to distinguish a completely neutral sequence variant from a true phenotypemodifying or pathogenic mutation is achieved.g. and when an accurate assessment of heteroplasmy can be determined with fidelity. all affecting ETC function. Heteroplasmy can also be detected at the genetic level through direct mtDNA genotyping under special conditions. are encoded by mtDNA. with a mosaic pattern indicating heterogeneity of the genotype for the coding region for the mtDNA-encoded enzyme. certain heteroplasmic mtDNA sequence variants may drift to a state of homoplasmy. and tissues of the affected individual.g. and endocrine and metabolic systems (including diabetes mellitus). It is not always possible to detect heteroplasmy readily in genomic samples extracted from whole blood. Only when a substantial proportion of mtDNA molecules carry the mutant genotype within a sampled tissue does heteroplasmy become detectable by more conventional sequencing or genotyping approaches. Thus. recent research and clinical attention have focused on the potential for certain of these homoplasmic mtDNA sequence variants to contribute to the evolutionary adaptation of populations to their climatic environment or to predispose to heritable late postreproductive and age-associated disease predisposition. while fairly consistent and well-defined “classic” syndromes have been attributed to specific mutations. there is often a clustering of some combination of abnormalities affecting the neurologic system (including optic nerve atrophy. sensorineural hearing loss). mtDNA mutations causing Leber hereditary optic neuropathy. complexes I. This arises due to a “bottleneck” effect followed by genetic drift during the very process of oogenesis itself (Fig. e39-6). The offspring of a woman bearing an mtDNA sequence variant or mutation that has become homoplasmic will also be homoplasmic for that variant. wherein the actual expression of disease depends upon the relative percentage of mitochondria whose function is disrupted by mtDNA mutations. (3) a complex of laboratory and pathologic abnormalities that reflect disruption in cellular energetics (e. In contrast. lactic acidosis and neurodegenerative and myodegenerative symptoms with the finding of ragged red fibers. cytochrome-c oxidase. assessment of the impact of the accumulation of acquired somatic mtDNA mutations on late-onset common disease predisposition. cells. wherein all of the mtDNA molecules in the organism contain the new sequence variant. or on diseases arising from exposure to metabolic stress. succinate dehydrogenase (Fig. The phenotypic effect or disease impact of a given mtDNA sequence variant will be a function not only of its inherent disruptive effect (pathogenicity) on the mtDNA-encoded gene (coding region mutations) or integrity of the mtDNA molecule (control region mutations). A number of clues can increase the index of suspicion for mtDNA mutation as an etiology of a heritable trait or disease. Complex II. During the course of human evolution. the combination of interactions of mtDNA sequence variation with mutations in the nuclear Copyright © 2008 The McGraw-Hill Companies. the challenge of detecting and assessing heteroplasmy in different affected tissues. Figure e39-5 provides an mtDNA map of some of the better characterized disorders. Finally. or one of the 24 protein synthetic PART 18 e-Chapters from International Advisory Editors MITOCHONDRIAL DNA DISEASE The true prevalence of mtDNA disease is difficult to estimate because of the phenotypic heterogeneity that occurs as a function of heteroplasmy. as well as complexity of organ system involvement among the offspring of women with pathogenic heteroplasmic mutations. More than 200 different disease-causing mtDNA mutations have been described to date. and gastrointestinal systems. genome also complicates our ability to ascertain the extent of contribution of heritable mtDNA mutations to human illness. and V contain at least some subunits encoded by mtDNA. including (1) familial clustering with absence of paternal transmission. but also of its distribution among the multiple copies of mtDNA in the various mitochondria. However. The true overall impact of mtDNA mutation in human health and disease is certainly much greater.e314 and only detectable upon mtDNA sequencing. will the true extent and contribution of mtDNA sequence variation to human traits and health be determined. conversely. Just 3 of the 13 subunits of the ETC complex IV enzyme. Additional organ systems that may be affected include the hematopoietic. the most striking overall characteristic of mitochondrial genetic disease is the phenotypic heterogeneity associated with mtDNA mutations. and the other unique features of mtDNA function and inheritance described above. In both classic and nonclassic mtDNA disorders. and throughout the lifetime of the individual. In addition. (2) adherence to one of the classic syndromes (see below) or paradigmatic combinations of disease phenotypes involving several organ systems that normally do not fit together within a single nuclear genomic mutation category. or (4) a mosaic pattern reflecting a heteroplasmic state. if the potential contribution of homoplasmic mtDNA sequence variation to common complex diseases appearing in the postreproductive age is also considered. CoQ. In other words. e39-4). OVERVIEW OF CLINICAL AND PATHOLOGIC FEATURES OF HUMAN mtDNA DISEASE Given the vital roles of mitochondria in all nucleated cells. By contrast. therefore. frequently “nonclassic” combinations of disease phenotypes ranging from isolated myopathy to extensive multisystem disease are often encountered. also needs to be considered in order to appreciate the full impact of mtDNA in human health and disease. most homoplasmic mutations were considered to be neutral markers of human evolution—useful and interesting in the population genetics analysis of shared maternal ancestry but with little significance in human phenotypic variation or disease predisposition. This extends to intrafamilial phenotypic heterogeneity for the same mtDNA pathogenic mutation and.. to the overlap of phenotypic disease manifestations with distinct mutations. All rights reserved. the mtDNA copy number becomes substantially reduced.

indicating that additional environmental (e. MELAS. inheritance. sideroblastic anemia PPK. seizures. progressive external ophthalmoplegia. ataxia. cerebellar ataxia. ataxia. PT Cyt b E cardiomyopathy. the other three result from rearrangements or deletions that usually do not involve the germ line. In some instances. All rights reserved. and short stature are often present. myopathy. Recurrent migraine-like headache and vomiting. PEO Myopathy. lactic acidosis. or diabetes mellitus). and SIDS. neuropathy. myopathy. consisting of a progressive encephalomyopathy characterized by repeated stroke-like events involving mainly posterior cerebral areas. Clinical manifestations do not readily distinguish these two categories. deafness. seizures. mitochondrial encephalomyopathy. FBSN encephalomyopathy LS. palmoplantar keratoderma. Leber hereditary optic neuropgenes.) fect genes encoding different subunits of complex I of the mitochondrial ETC. myopathy. (2) classic mtDNA syndromes. lactic acidosis. PEO. Both the nuclear as well as mitochondrial genomic background modify disease penetrance. Cardiomyopathy. LHON.g. MILS. epilepsy. ataxia. exercise intolerance. Of interest. In >95% of cases. and (3) clinical presentation confined to one organ system (e. Disorders that are frequently or prominently associated with mutations in a particular gene are shown in boldface. Diseases due to mutations that impair mitochondrial protein synthesis are shown in blue.. . PEO ECM Myoglobinuria. peripheral neuropathy. MELAS. either defective ATP production due to disturbances in the ETC or enhanced generation of reactive oxygen species has been invoked as the mediating biochemical mechanism between mtDNA mutation and disease manifestation. MELAS and parkinsonism Cardiomyopathy ECM LHON. In all cases. isolated sensorineural deafness. maternally inherited Leigh’s syndrome. lymphoma Cardiomyopathy LHON LS. LHON cardiomyopathy. ECM PEO. NARP. Almost all MERRF patients have Copyright © 2008 The McGraw-Hill Companies. MERRF-MELAS PEO I Q M ND2 W A N C Y COXI S1 D ND4L ND3 R G ND4 L1 ND1 ND6 MELAS myoglobinuria Myopathy. sudden infant death syndrome. not all individuals who inherit a primary LHON mtDNA mutation develop optic neuropathy. MELAS. myopathy. LHON has a greater penetrance and severity in men than in women. SIDS. PPK. sideroblastic anemia Diabetes and deafness LHON. familial bilateral striatal necrosis. Leigh’s syndrome. NARP. however. LHON. and retinitis pigmentosa. LHON.Parkinsonism. LHON and dystonia ND5 LS.. deafness Progressive myoclonus. diabetes and deafness Myopathy. with symptoms developing in the other eye 6–12 weeks after the initial onset. and clinical presentation. Diseases due to mutations in protein-coding genes are shown in red. and lactic acidosis are other frequent clinical features. (Reproduced with permission from DiMauro and Schon. ECM. LHON typically presents during young adulthood with subacute painless loss of vision in one eye. chorea. Leber hereditary optic neuropathy (LHON) is a common cause of maternally inherited visual failure. diabetes. mtDNA DISEASE PRESENTATIONS The clinical presentation of adult patients with mtDNA disease can be divided into three categories: (1) clinical features suggestive of mitochondrial disease (Table e39-2). pointing to an epistatic interaction with the nuclear genome. for example. myoglobinuria PEO. LS. cardiomyopathy. aminoglycoside-induced deafness LS. The most commonly described pathogenic point mutations are A3243G and T3271C in the gene encoding the leucine tRNA. MELAS. tobacco exposure) or genetic factors are important in the etiology of the disorder. exercise intolerance. with certain haplotypes being protective. Of note. MERRF. and myopathy with ragged red fibers. cardiomyopathy. FBSN. multisystem disease Cardiomyopathy PEO. The first five of these syndromes result from heritable point mutations in either protein encoding or protein synthetic mtDNA genes. disease susceptibility for a given mutation is modulated by mtDNA haplotype background. and cardiac conduction defects are observed. motor neuron disease. Table e39-3 provides a summary of eight illustrative classic mtDNA syndromes or disorders that affect adult patients and highlights some of the most interesting features of mtDNA disease in terms of molecular pathogenesis.g. multisystem disease. Mitochondrial encephalomyopathy. myopathy PEO Myopathy. and optic atrophy Cardiomyopathy. Moreover. and strokelike episodes (MELAS) is probably the most common mtDNA disease. LHON is due to one of three homoplasmic point mutations of mtDNA that af- athy. The somewhat later onset in young adulthood and modifying effect of genetic background may have enabled homoplasmic pathogenic mutations to have escaped evolutionary censoring. and stroke-like episodes. MELAS Cardiomyopathy. patients with this syndrome are often homoplasmic for the disease-causing mutation. LHON and dystonia e315 16S V 12s F L2 S2 H CHAPTER e39 Mitochondrial DNA and Heritable Traits and Diseases COXII A8 K A6 COXIII Cardiomyopathy myoclonus LHON Myopathy. Hearing loss. MELAS Myopathy. ECM FIGURE e39-5 Mutations in the human mitochondrial genome known to cause disease. myoclonic epilepsy with ragged red fibers. MELAS. ECM denotes encephalomyopathy. neuropathy. though lactic acidosis and muscle pathologic findings tend to be more prominent in the latter. Myoclonic epilepsy with ragged red fibers (MERRF) is a multisystem disorder characterized by myoclonus. brain lesions do not respect the distribution of vascular territories. but not a well-defined classic syndrome. short stature. MERRF. Thus. MILS. PEO Cardiomyopathy ECM ECM.

hypothyroidism. B. e39-7. Histochemical analysis may show subsarcolemmal accumulation of mitochondria with the appearance of ragged red fibers. therefore. Neurogenic weakness. myalgia Cardiac: conduction block. A brain CT scan may show calcified basal ganglia or bilateral hypodense regions with cortical atrophy. ataxia. characterized by late-onset progressive external ophthalmoplegia. A raised cerebrospinal fluid lactate is a more specific test for mitochondrial disease if there is central neurologic involvement. 95% of patients with LHON harbor one of three mtDNA point mutations (A11778G. All rights reserved. A section of cerebellum from a patient with mtDNA rearrangement that highlights the presence of COX-deficient neurons. an elevated blood lactate level is neither specific nor sensitive because there are many causes of blood lactic acidosis. pigment retinopathy. Since germ line involvement is rare. with many muscle fibers harboring levels of mutated mtDNA that are above the crucial threshold to produce a functional enzyme complex. and exercise intolerance. The section shows a typical “mosaic” pattern of COX activity. even in the presence of a proximal myopathy. migraine headache. with COX-positive cells shown in brown and COX-deficient cells shown in blue. groupings of disease manifestations in multiple organ systems. Every patient with seizures or cognitive decline should have an electroencephalogram. A3460G. together with pancytopenia and lactic acidosis. or unexplained isolated presentations of one of the disease features of a classic mtDNA syndrome should prompt a systematic clinical investigation as outlined in Fig. Cerebellar syndrome. The serum creatine kinase may be elevated but is often normal. neuroradiologic and neuropathologic picture (Leigh’s syndrome) emerges. and T14484C). and short stature are also part of the syndrome. cardiomyopathy Respiratory: hypoventilation. and Pearson syndrome are three disease phenotypes caused by large-scale mtDNA rearrangements including partial deletions or partial duplication. In both KSS and PEO. proximal myopathy. neurologic and myopathic (optic atrophy. most cases are sporadic rather than inherited. Single deletions/duplication can also result in milder phenotypes such as PEO. chronic progressive external ophthalmoplegia. premature ovarian failure. it is possible to obtain an accurate diagnosis with a simple molecular genetic screen. ophthalmoplegia) THE INVESTIGATION OF SUSPECTED mtDNA DISEASE The clinical presentations of classic syndromes. which opens a pathway for a simple pharmacogenetic test in the appropriate clinical settings.) mutation in the mtDNA tRNAlys gene and the A8344G mutation in the mtDNA gene encoding the lysine amino acid tRNA is responsible for 80–90% of MERRF cases. Muscle biopsy histochemical analysis is the cornerstone for investigation of patients with suspected mitochondrial disease. C. Transverse tissue sections that are reacted for both cytochrome-c oxidase (COX) and succinate dehydrogenase (SDH) activities sequentially. sensorineural deafness. Point mutations in the mtDNA gene encoding the 12S rRNA result in heritable nonsyndromic hearing loss. Skeletal muscle from a patient with a heteroplasmic mitochondrial tRNA point mutation. PART 18 e-Chapters from International Advisory Editors TABLE e39-2 COMMON FEATURES OF mtDNA-ASSOCIATED DISEASES IN ADULTS Neurologic: stroke. appropriate to send a blood sample for molecular genetic analysis by polymerase chain reaction (PCR) or restriction fragment length polymorphism. dysphasia) Skeletal myopathy: ophthalmoplegia. These patients have very high levels of mutated mtDNA in peripheral blood cells. Urine organic and amino acids may also be abnormal. cranial neuropathy (optic atrophy. A heteroplasmic T8993G mutation in the gene ATPase 6 subunit gene has been identified as causative. epilepsy. For some mitochondrial diseases. Kearns-Sayre syndrome (KSS). MRI is indicated in patients with brain stem signs or stroke-like episodes. . Ragged red fibers are not observed in muscle biopsy. KSS is characterized by the triad of onset before age 20. Electron microscopy might show abnormal mitochondria with paracrystalline inclusions. A. caused by the largescale sporadic deletion of several mtDNA genes. When >95% of mtDNA molecules are mutant. Pearson syndrome is also characterized by diabetes mellitus from pancreatic insufficiency. increased cerebrospinal fluid protein content. Despite the centrality of disruptive oxidative phosphorylation. Tissues that show COX deficiency due to clonal expansion of somatic mtDNA mutations within single cells—a phenomenon that is seen in both postmitotic cells (D. diabetes mellitus and hearing loss are frequent accompaniments. and pigmentary retinopathy. One such mutation causes heritable ototoxic susceptibility to aminoglycoside antibiotics. then patients with a negative result should be investigated further by performing a skeletal muscle biopsy. (Reproduced with permission from Taylor and Turnbull. colonic crypt) in aging humans. Muscle histochemistry may show cytochrome-c oxidase (COX)–deficient fi- Copyright © 2008 The McGraw-Hill Companies. The same is true for most MERRF patients who harbor a point mutation in the lysine tRNA gene at position 8344. sporadic progressive external ophthalmoplegia (PEO). aspiration pneumonitis Endocrine: diabetes mellitus. exercise intolerance. and retinitis pigmentosa (NARP) is characterized by moderate diffuse cerebral and cerebellar atrophy and symmetric lesions of the basal ganglia on MRI. heart block. peripheral neuropathy. whichdemonstrates an absence of COX in most cells.e316 FIGURE e39-6 Cytochrome-c oxidase deficiency in mitochondrial DNA–associated disease. In contrast. Cardiac tissue (left ventricle) from a patient with a homoplasmic tRNA mutation that causes hypertrophic cardiomyopathy. E. and it is. D. If clinical suspicion is strong enough to warrant peripheral blood testing. hypoparathyroidism Ophthalmologic: cataracts. and many patients with mtDNA defects presenting in adulthood have normal blood lactate. extraocular muscles) and rapidly dividing cells (E. diabetes. occurring in the maternal oocyte or during early embryonic development. patients with the A3243G MELAS mutation often have low levels of mutated mtDNA in blood. dysphagia. For examples. The majority of single large-scale re- arrangements of mtDNA are thought to result from clonal amplification of a single sporadic mutational event. a more severe clinical.

protein. thereCLINICAL AND LABORATORY INVESTIGATION OF SUSPECTED MTDNA DISORDER Clinical investigations Blood: creatine kinase. Mean life expectancy has risen from ~47 years to ~77 years during the past century alone. retinal pigmentation. Either of these two abnormalities confirm that a patient has mitochondrial disease. drift to homoplasmy of such mutations would be precluded normally by the severity of impaired oxidative phosphorylation and the consequent reduction in reproductive fitness. electroencephalogram. A potential health implication of this finding is the possibility that these same mutations might result in deleterious effects on energy metabolism and caloric balance in the current era of human transglobal migration or climate control. Leber hereditary optic neuropathy. MERFF. it was shown that ancient missense mutations that define these haplogroups alter amino acids that are as highly conserved in evolution as are those known to result from pathogenic mutations. only a limited number of haplogroups and their derivative lineages successfully colonized all of Eurasia and then the Americas. MERRF. Respiratory chain complex assays may also show a deficiency. ataxia Most Frequent mtDNA Mutations G1778A. lactic acidemia Mitochondrial encephalomyopathy. myoclonic epilepsy with ragged red fibers. somatic mutations Sporadic. T14484C. and this should lead to in-depth molecular genetic analysis. All rights reserved. Leigh’s disease MELAS MERRF Deafness Chronic progressive external ophthalmoplegia (PEO) Pearson syndrome Kearn-Sayre syndrome (KSS) Note: CSF. As noted above. EMG. polymerase chain reaction. somatic mutations Phenotype Loss of central vision leading to blindness in young adult life Neuropathy. lactate Urine: organic and amino acids CSF: glucose. Therefore. For example. demography.g. e39-6). lactic acidosis.. somatic mutations Sporadic. restriction fragment length polymorphism. CSF. and disease phenotype simplifies inference of a clear causative relationship between heteroplasmic mutation and disease. tissue distribution of the mutant mtDNA. liver functions. EMG. over many tens of thousands of years. ECG. pancytopenia. increased CSF protein. and stoke-like episodes.TABLE e39-3 MITOCHONDRIAL DISEASES DUE TO mtDNA POINT MUTATIONS AND LARGE-SCALE REARRANGEMENTS Disease Leber hereditary optic neuropathy (LHO